bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022‒02‒27
forty-nine papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
  2. Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation.
  3. LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain.
  4. Site-specific mitochondrial dysfunction in neurodegeneration.
  5. Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.
  6. Brain cell type-specific cholesterol metabolism and implications for learning and memory.
  7. Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFα-induced inflammatory responses.
  8. Sphingosine kinase-dependent regulation of pro-resolving lipid mediators in Alzheimer's disease.
  9. Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.
  10. A novel natural PPARγ agonist, Gypenoside LXXV, ameliorates cognitive deficits by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.
  11. Relationship between Cognitive Dysfunction and Age-Related Variability in Oxidative Markers in Isolated Mitochondria of Alzheimer's Disease Transgenic Mouse Brains.
  12. Time Course of Neurobehavioral Disruptions and Regional Brain Metabolism Changes in the Rotenone Mice Model of Parkinson's Disease.
  13. Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?
  14. The Key Role of GM1 Ganglioside in Parkinson's Disease.
  15. Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice.
  16. Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype.
  17. Calycosin Alleviates Paraquat-Induced Neurodegeneration by Improving Mitochondrial Functions and Regulating Autophagy in a Drosophila Model of Parkinson's Disease.
  18. Ferroptosis is Involved in Hypoxic-ischemic Brain Damage in Neonatal Rats.
  19. Interaction of Mitochondrial Calcium and ROS in Neurodegeneration.
  20. Modifying the maternal microbiota alters the gut-brain metabolome and prevents emotional dysfunction in the adult offspring of obese dams.
  21. Co-Delivery of Docosahexaenoic Acid and Brain-Derived Neurotropic Factor from Electrospun Aligned Core-Shell Fibrous Membranes in Treatment of Spinal Cord Injury.
  22. Environmental Enrichment Sex-dependently Rescues Memory Impairment in FABP5 KO Mice Not Mediated by Brain-Derived Neurotrophic Factor.
  23. Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial Ca2+-Independent Phospholipase A2γ in the Brain.
  24. AP-4-mediated axonal transport controls endocannabinoid production in neurons.
  25. The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study.
  26. Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection.
  27. Mitochondrial dysfunction associated with TANGO2 deficiency.
  28. Human Brain Lipidomics: Pilot Analysis of the Basal Ganglia Sphingolipidome in Parkinson's Disease and Lewy Body Disease.
  29. Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging.
  30. Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
  31. Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells.
  32. Lipid mediator n-3 docosapentaenoic acid-derived protectin D1 enhances synaptic inhibition of hippocampal principal neurons by interaction with a G-protein-coupled receptor.
  33. Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway.
  34. nEffects of ketogenic diet on cognitive functions of mice fed high-fat-high-cholesterol diet.
  35. Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson's Disease Models.
  36. Metabolic profiling in the hypothalamus of aged mice.
  37. Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients.
  38. Hypertonic lactate for the treatment of intracranial hypertension in patients with acute brain injury.
  39. Frequency- and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical.
  40. The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation.
  41. GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates.
  42. m.3685T>C is a Novel Mitochondrial DNA Variant That Causes Leigh Syndrome.
  43. Lysophosphatidic Acid Receptor 3 Promotes Mitochondrial Homeostasis against Oxidative Stress: Potential Therapeutic Approaches for Hutchinson-Gilford Progeria Syndrome.
  44. Preventive Impact of Long-Term Ingestion of Chestnut Honey on Glucose Disorders and Neurodegeneration in Obese Mice.
  45. C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration.
  46. Research Progress on Neuroprotection of Insulin-like Growth Factor-1 towards Glutamate-Induced Neurotoxicity.
  47. TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.
  48. Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review.
  49. Glutamate and N-Acetylaspartate Alterations Observed in Early Phase Psychosis: A Systematic Review of Proton Magnetic Resonance Spectroscopy Studies.
  1. Elife. 2022 02 21. pii: e72595. [Epub ahead of print]11
    Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
    Andres De La Rossa, Marine H Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Fernández, Pablo Mendez, Abbas Khani, Charles Quairiaux, Eric B Taylor, Jared Rutter, José Manuel Nunes, Alan Carleton, Michael R Duchen, Carmen Sandi, Jean-Claude Martinou.
      Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.
    Keywords:  calcium; kcnq kv.7 channel; ketogenic diet; metabolism; mitochondrial pyruvate carrier; mouse; neuronal excitability; neuroscience
    DOI:  https://doi.org/10.7554/eLife.72595
  2. Pharmaceuticals (Basel). 2022 Jan 31. pii: 182. [Epub ahead of print]15(2):
    Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation.
    Artem V Artiukhov, Anastasia V Graf, Alexey V Kazantsev, Alexandra I Boyko, Vasily A Aleshin, Alexander L Ksenofontov, Victoria I Bunik.
      Specific inhibitors of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) are administered to animals to model the downregulation of the enzyme as observed in neurodegenerative diseases. Comparison of the effects of succinyl phosphonate (SP, 0.02 mmol/kg) and its uncharged precursor, triethyl succinyl phosphonate (TESP, 0.02 and 0.1 mmol/kg) reveals a biphasic response of the rat brain metabolism and physiology to increasing perturbation of OGDH function. At the low (TE)SP dose, glutamate, NAD+, and the activities of dehydrogenases of 2-oxoglutarate and malate increase, followed by their decreases at the high TESP dose. The complementary changes, i.e., an initial decrease followed by growth, are demonstrated by activities of pyruvate dehydrogenase and glutamine synthetase, and levels of oxidized glutathione and citrulline. While most of these indicators return to control levels at the high TESP dose, OGDH activity decreases and oxidized glutathione increases, compared to their control values. The first phase of metabolic perturbations does not cause significant physiological changes, but in the second phase, the ECG parameters and behavior reveal decreased adaptability and increased anxiety. Thus, lower levels of OGDH inhibition are compensated by the rearranged metabolic network, while the increased levels induce a metabolic switch to a lower redox state of the brain, associated with elevated stress of the animals.
    Keywords:  2-oxoglutarate dehydrogenase; anxiety; locomotion; redox potential; succinyl phosphonate; triethyl succinyl phosphonate
    DOI:  https://doi.org/10.3390/ph15020182
  3. Antioxidants (Basel). 2022 Jan 28. pii: 261. [Epub ahead of print]11(2):
    LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain.
    Jun Sung Park, Kamran Saeed, Myeung Hoon Jo, Min Woo Kim, Hyeon Jin Lee, Chan-Bae Park, Gwang Lee, Myeong Ok Kim.
      Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb-/-) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb-/-) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb-/- mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb-/- mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb-/- mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb-/- mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb-/- mice.
    Keywords:  Lactate dehydrogenase-B; inflammation; mitochondrial dysfunction; neurodegeneration; osmotin; oxidative stress; p-AMPK/Sirt1/PGC-1alpha signaling
    DOI:  https://doi.org/10.3390/antiox11020261
  4. Mitochondrion. 2022 Feb 16. pii: S1567-7249(22)00010-1. [Epub ahead of print]64 1-18
    Site-specific mitochondrial dysfunction in neurodegeneration.
    Anežka Vodičková, Shon A Koren, Andrew P Wojtovich.
      Mitochondria are essential for neuronal survival and mitochondrial dysfunction is a hallmark of neurodegeneration. The loss in mitochondrial energy production, oxidative stress, and changes in calcium handling are associated with neurodegenerative diseases; however, different sites and types of mitochondrial dysfunction are linked to distinct neuropathologies. Understanding the causal or correlative relationship between changes in mitochondria and neuropathology will lead to new therapeutic strategies. Here, we summarize the evidence of site-specific mitochondrial dysfunction and mitochondrial-related clinical trials for neurodegenerative diseases. We further discuss potential therapeutic approaches, such as mitochondrial transplantation, restoration of mitochondrial function, and pharmacological alleviation of mitochondrial dysfunction.
    Keywords:  Mitochondria-targeting therapeutics; Mitochondrial dysfunction; Neurodegeneration; Optogenetics; Transplantation
    DOI:  https://doi.org/10.1016/j.mito.2022.02.004
  5. Brain. 2022 Feb 25. pii: awab295. [Epub ahead of print]
    Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.
    Michael J Rigby, Nicola Salvatore Orefice, Alexis J Lawton, Min Ma, Samantha L Shapiro, Sue Y Yi, Inca A Dieterich, Alyssa Frelka, Hannah N Miles, Robert A Pearce, John Paul J Yu, Lingjun Li, John M Denu, Luigi Puglielli.
      N ε-lysine acetylation within the lumen of the endoplasmic reticulum is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the endoplasmic reticulum acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter and ATP citrate lyase, which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder, suggesting that aberrant cytosolic-to-endoplasmic reticulum flux of acetyl-CoA can be a mechanistic driver for the development of autism spectrum disorder. We therefore generated a SLC25A1 neuron transgenic mouse with overexpression specifically in the forebrain neurons. The mice displayed autistic-like behaviours with a jumping stereotypy. They exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia and altered synaptic plasticity and morphology. Finally, quantitative proteomic and acetyl-proteomic analyses revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosolic-to-endoplasmic reticulum acetyl-CoA flux and the development of an autistic-like phenotype.
    Keywords:  acetyl-CoA; autism spectrum disorder; lysine acetylation; secretory pathway; white matter
    DOI:  https://doi.org/10.1093/brain/awab295
  6. Trends Neurosci. 2022 Feb 17. pii: S0166-2236(22)00014-5. [Epub ahead of print]
    Brain cell type-specific cholesterol metabolism and implications for learning and memory.
    Dingfeng Li, Juan Zhang, Qiang Liu.
      Cholesterol homeostasis is vital for brain function. Brain cholesterol is locally synthesized, with varying synthesis capacities across different cell types. Moreover, brain cholesterol horizontally transfers across various cell types not only to accommodate distinct cholesterol needs, but also to fulfill regulatory functions in target cells. Cholesterol metabolism within individual cell types is essential for brain functioning, and the role of cholesterol-related communication between different cell types is gaining growing recognition. Cholesterol metabolism dysfunction is tightly associated with brain aging and Alzheimer's disease (AD). Here, we provide an overview of recent studies on cholesterol metabolism within specific cell types and in relation to the interplay between different cell types. We also discuss the implications of these processes for learning and memory, and their relevance to brain aging and AD.
    Keywords:  Alzheimer’s disease; ApoE; brain aging; glia; neuron–glia crosstalk; synaptic function
    DOI:  https://doi.org/10.1016/j.tins.2022.01.002
  7. Sci Rep. 2022 02 23. 12(1): 3049
    Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFα-induced inflammatory responses.
    Parijat Kabiraj, Ethan M Grund, Benjamin D S Clarkson, Renee K Johnson, Reghann G LaFrance-Corey, Claudia F Lucchinetti, Charles L Howe.
      Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 μM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.
    DOI:  https://doi.org/10.1038/s41598-022-07024-7
  8. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb 21. pii: S1388-1981(22)00016-6. [Epub ahead of print] 159126
    Sphingosine kinase-dependent regulation of pro-resolving lipid mediators in Alzheimer's disease.
    Maria Ayub, Hee Kyung Jin, Jae-Sung Bae.
      The majority of peripheral and central nervous system disorders are related to hyperactive inflammatory responses, leading to irreversible and persistent cellular defects, functional impairments, and behavioral deficits. Advances in our understanding of these disorders have revealed the disruption of inflammation resolution pathways due to abrogated responses by specialized pro-resolving lipid mediators (SPMs). SPMs comprise a class of bioactive lipids and cell signaling molecules that function to resolve inflammation, pain, and function in host defense and tissue remodeling. Their cellular and systemic levels during physiology and pathology are regulated by sphingosine kinases (especially SphK1) that act by monitoring cyclooxygenase-2 (COX2), a potent inhibitor of SPMs production. This review presents the current understanding of the convergent mechanisms shared by bioactive lipids with SphK1 and COX2 in the etiology of chronic inflammatory disorders, focusing on neuroinflammation, as well as describes the translational directions of this trilogy for the treatment of Alzheimer's disease.
    Keywords:  Alzheimer's disease; COX2; Inflammation; Lipid mediators; Sphingosine kinase 1
    DOI:  https://doi.org/10.1016/j.bbalip.2022.159126
  9. J Transl Med. 2022 Feb 23. 20(1): 103
    Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.
    Yanan Li, Jeffrey Steinberg, Zane Coleman, Shubo Wang, Chitra Subramanian, Yimei Li, Zoltan Patay, Walter Akers, Charles O Rock, Suzanne Jackowski, Puneet Bagga.
      BACKGROUND: Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed.METHODS: We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671.
    RESULTS: 1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre+ Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre+ Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment.
    CONCLUSIONS: BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.
    Keywords:  1H magnetic resonance spectroscopy; Coenzyme A; Metabolites; Neurodegeneration; Pantothenate kinase; Pantothenate kinase-associated neurodegeneration; Therapeutics
    DOI:  https://doi.org/10.1186/s12967-022-03304-y
  10. Phytother Res. 2022 Feb 22.
    A novel natural PPARγ agonist, Gypenoside LXXV, ameliorates cognitive deficits by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.
    Xiangbao Meng, Yuan Zhang, Zongyang Li, Jinxian Hu, Di Zhang, Weiwei Cao, Min Li, Guoxu Ma, Sicen Wang, Ping Cui, Qian Cai, Guodong Huang.
      Targeting the PPARγ might be a potential therapeutic strategy for diabetes-associated cognitive decline (DACD). In this study, Gypenoside LXXV (GP-75), a dammarane-type triterpene compound isolated from Gynostemma pentaphyllum, was found to be a novel PPARγ agonist using a dual-luciferase reporter assay system. However, whether GP-75 has protective effects against DACD remains unknown. Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 12 weeks significantly attenuated the cognitive deficit in db/db mice. GP-75 treatment significantly improved the glucose tolerance and lipid metabolism, and suppressed neuroinflammation. Notably, GP-75 treatment dramatically increased the uptake of glucose by the brain, as detected by 18 F-FDG PET. Incubation of primary cortical neurons with GP-75 significantly increased 2-deoxyglucose uptake. In addition, GP-75 treatment markedly increased the p-Akt (Ser 473)/total Akt levels and the expression levels of PPARγ and GLUT4, while decreasing the levels of p-IRS-1 (Ser 616)/total IRS-1. Importantly, all of these protective effects mediated by GP-75 were abolished by cotreatment with the PPARγ antagonist, GW9662. However, GP-75-mediated PPARγ upregulation was not affected by coincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002. Collectively, GP-75 might be a novel PPARγ agonist that ameliorates cognitive deficit by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.
    Keywords:  PPARγ; glucose transporter 4; insulin resistance; microPET; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1002/ptr.7413
  11. Biomedicines. 2022 Jan 26. pii: 281. [Epub ahead of print]10(2):
    Relationship between Cognitive Dysfunction and Age-Related Variability in Oxidative Markers in Isolated Mitochondria of Alzheimer's Disease Transgenic Mouse Brains.
    Naoki Yoshida, Yugo Kato, Hirokatsu Takatsu, Koji Fukui.
      Many neurodegenerative disorders, including Alzheimer's disease (AD), are strongly associated with the accumulation of oxidative damage. Transgenic animal models are commonly used to elucidate the pathogenic mechanism of AD. Beta amyloid (Aβ) and tau hyperphosphorylation are very famous hallmarks of AD and well-studied, but the relationship between mitochondrial dysfunction and the onset and progression of AD requires further elucidation. In this study we used transgenic mice (the strain name is 5xFAD) at three different ages (3, 6, and 20 months old) as an AD model. Cognitive impairment in AD mice occurred in an age-dependent manner. Aβ1-40 expression significantly increased in an age-dependent manner in all brain regions with or without AD, and Aβ1-42 expression in the hippocampus increased at a young age. In a Western blot analysis using isolated mitochondria from three brain regions (cerebral cortex, cerebellum, and hippocampus), NMNAT-3 expression in the hippocampi of aged AD mice was significantly lower than that of young AD mice. SOD-2 expression in the hippocampi of AD mice was lower than for the age-matched controls. However, 3-NT expression in the hippocampi of AD mice was higher than for the age-matched controls. NQO-1 expression in the cerebral cortex of AD mice was higher than for the age-matched controls at every age that we examined. However, hippocampal NQO-1 expression in 6-month-old AD mice was significantly lower than in 3-month-old AD mice. These results indicate that oxidative stress in the hippocampi of AD mice is high compared to other brain regions and may induce mitochondrial dysfunction via oxidative damage. Protection of mitochondria from oxidative damage may be important to maintain cognitive function.
    Keywords:  Alzheimer’s disease; cognitive impairment; mitochondria; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/biomedicines10020281
  12. Biomedicines. 2022 Feb 16. pii: 466. [Epub ahead of print]10(2):
    Time Course of Neurobehavioral Disruptions and Regional Brain Metabolism Changes in the Rotenone Mice Model of Parkinson's Disease.
    Dmitry Troshev, Dmitry Voronkov, Anastasia Pavlova, Denis Abaimov, Alexander Latanov, Tatiana Fedorova, Daniil Berezhnoy.
      Parkinson's disease (PD) is characterized by slow progression with a long prodromal stage and the gradual evolution of both neuropsychological symptoms and subtle motor changes, preceding motor dysfunction. Thus, in order for animal models of PD to be valid, they should reproduce these characteristics of the disease. One of such models, in which neuropathology is induced by chronic injections of low doses of mitochondrial toxin rotenone, is well established in rats. However, data on this model adapted to mice remain controversial. We have designed the study to describe the timecourse of motor and non-motor symptoms during chronic subcutaneous administration of rotenone (4 mg/kg daily for 35 days) in C57BL/6 mice. We characterize the underlying neuropathological processes (dopaminergic neuron degeneration, regional brain metabolism, monoamine neurotransmitter and lipid peroxidation changes) at different timepoints: 1 day, 2 weeks and 5 weeks of daily rotenone exposure. Based on the behavioral data, we can describe three stages of pathology: cognitive changes from week 2 of rotenone exposure, subtle motor changes in week 3-4 and motor dysfunction starting roughly from week 4. Neuropathological changes in this model include a general decrease in COX activity in different areas of the brain (acute effect of rotenone) and a more specific decrease in midbrain (chronic effect), followed by significant neurodegeneration in SNpc but not VTA by the 5th week of rotenone exposure. However, we were unable to find changes in the level of monoamine neurotransmitters neither in the striatum nor in the cortex, nor in the level of lipid peroxidation in the brainstem. Thus, the gradual progression of pathology in this model is linked with metabolic changes, rather than with oxidative stress or tonic neurotransmitter release levels. Overall, this study supports the idea that a low-dose rotenone mouse model can also reproduce different stages of PD as well as rats.
    Keywords:  C57BL/6 mice; Parkinson’s disease model; behavior; catecholamines; cytochrome-C oxidase; learning; neurodegeneration; rotenone
    DOI:  https://doi.org/10.3390/biomedicines10020466
  13. Cells. 2022 Feb 11. pii: 623. [Epub ahead of print]11(4):
    Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?
    Georgia Colleluori, Chiara Galli, Ilenia Severi, Jessica Perugini, Antonio Giordano.
      Obesity disease results from a dysfunctional modulation of the energy balance whose master regulator is the central nervous system. The neural circuitries involved in such function complete their maturation during early postnatal periods, when the brain is highly plastic and profoundly influenced by the environment. This phenomenon is considered as an evolutionary strategy, whereby metabolic functions are adjusted to environmental cues, such as food availability and maternal care. In this timeframe, adverse stimuli may program the body metabolism to maximize energy storage abilities to cope with hostile conditions. Consistently, the prevalence of obesity is higher among individuals who experienced early life stress (ELS). Oxytocin, a hypothalamic neurohormone, regulates the energy balance and modulates social, emotional, and eating behaviors, exerting both central and peripheral actions. Oxytocin closely cooperates with leptin in regulating energy homeostasis. Both oxytocin and leptin impact the neurodevelopment during critical periods and are affected by ELS and obesity. In this review article, we report evidence from the literature describing the effect of postnatal ELS (specifically, disorganized/inconstant maternal care) on the vulnerability to obesity with a focus on the role of oxytocin. We emphasize the existing research gaps and highlight promising directions worthy of exploration. Based on the available data, alterations in the oxytocin system may in part mediate the ELS-induced susceptibility to obesity.
    Keywords:  dysfunctional eating; eating disorders; energy homeostasis; hypothalamus; lactation; leptin; postnatal development; trauma
    DOI:  https://doi.org/10.3390/cells11040623
  14. Biomolecules. 2022 Jan 21. pii: 173. [Epub ahead of print]12(2):
    The Key Role of GM1 Ganglioside in Parkinson's Disease.
    Suman Chowdhury, Robert Ledeen.
      We have endeavored in this review to summarize our findings, which point to a systemic deficiency of ganglioside GM1 in Parkinson's disease (PD) tissues. These include neuronal tissues well known to be involved in PD, such as substantia nigra of the brain and those of the peripheral nervous system, such as the colon and heart. Moreover, we included skin and fibroblasts in the study as well as peripheral blood mononuclear cells; these are tissues not directly involved in neuronal signaling. We show similar findings for ganglioside GD1a, which is the metabolic precursor to GM1. We discuss the likely causes of these GM1 deficiencies and the resultant biochemical mechanisms underlying loss of neuronal viability and normal functioning. Strong support for this hypothesis is provided by a mouse PD model involving partial GM1 deficiency based on mono-allelic disruption of the B4galnt1 gene. We point out that progressive loss of GM1/GD1a occurs in the periphery as well as the brain, thus obviating the need to speculate PD symptom transfer between these tissues. Finally, we discuss how these findings point to a potential disease-altering therapy for PD:GM1 replacement, as is strongly implicated in animal studies and clinical trials.
    Keywords:  GM1; Parkinson’s disease; ganglioside; multi-system disorder; neuroprotection
    DOI:  https://doi.org/10.3390/biom12020173
  15. Int J Mol Sci. 2022 Feb 12. pii: 2049. [Epub ahead of print]23(4):
    Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice.
    Aseel El Hajj, Ameziane Herzine, Gaetano Calcagno, Frédéric Désor, Fathia Djelti, Vincent Bombail, Isabelle Denis, Thierry Oster, Catherine Malaplate, Maxime Vigier, Sandra Kaminski, Lynn Pauron, Catherine Corbier, Frances T Yen, Marie-Claire Lanhers, Thomas Claudepierre.
      Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia-neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/- mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer's disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration.
    Keywords:  Alzheimer’s disease; astroglial activation; cholesterol; glia; memory; olfaction
    DOI:  https://doi.org/10.3390/ijms23042049
  16. Cell Death Dis. 2022 Feb 25. 13(2): 185
    Massive iron accumulation in PKAN-derived neurons and astrocytes: light on the human pathological phenotype.
    Paolo Santambrogio, Maddalena Ripamonti, Anna Cozzi, Marzia Raimondi, Chiara Cavestro, Ivano Di Meo, Alicia Rubio, Stefano Taverna, Valeria Tiranti, Sonia Levi.
      Neurodegeneration associated with defective pantothenate kinase-2 (PKAN) is an early-onset monogenic autosomal-recessive disorder. The hallmark of the disease is the massive accumulation of iron in the globus pallidus brain region of patients. PKAN is caused by mutations in the PANK2 gene encoding the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway. To date, the way in which this alteration leads to brain iron accumulation has not been elucidated. Starting from previously obtained hiPS clones, we set up a differentiation protocol able to generate inhibitory neurons. We obtained striatal-like medium spiny neurons composed of approximately 70-80% GABAergic neurons and 10-20% glial cells. Within this mixed population, we detected iron deposition in both PKAN cell types, however, the viability of PKAN GABAergic neurons was strongly affected. CoA treatment was able to reduce cell death and, notably, iron overload. Further differentiation of hiPS clones in a pure population of astrocytes showed particularly evident iron accumulation, with approximately 50% of cells positive for Perls staining. The analysis of these PKAN astrocytes indicated alterations in iron metabolism, mitochondrial morphology, respiratory activity, and oxidative status. Moreover, PKAN astrocytes showed signs of ferroptosis and were prone to developing a stellate phenotype, thus gaining neurotoxic features. This characteristic was confirmed in iPS-derived astrocyte and glutamatergic neuron cocultures, in which PKAN glutamatergic neurons were less viable in the presence of PKAN astrocytes. This newly generated astrocyte model is the first in vitro disease model recapitulating the human phenotype and can be exploited to deeply clarify the pathogenetic mechanisms underlying the disease.
    DOI:  https://doi.org/10.1038/s41419-022-04626-x
  17. Antioxidants (Basel). 2022 Jan 24. pii: 222. [Epub ahead of print]11(2):
    Calycosin Alleviates Paraquat-Induced Neurodegeneration by Improving Mitochondrial Functions and Regulating Autophagy in a Drosophila Model of Parkinson's Disease.
    Hitesh Singh Chaouhan, Xin Li, Kuo-Ting Sun, I-Kuan Wang, Tung-Min Yu, Shao-Hua Yu, Kuen-Bao Chen, Wei-Yong Lin, Chi-Yuan Li.
      Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons' survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.
    Keywords:  Drosophila; Parkinson’s disease; autophagy; calycosin; neurodegeneration; paraquat
    DOI:  https://doi.org/10.3390/antiox11020222
  18. Neuroscience. 2022 Feb 17. pii: S0306-4522(22)00067-7. [Epub ahead of print]
    Ferroptosis is Involved in Hypoxic-ischemic Brain Damage in Neonatal Rats.
    Wei Lin, Tianlei Zhang, Jinyu Zheng, Yiyang Zhou, Zhenlang Lin, Xiaoqin Fu.
      Ferroptosis is an iron-dependent form of regulated cell death, which is driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid peroxidation. Ferroptosis is implicated in various diseases involving neuronal injury. However, the role of ferroptosis in hypoxic-ischemic brain damage (HIBD) has not been elucidated. The objectives of this study were to evaluate whether ferroptosis is involved in hypoxic-ischemic brain damage and its mechanisms through the HIBD model. A 7-day-old male Sprague-Dawley neonatal rat HIBD model was established by blocking the left common carotid artery. Laser speckle contrast imaging, immunohistochemical staining, transmission electron microscopy were used to measure the effects of ferroptosis on HIBD. Brain tissue on the damaged side in the HIBD group showed atrophied, even liquefied, glial cells increased, and blood perfusion was significantly reduced. The HIBD group insult significantly increased reactive oxygen species levels, as well as the protein levels of iron metabolism-related proteins transferrin receptor (TFRC), ferritin heavy chain (FHC), and ferritin light chain (FLC), while reducing the levels of Solute Carrier Family 7 Member 11 (SLC7A11), glutathione (GSH), and GPX4. These changes resulted in diminished cellular antioxidant capacity and mitochondrial damage, causing neuronal ferroptosis in the cerebral cortex. We conclude that ferroptosis plays a role in HIBD in neonatal rats. Ferroptosis-related mechanisms such as abnormalities in iron metabolism, amino acid metabolism, and lipid peroxidation regulation play important roles in HIBD.
    Keywords:  GPX4; ROS; ferroptosis; hypoxic-ischemic brain damage
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.02.013
  19. Cells. 2022 Feb 17. pii: 706. [Epub ahead of print]11(4):
    Interaction of Mitochondrial Calcium and ROS in Neurodegeneration.
    Artyom Y Baev, Andrey Y Vinokurov, Irina N Novikova, Viktor V Dremin, Elena V Potapova, Andrey Y Abramov.
      Neurodegenerative disorders are currently incurable devastating diseases which are characterized by the slow and progressive loss of neurons in specific brain regions. Progress in the investigation of the mechanisms of these disorders helped to identify a number of genes associated with familial forms of these diseases and a number of toxins and risk factors which trigger sporadic and toxic forms of these diseases. Recently, some similarities in the mechanisms of neurodegenerative diseases were identified, including the involvement of mitochondria, oxidative stress, and the abnormality of Ca2+ signaling in neurons and astrocytes. Thus, mitochondria produce reactive oxygen species during metabolism which play a further role in redox signaling, but this may also act as an additional trigger for abnormal mitochondrial calcium handling, resulting in mitochondrial calcium overload. Combinations of these factors can be the trigger of neuronal cell death in some pathologies. Here, we review the latest literature on the crosstalk of reactive oxygen species and Ca2+ in brain mitochondria in physiology and beyond, considering how changes in mitochondrial metabolism or redox signaling can convert this interaction into a pathological event.
    Keywords:  calcium; cell death; mitochondria; neurodegeneration; neuron; permeability transition pore; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells11040706
  20. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2108581119. [Epub ahead of print]119(9):
    Modifying the maternal microbiota alters the gut-brain metabolome and prevents emotional dysfunction in the adult offspring of obese dams.
    Daniel E Radford-Smith, Fay Probert, Philip W J Burnet, Daniel C Anthony.
      Maternal obesity disturbs brain-gut-microbiota interactions and induces negative affect in the offspring, but its impact on gut and brain metabolism in the offspring (F1) are unknown. Here, we tested whether perinatal intake of a multispecies probiotic could mitigate the abnormal emotional behavior in the juvenile and adult offspring of obese dams. Untargeted NMR-based metabolomic profiling and gene-expression analysis throughout the gut-brain axis were then used to investigate the biology underpinning behavioral changes in the dams and their offspring. Prolonged high-fat diet feeding reduced maternal gut short-chain fatty acid abundance, increased markers of peripheral inflammation, and decreased the abundance of neuroactive metabolites in maternal milk during nursing. Both juvenile (postnatal day [PND] 21) and adult (PND112) offspring of obese dams exhibited increased anxiety-like behavior, which were prevented by perinatal probiotic exposure. Maternal probiotic treatment increased gut butyrate and brain lactate in the juvenile and adult offspring and increased the expression of prefrontal cortex PFKFB3, a marker of glycolytic metabolism in astrocytes. PFKFB3 expression correlated with the increase in gut butyrate in the juvenile and adult offspring. Maternal obesity reduced synaptophysin expression in the adult offspring, while perinatal probiotic exposure increased expression of brain-derived neurotrophic factor. Finally, we showed that the resilience of juvenile and adult offspring to anxiety-like behavior was most prominently associated with increased brain lactate abundance, independent of maternal group. Taken together, we show that maternal probiotic supplementation exerts a long-lasting effect on offspring neuroplasticity and the offspring gut-liver-brain metabolome, increasing resilience to emotional dysfunction induced by maternal obesity.
    Keywords:  SCFA; anxiety; lactate; maternal obesity; metabolomics
    DOI:  https://doi.org/10.1073/pnas.2108581119
  21. Pharmaceutics. 2022 Jan 28. pii: 321. [Epub ahead of print]14(2):
    Co-Delivery of Docosahexaenoic Acid and Brain-Derived Neurotropic Factor from Electrospun Aligned Core-Shell Fibrous Membranes in Treatment of Spinal Cord Injury.
    Zhuo-Hao Liu, Yin-Cheng Huang, Chang-Yi Kuo, Chi-Cheng Chuang, Ching-Chang Chen, Nan-Yu Chen, Ping K Yip, Jyh-Ping Chen.
      To restore lost functions while repairing the neuronal structure after spinal cord injury (SCI), pharmacological interventions with multiple therapeutic agents will be a more effective modality given the complex pathophysiology of acute SCI. Toward this end, we prepared electrospun membranes containing aligned core-shell fibers with a polylactic acid (PLA) shell, and docosahexaenoic acid (DHA) or a brain-derived neurotropic factor (BDNF) in the core. The controlled release of both pro-regenerative agents is expected to provide combinatory treatment efficacy for effective neurogenesis, while aligned fiber topography is expected to guide directional neurite extension. The in vitro release study indicates that both DHA and BDNF could be released continuously from the electrospun membrane for up to 50 days, while aligned microfibers guide the neurite extension of primary cortical neurons along the fiber axis. Furthermore, the PLA/DHA/BDNF core-shell fibrous membrane (CSFM) provides a significantly higher neurite outgrowth length from the neuron cells than the PLA/DHA CSFM. This is supported by the upregulation of genes associated with neuroprotection and neuroplasticity from RT-PCR analysis. From an in vivo study by implanting a drug-loaded CSFM into the injury site of a rat suffering from SCI with a cervical hemisection, the co-delivery of DHA and BDNF from a PLA/DHA/BDNF CSFM could significantly improve neurological function recovery from behavioral assessment, as well as provide neuroprotection and promote neuroplasticity changes in recovered neuronal tissue from histological analysis.
    Keywords:  brain-derived neurotrophic factor; docosahexaenoic acid; electrospinning; regenerative medicine; spinal cord injury
    DOI:  https://doi.org/10.3390/pharmaceutics14020321
  22. Behav Brain Res. 2022 Feb 21. pii: S0166-4328(22)00082-1. [Epub ahead of print] 113814
    Environmental Enrichment Sex-dependently Rescues Memory Impairment in FABP5 KO Mice Not Mediated by Brain-Derived Neurotrophic Factor.
    Matthew Marion, John Hamilton, Brittany Richardson, Nicole Roeder, Antonio Figueiredo, Amanda Nubelo, Eleftherios Hetelekides, Samantha Penman, Yuji Owada, Yoshiteru Kagawa, Panayotis K Thanos.
      Fatty acid-binding proteins (FABPs) are intracellular carriers of bioactive lipids and play a role in the trafficking of endocannabinoids as well as polyunsaturated fatty acids. Mice lacking the FABP5 gene have memory impairments. Environmental enrichment is a potent manipulation known to rescue or improve memory performance. The extent to which the memory impairments in FABP5 knockout (KO) mice can be rescued or improved through environmental conditions remains to be understood. To address this, we raised wild type (WT) and FABP5 KO mice in either socially isolated or environmental enrichment conditions during adolescence. Once in adulthood, mice were tested for Novel Object Recognition (NOR), T-maze, and Morris Water Maze (MWM) to evaluate memory performance. Mice were then euthanized to assess hippocampal brain-dervied neurotrophic factor (BDNF) concentrations. MWM results showed that male FABP5 KO mice performed worse compared to WT counterparts. Male and female mice raised in an enriched environment improved performance regardless of genotype. Results on the NOR test showed that male FABP5 KO mice displayed lower object recognition compared to WT counterparts across both environments. No differences of genotype or environment were seen in female mice. T maze findings showed that impaired performance in socially isolated FABP5 KO mice. Adolescent environmental enrichment rescued this deficit in male, but not female, FABP5 KO mice. Lastly, environmental enrichment increased hippocampal BDNF levels in male WT mice only. Our results corroborate the previously observed role of the FABP5 gene on memory performance and identify an important interaction with the environment during adolescence.
    Keywords:  FABP; brain-derived neurotrophic factor; environmental enrichment; fatty acid-binding protein; memory; social isolation
    DOI:  https://doi.org/10.1016/j.bbr.2022.113814
  23. Antioxidants (Basel). 2022 Jan 20. pii: 198. [Epub ahead of print]11(2):
    Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial Ca2+-Independent Phospholipase A2γ in the Brain.
    Pavla Průchová, Klára Gotvaldová, Katarína Smolková, Lukáš Alán, Blanka Holendová, Jan Tauber, Alexander Galkin, Petr Ježek, Martin Jabůrek.
      Mitochondrial Ca2+-independent phospholipase A2γ (iPLA2γ/PNPLA8) was previously shown to be directly activated by H2O2 and release free fatty acids (FAs) for FA-dependent H+ transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLA2γ in the brain is not completely understood. Here, using wild-type and iPLA2γ-KO mice, we demonstrate the ability of tert-butylhydroperoxide (TBHP) to activate iPLA2γ in isolated brain mitochondria, with consequent liberation of FAs and lysophospholipids. The liberated FA caused an increase in respiratory rate, which was fully inhibited by carboxyatractyloside (CATR), a specific inhibitor of ANT. Employing detailed lipidomic analysis, we also demonstrate a typical cleavage pattern for TBHP-activated iPLA2γ, reflecting cleavage of glycerophospholipids from both sn-1 and sn-2 positions releasing saturated FAs, monoenoic FAs, and predominant polyunsaturated FAs. The acute antioxidant role of iPLA2γ-released FAs is supported by monitoring both intramitochondrial superoxide and extramitochondrial H2O2 release. We also show that iPLA2γ-KO mice were more sensitive to stimulation by pro-inflammatory lipopolysaccharide, as reflected by the concomitant increase in protein carbonyls in the brain and pro-inflammatory IL-6 release in the serum. These data support the antioxidant and anti-inflammatory role of iPLA2γ in vivo. Our data also reveal a substantial decrease of several high molecular weight cardiolipin (CL) species and accumulation of low molecular weight CL species in brain mitochondria of iPLA2γ-KO mice. Collectively, our results support a key role of iPLA2γ in the remodeling of lower molecular weight immature cardiolipins with predominantly saturated acyl chains to high molecular weight mature cardiolipins with highly unsaturated PUFA acyl chains, typical for the brain.
    Keywords:  adenine nucleotide translocase; cardiolipin remodeling; mitochondria; phospholipase iPLA2γ/PNPLA8; redox homeostasis
    DOI:  https://doi.org/10.3390/antiox11020198
  24. Nat Commun. 2022 Feb 25. 13(1): 1058
    AP-4-mediated axonal transport controls endocannabinoid production in neurons.
    Alexandra K Davies, Julian E Alecu, Marvin Ziegler, Catherine G Vasilopoulou, Fabrizio Merciai, Hellen Jumo, Wardiya Afshar-Saber, Mustafa Sahin, Darius Ebrahimi-Fakhari, Georg H H Borner.
      The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the trans-Golgi network of AP-4-deficient cells, that axonal DAGLB levels are reduced in neurons from a patient with AP-4 deficiency, and that 2-AG levels are reduced in the brains of AP-4 knockout mice. Importantly, we demonstrate that neurite growth defects of AP-4-deficient neurons are rescued by inhibition of MGLL (monoacylglycerol lipase), the enzyme responsible for 2-AG hydrolysis. Our study supports a new model for AP-4 deficiency syndrome in which axon growth defects arise through spatial dysregulation of endocannabinoid signalling.
    DOI:  https://doi.org/10.1038/s41467-022-28609-w
  25. Biomedicines. 2022 Jan 24. pii: 243. [Epub ahead of print]10(2):
    The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study.
    Madis Parksepp, Liina Haring, Kalle Kilk, Kadri Koch, Kärt Uppin, Raul Kangro, Mihkel Zilmer, Eero Vasar.
      Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor's phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.
    Keywords:  CB1 receptors; N-acylethanolamines; PPARs; antipsychotic treatment; endocannabinoid system; endocannabinoids; first-episode psychosis; phosphatidylcholines; schizophrenia spectrum disorders
    DOI:  https://doi.org/10.3390/biomedicines10020243
  26. Antioxidants (Basel). 2022 Jan 20. pii: 195. [Epub ahead of print]11(2):
    Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection.
    Sun Joo Cha, Kiyoung Kim.
      Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in various diseases, especially neurodegenerative diseases. In 2015, edaravone was approved in Japan to treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of neurodegenerative diseases include high reactive oxygen species levels and mitochondrial dysfunction. However, the correlation between mitochondria and edaravone has not been elucidated. This review highlights recent studies on novel therapeutic perspectives of edaravone in terms of its effect on oxidative stress and mitochondrial function.
    Keywords:  amyotrophic lateral sclerosis; antioxidant; edaravone; mitochondria; neurodegenerative disease; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11020195
  27. Sci Rep. 2022 02 23. 12(1): 3045
    Mitochondrial dysfunction associated with TANGO2 deficiency.
    Paige Heiman, Al-Walid Mohsen, Anuradha Karunanidhi, Claudette St Croix, Simon Watkins, Erik Koppes, Richard Haas, Jerry Vockley, Lina Ghaloul-Gonzalez.
      Transport and Golgi Organization protein 2 Homolog (TANGO2)-related disease is an autosomal recessive disorder caused by mutations in the TANGO2 gene. Symptoms typically manifest in early childhood and include developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias, along with severe metabolic crises including hypoglycemia, lactic acidosis, and hyperammonemia. Severity varies among and within families. Previous studies have reported contradictory evidence of mitochondrial dysfunction. Since the clinical symptoms and metabolic abnormalities are suggestive of a broad dysfunction of mitochondrial energy metabolism, we undertook a broad examination of mitochondrial bioenergetics in TANGO2 deficient patients utilizing skin fibroblasts derived from three patients exhibiting TANGO2-related disease. Functional studies revealed that TANGO2 protein was present in mitochondrial extracts of control cells but not patient cells. Superoxide production was increased in patient cells, while oxygen consumption rate, particularly under stress, along with relative ATP levels and β-oxidation of oleate were reduced. Our findings suggest that mitochondrial function should be assessed and monitored in all patients with TANGO2 mutation as targeted treatment of the energy dysfunction could improve outcome in this condition.
    DOI:  https://doi.org/10.1038/s41598-022-07076-9
  28. Metabolites. 2022 Feb 18. pii: 187. [Epub ahead of print]12(2):
    Human Brain Lipidomics: Pilot Analysis of the Basal Ganglia Sphingolipidome in Parkinson's Disease and Lewy Body Disease.
    Aaron W Beger, Beatrix Dudzik, Randall L Woltjer, Paul L Wood.
      Sphingolipids constitute a complex class of bioactive lipids with diverse structural and functional roles in neural tissue. Lipidomic techniques continue to provide evidence for their association in neurological diseases, including Parkinson's disease (PD) and Lewy body disease (LBD). However, prior studies have primarily focused on biological tissues outside of the basal ganglia, despite the known relevancy of this brain region in motor and cognitive dysfunction associated with PD and LBD. Therefore electrospray ionization high resolution mass spectrometry was used to analyze levels of sphingolipid species, including ceramides (Cer), dihydroceramides (DHC), hydoxyceramides (OH-Cer), phytoceramides (Phyto-Cer), phosphoethanolamine ceramides (PE-Cer), sphingomyelins (SM), and sulfatides (Sulf) in the caudate, putamen and globus pallidus of PD (n = 7) and LBD (n = 14) human subjects and were compared to healthy controls (n = 9). The most dramatic alterations were seen in the putamen, with depletion of Cer and elevation of Sulf observed in both groups, with additional depletion of OH-Cer and elevation of DHC identified in LBD subjects. Diverging levels of DHC in the caudate suggest differing roles of this lipid in PD and LBD pathogenesis. These sphingolipid alterations in PD and LBD provide evidence for biochemical involvement of the neuronal cell death that characterize these conditions.
    Keywords:  alpha synuclein; ceramide; dihydroceramide; globus pallidus; sphingolipid; sphingomyelin; striatum; sulfatide
    DOI:  https://doi.org/10.3390/metabo12020187
  29. Antioxidants (Basel). 2022 Jan 19. pii: 192. [Epub ahead of print]11(2):
    Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging.
    Jinoh Kim, Hua Bai.
      Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as "peroxisomal stress response pathways". Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research.
    Keywords:  ER stress; acetyl-CoA; apoptosis; mitochondrial dysfunction; peroxisome; pexophagy; plasmalogen; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11020192
  30. Redox Biol. 2022 Feb 06. pii: S2213-2317(22)00030-1. [Epub ahead of print]51 102258
    Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.
    Belem Yoval-Sánchez, Fariha Ansari, Joel James, Zoya Niatsetskaya, Sergey Sosunov, Peter Filipenko, Irina G Tikhonova, Vadim Ten, Ilka Wittig, Ruslan Rafikov, Alexander Galkin.
      Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.
    Keywords:  Brain; Cardiac infarction; Flavin mononucleotide; Heart; Isoforms; Mitochondrial complex I; Reverse electron transfer; Stroke; Tissue-specificity
    DOI:  https://doi.org/10.1016/j.redox.2022.102258
  31. Cells. 2022 Feb 11. pii: 639. [Epub ahead of print]11(4):
    Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells.
    Leonhard Webert, Dennis Faro, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit.
      Glucose provides vital energy for cells and contributes to gene expression. The hypothalamus is key for metabolic homeostasis, but effects of glucose on hypothalamic gene expression have not yet been investigated in detail. Thus, herein, we monitored the glucose-dependent transcriptome in murine hypothalamic mHypoA-2/10 cells by total RNA-seq analysis. A total of 831 genes were up- and 1390 genes were downregulated by at least 50%. Key genes involved in the cholesterol biosynthesis pathway were upregulated, and total cellular cholesterol levels were significantly increased by glucose. Analysis of single genes involved in fundamental cellular signaling processes also suggested a significant impact of glucose. Thus, we chose ≈100 genes involved in signaling and validated the effects of glucose on mRNA levels by qRT-PCR. We identified Gnai1-3, Adyc6, Irs1, Igfr1, Hras, and Elk3 as new glucose-dependent genes. In line with this, cAMP measurements revealed enhanced noradrenalin-induced cAMP levels, and reporter gene assays elevated activity of the insulin-like growth factor at higher glucose levels. Key data of our studies were confirmed in a second hypothalamic cell line. Thus, our findings link extra cellular glucose levels with hypothalamic lipid synthesis and pivotal intracellular signaling processes, which might be of particular interest in situations of continuously increased glucose levels.
    Keywords:  RNA-seq; cAMP; cholesterol; glucose; hypothalamus; insulin-like growth factor; noradrenalin; serum response element
    DOI:  https://doi.org/10.3390/cells11040639
  32. FASEB J. 2022 03;36(3): e22203
    Lipid mediator n-3 docosapentaenoic acid-derived protectin D1 enhances synaptic inhibition of hippocampal principal neurons by interaction with a G-protein-coupled receptor.
    Apostolos Mikroulis, Marco Ledri, Gabriele Ruffolo, Eleonora Palma, Günther Sperk, Jesmond Dalli, Annamaria Vezzani, Merab Kokaia.
      Epilepsy is a severe neurological disease manifested by spontaneous recurrent seizures due to abnormal hyper-synchronization of neuronal activity. Epilepsy affects about 1% of the population and up to 40% of patients experience seizures that are resistant to currently available drugs, thus highlighting an urgent need for novel treatments. In this regard, anti-inflammatory drugs emerged as potential therapeutic candidates. In particular, specific molecules apt to resolve the neuroinflammatory response occurring in acquired epilepsies have been proven to counteract seizures in experimental models, and humans. One candidate investigational molecule has been recently identified as the lipid mediator n-3 docosapentaenoic acid-derived protectin D1 (PD1n-3DPA ) which significantly reduced seizures, cell loss, and cognitive deficit in a mouse model of acquired epilepsy. However, the mechanisms that mediate the PD1n-3DPA effect remain elusive. We here addressed whether PD1n-3DPA has direct effects on neuronal activity independent of its anti-inflammatory action. We incubated, therefore, hippocampal slices with PD1n-3DPA and investigated its effect on excitatory and inhibitory synaptic inputs to the CA1 pyramidal neurons. We demonstrate that inhibitory drive onto the perisomatic region of the pyramidal neurons is increased by PD1n-3DPA , and this effect is mediated by pertussis toxin-sensitive G-protein coupled receptors. Our data indicate that PD1n-3DPA acts directly on inhibitory transmission, most likely at the presynaptic site of inhibitory synapses as also supported by Xenopus oocytes and immunohistochemical experiments. Thus, in addition to its anti-inflammatory effects, PD1n-3DPA anti-seizure and neuroprotective effects may be mediated by its direct action on neuronal excitability by modulating their synaptic inputs.
    Keywords:  GABAA receptors; PD1n-3DPA; antiepileptic mechanism; mouse hippocampus; perisomatic inhibition
    DOI:  https://doi.org/10.1096/fj.202101815R
  33. Antioxidants (Basel). 2022 Jan 19. pii: 189. [Epub ahead of print]11(2):
    Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway.
    Jiwon Ko, Soyoung Jang, Wookbong Kwon, Si-Yong Kim, Soyeon Jang, Eungyung Kim, Young-Rae Ji, Sijun Park, Myoung-Ok Kim, Seong-Kyoon Choi, Dong-Hyung Cho, Hyun-Shik Lee, Su-Geun Lim, Zae-Young Ryoo.
      The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines.
    Keywords:  cellular oxidative homeostasis; ferroptosis; glucose-dependent insulinotropic polypeptide; mitogen-activated protein kinase; monosodium glutamate; mouse hippocampal HT-22 cells; neurotoxicity; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11020189
  34. J Nutr Biochem. 2022 Feb 20. pii: S0955-2863(22)00045-6. [Epub ahead of print] 108974
    nEffects of ketogenic diet on cognitive functions of mice fed high-fat-high-cholesterol diet.
    Dai-Ting Lin, Ning-Juo Kao, Tzu-Wen L Cross, Wei-Ju Lee, Shyh-Hsiang Lin.
      BACKGROUND AND OBJECTIVE: Long-term dietary intake of elevated levels of refined sugars, fats and cholesterols is among the factors causing cognitive impairment. Ketone bodies can be used as an alternative energy source when glucose is not available. The study investigated the effects of a ketogenic diet (medium chain triglyceride, MCT) on cognitive performance after a long-term consumption of a high-fat-high-cholesterol diet using a mice model.MATERIAL AND METHODS: Seventy of eight-week-old male C57BL/6 mice were fed an HFHC diet for 16 weeks to establish a model of an HFHC dietary pattern, before receiving intervention diets containing MCT diet or with Metformin for another 8 weeks in the second part of the experiment. Spatial learning, memory performance, and cortical and hippocampal protein expression levels were assessed.
    RESULTS: After consuming the HFHC diet for 16 weeks and subsequently receiving the MCT diet for 8 weeks, results showed that the mice fed a MCT diet had significantly better spatial learning and memory performance, lower expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), amyloid protein precursor (APP) and phosphate tau, and higher expression of brain-derived neurotrophic factor (BDNF) than the mice fed the HFHC diet.
    CONCLUSION: Long-term consumption of an HFHC diet caused a decline in cognitive functions and increased the risk factors for neurodegeneration, such as BBB permeability, neuropathy and inflammation. An MCT diet can be considered as an option for slowing down the early stage of neurodegeneration in mice.
    Keywords:  Alzheimer's disease; MCT; blood-brain barrier; ketogenic diet
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.108974
  35. Brain Sci. 2022 Feb 14. pii: 268. [Epub ahead of print]12(2):
    Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson's Disease Models.
    Satoshi Tada, Mohammed E Choudhury, Madoka Kubo, Rina Ando, Junya Tanaka, Masahiro Nagai.
      Mitochondrial dysfunction and exacerbated neuroinflammation are critical factors in the pathogenesis of both familial and non-familial forms of Parkinson's disease (PD). This study aims to understand the possible ameliorative effects of zonisamide on microglial mitochondrial dysfunction in PD. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and lipopolysaccharide (LPS) co-treated mouse models of PD to investigate the effects of zonisamide on mitochondrial reactive oxygen species generation in microglial cells. Consequently, we utilised a mouse BV2 cell line that is commonly used for microglial studies to determine whether zonisamide could ameliorate LPS-treated mitochondrial dysfunction in microglia. Flow cytometry assay indicated that zonisamide abolished microglial reactive oxygen species (ROS) generation in PD models. Extracellular flux assays showed that LPS exposure to BV2 cells at 1 μg/mL drastically reduced the mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Zonisamide overcame the inhibitory effects of LPS on mitochondrial OCR. Our present data provide novel evidence on the ameliorative effect of zonisamide against microglial mitochondrial dysfunction and support its clinical use as an antiparkinsonian drug.
    Keywords:  Parkinson’s disease; inflammation; microglia; mitochondria; zonisamide
    DOI:  https://doi.org/10.3390/brainsci12020268
  36. Biochem Biophys Res Commun. 2022 Feb 11. pii: S0006-291X(22)00231-5. [Epub ahead of print]599 134-141
    Metabolic profiling in the hypothalamus of aged mice.
    Ye Jin Kim, Byong Seo Park, Nuri Song, Thai Hien Tu, Sewon Lee, Jae Kwang Kim, Jae Geun Kim.
      Metabolic abnormalities are tightly connected to the perturbation of normal brain functions, thereby causing multiple neurodegenerative diseases. The hypothalamus is the master unit that controls the whole-body energy homeostasis. Thus, altered metabolic activity in the hypothalamus could be a crucial clue to better understand the development of metabolic disorders during aging. The current study aimed to investigate the changes in hypothalamic metabolites according to the aging process using gas chromatography-mass spectrometry. We identified that multiple metabolites and neurotransmitters were effectively reduced in the hypothalamus of aged mice. In addition, we observed increased levels of genes linked to the production and utilization of monocarboxylates in the aged hypothalamus, indicating the initiation of metabolic activity to produce alternative nutrient sources. Lastly, we found a reduced number of astrocytes in the hypothalamus of aged mice, suggesting that reduced nutrient availability in the hypothalamus might be associated with the decreased activity of astrocytes during aging. Collectively, the present study suggests that the deterioration of metabolic activities in the hypothalamus might be a primary cause and/or outcome of metabolic diseases associated with the aging process.
    Keywords:  Aging; Astrocytes; Degeneration; Hypothalamus; Metabolites
    DOI:  https://doi.org/10.1016/j.bbrc.2022.02.042
  37. Aging (Albany NY). 2022 Feb 23. 14(undefined):
    Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients.
    Michela Murdocca, Paola Spitalieri, Angela Cappello, Fiorella Colasuonno, Sandra Moreno, Eleonora Candi, Maria Rosaria D'Apice, Giuseppe Novelli, Federica Sangiuolo.
      Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells. The expression level of genes related to mitochondrial biogenesis and activity also revealed a significant reduction, highlighting a mitochondrial dysfunction in MDPL cells. Even the expression levels of mitochondrial marker SOD2, as assessed by immunofluorescence, were reduced. The decrease in this antioxidant enzyme correlated with increased production of mitochondrial ROS in MDPL cells, compared to WT. Consistent with these data, Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) analysis revealed in MDPL cells fewer mitochondria, which also displayed morphological abnormalities. Accordingly, we detected autophagic vacuoles containing partially digested mitochondria. Overall, our results demonstrate a dramatic impairment of mitochondrial biogenesis and activity in MDPL Syndrome. Administration of Metformin, though unable to restore mitochondrial impairment, proved efficient in rescuing nuclear abnormalities, suggesting its use to specifically ameliorate the premature aging phenotype.
    Keywords:  FIB/SEM; MDPL syndrome; ROS production; SOD2; autophagy; metformin; mitochondria; premature aging syndrome
    DOI:  https://doi.org/10.18632/aging.203910
  38. Sci Rep. 2022 02 22. 12(1): 3035
    Hypertonic lactate for the treatment of intracranial hypertension in patients with acute brain injury.
    Adriano Bernini, John-Paul Miroz, Samia Abed-Maillard, Eva Favre, Carolina Iaquaniello, Nawfel Ben-Hamouda, Mauro Oddo.
      Hypertonic lactate (HL) is emerging as alternative treatment of intracranial hypertension following acute brain injury (ABI), but comparative studies are limited. Here, we examined the effectiveness of HL on main cerebral and systemic physiologic variables, and further compared it to that of standard hypertonic saline (HS). Retrospective cohort analysis of ABI subjects who received sequential osmotherapy with 7.5% HS followed by HL-given at equi-osmolar (2400 mOsmol/L) and isovolumic (1.5 mL/kg) bolus doses-to reduce sustained elevations of ICP (> 20 mmHg). The effect of HL on brain (intracranial pressure [ICP], brain tissue PO2 [PbtO2], cerebral microdialysis [CMD] glucose and lactate/pyruvate ratio [LPR]) and blood (chloride, pH) variables was examined at different time-points (30, 60, 90, 120 min vs. baseline), and compared to that of HS. A total of 34 treatments among 17 consecutive subjects (13 traumatic brain injury [TBI], 4 non-TBI) were studied. Both agents significantly reduced ICP (p < 0.001, at all time-points tested): when comparing treatment effectiveness, absolute ICP decrease in mmHg and the duration of treatment effect (median time with ICP < 20 mmHg following osmotherapy 183 [108-257] vs. 150 [111-419] min) did not differ significantly between HL and HS (all p > 0.2). None of the treatment had statistically significant effects on PbtO2 and CMD biomarkers. Treatment with HL did not cause hyperchloremia and resulted in a more favourable systemic chloride balance than HS (Δ blood chloride - 1 ± 2.5 vs. + 4 ± 3 mmol/L; p < 0.001). This is the first clinical study showing that HL has comparative effectiveness than HS for the treatment of intracranial hypertension, while at the same time avoiding hyperchloremic acidosis. Both agents had no significant effect on cerebral oxygenation and metabolism.
    DOI:  https://doi.org/10.1038/s41598-022-07129-z
  39. Elife. 2022 Feb 22. pii: e74606. [Epub ahead of print]11
    Frequency- and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical.
    Ohad Stoler, Alexandra Stavsky, Yana Khrapunsky, Israel Melamed, Grace E Stutzmann, Daniel Gitler, Israel Sekler, Ilya Fleidervish.
      Mitochondrial activity is crucial for the plasticity of central synapses, but how the firing pattern of pre- and postsynaptic neurons affects the mitochondria remains elusive. We recorded changes in the fluorescence of cytosolic and mitochondrial Ca2+ indicators in cell bodies, axons, and dendrites of cortical pyramidal neurons in mouse brain slices while evoking pre- and postsynaptic spikes. Postsynaptic spike firing elicited fast mitochondrial Ca2+ responses that were about threefold larger in the somas and apical dendrites than in basal dendrites and axons. The amplitude of these responses and metabolic activity were extremely sensitive to the firing frequency. Furthermore, while an EPSP alone caused no detectable Ca2+ elevation in the dendritic mitochondria, the coincidence of EPSP with a backpropagating spike produced prominent, highly localized mitochondrial Ca2+ hotspots. Our results indicate that mitochondria decode the spike firing frequency and the Hebbian temporal coincidences into the Ca2+ signals, which are further translated into the metabolic output and most probably lead to long-term changes in synaptic efficacy.
    Keywords:  mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.74606
  40. Front Pharmacol. 2021 ;12 806417
    The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation.
    Alexander P Young, Eileen M Denovan-Wright.
      Microglia, the resident immune cells of the brain, can take on a range of pro- or anti-inflammatory phenotypes to maintain homeostasis. However, the sustained activation of pro-inflammatory microglia can lead to a state of chronic neuroinflammation characterized by high concentrations of neurotoxic soluble factors throughout the brain. In healthy brains, the inflammatory processes cease and microglia transition to an anti-inflammatory phenotype, but failure to halt the pro-inflammatory processes is a characteristic of many neurological disorders. The endocannabinoid system has been identified as a promising therapeutic target for chronic neuroinflammation as there is evidence that synthetic and endogenously produced cannabinoids temper the pro-inflammatory response of microglia and may encourage a switch to an anti-inflammatory phenotype. Activation of cannabinoid type 2 (CB2) receptors has been proposed as the mechanism of action responsible for these effects. The abundance of components of the endocannabinoid system in microglia also change dynamically in response to several brain pathologies. This can impact the ability of microglia to synthesize and degrade endocannabinoids or react to endogenous and exogenous cannabinoids. Cannabinoid receptors also participate in the formation of receptor heteromers which influences their function specifically in cells that express both receptors, such as microglia. This creates opportunities for drug-drug interactions between CB2 receptor-targeted therapies and other classes of drugs. In this article, we review the roles of pro- and anti-inflammatory microglia in the development and resolution of neuroinflammation. We also discuss the fluctuations observed in the components of the endocannabinoid in microglia and examine the potential of CB2 receptors as a therapeutic target in this context.
    Keywords:  CB2 receptor; GPCR (G protein coupled receptor); MAPK signaling; endocannabinoid system; heteromer; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fphar.2021.806417
  41. Theranostics. 2022 ;12(4): 1518-1536
    GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates.
    Magdiel Salgado, Roberto Elizondo-Vega, Pablo S Villar, Macarena Konar, Scarlet Gallegos, Estefanía Tarifeño-Saldivia, Patricia Luz-Crawford, Luis G Aguayo, Ricardo C Araneda, Elena Uribe, María Ángeles García-Robles.
      Objectives: Glucokinase Regulatory Protein (GKRP) is the only known endogenous modulator of glucokinase (GK) localization and activity to date, and both proteins are localized in tanycytes, radial glia-like cells involved in metabolic and endocrine functions in the hypothalamus. However, the role of tanycytic GKRP and its impact on the regulation of feeding behavior has not been investigated. Here, we hypothesize that GKRP regulates feeding behavior by modulating tanycyte-neuron metabolic communication in the arcuate nucleus. Methods: We used primary cultures of tanycytes to evaluate the production of lactate and β-hydroxybutyrate (βHB). Similarly, we examined the electrophysiological responses to these metabolites in pro-opiomelanocortin (POMC) neurons in hypothalamic slices. To evaluate the role of GKRP in feeding behavior, we generated tanycyte-selective GKRP-overexpressing and GKRP-knock down mice (GKRPt-OE and GKRPt-KD respectively) using adenovirus-mediated transduction. Results: We demonstrated that lactate release induced by glucose uptake is favored in GKRP-KD tanycytes. Conversely, tanycytes overexpressing GKRP showed an increase in βHB efflux induced by low glucose concentration. In line with these findings, the excitability of POMC neurons was enhanced by lactate and decreased in the presence of βHB. In GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-KD caused a significant decrease in feeding and body weight, which is reverted when MCT1 is silenced. Conclusion: Our study highlights the role of tanycytic GKRP in metabolic regulation and positions this regulator of GK as a therapeutic target for boosting satiety in patients with obesity problems.
    Keywords:  GKRP; Tanycyte; feeding behavior; lactate; obesity; β-hydroxybutyrate
    DOI:  https://doi.org/10.7150/thno.66634
  42. Cold Spring Harb Mol Case Stud. 2022 Feb 25. pii: mcs.a006136. [Epub ahead of print]
    m.3685T>C is a Novel Mitochondrial DNA Variant That Causes Leigh Syndrome.
    Jeffrey Jean, Eirini Christodoulou, Xiaowu Gai, Benita Tamrazi, Moin Vera, Wendy G Mitchell, Ryan J Schmidt.
      Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a four year-old female who initially presented with generalized tonic-clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted MRI revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T>C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T>C variant occurred de novo. The m.3685T>C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T>C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.
    Keywords:  Elevated brain lactate level by MRS; Focal T2 hyperintense basal ganglia lesion; Generalized clonic seizures; Generalized tonic seizures; Hyperalaninemia
    DOI:  https://doi.org/10.1101/mcs.a006136
  43. Antioxidants (Basel). 2022 Feb 10. pii: 351. [Epub ahead of print]11(2):
    Lysophosphatidic Acid Receptor 3 Promotes Mitochondrial Homeostasis against Oxidative Stress: Potential Therapeutic Approaches for Hutchinson-Gilford Progeria Syndrome.
    Jui-Chung Chiang, Wei-Min Chen, Ciara Newman, Benjamin P C Chen, Hsinyu Lee.
      Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activation of multiple LPA G protein-coupled receptors. We previously reported that LPA suppresses oxidative stress in premature aging Hutchinson-Gilford progeria syndrome (HGPS) patient fibroblasts via its type 3 receptor (LPA3). Mitochondria have been suggested to be the primary origin of oxidative stress via the overproduction of reactive oxygen species (ROS). Mitochondria are responsible for producing ATP through oxidative phosphorylation (OXPHOS) and have a calcium buffering capacity for the cell. Defects in mitochondria will lead to declined antioxidant capacity and cell apoptosis. Therefore, we aim to demonstrate the regulatory role of LPA3 in mitochondrial homeostasis. siRNA-mediated depletion of LPA3 leads to the depolarization of mitochondrial potential (ΔΨm) and cellular ROS accumulation. In addition, the depletion of LPA3 enhances cisplatin-induced cytochrome C releasing. This indicates that LPA3 is essential to suppress the mitochondrial apoptosis pathway. LPA3 is also shown to improve mitochondrial ADP-ATP exchange by enhancing the protein level of ANT2. On the other hand, LPA3 regulates calcium uptake from the ER to mitochondria via the IP3R1-VDAC1 channel. Moreover, activation of LPA3 by selective agonist OMPT rescues mitochondrial homeostasis of H2O2-induced oxidative stress cells and HGPS patient fibroblasts by improving mitochondrial ΔΨm and OXPHOS. In summary, our findings imply that LPA3 acts as the gatekeeper for mitochondrial healthiness to maintain cell youth. Furthermore, LPA3 can be a promising therapeutic target to prevent mitochondrial oxidative stress in aging and HGPS.
    Keywords:  Hutchinson-Gilford progeria syndrome; lysophosphatidic acid; mitochondrial homeostasis; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11020351
  44. Nutrients. 2022 Feb 11. pii: 756. [Epub ahead of print]14(4):
    Preventive Impact of Long-Term Ingestion of Chestnut Honey on Glucose Disorders and Neurodegeneration in Obese Mice.
    Simona Terzo, Pasquale Calvi, Domenico Nuzzo, Pasquale Picone, Giacoma Galizzi, Luca Caruana, Marta Di Carlo, Laura Lentini, Roberto Puleio, Flavia Mulè, Antonella Amato.
      The purpose of the present study was to evaluate the impact of long-term honey ingestion on metabolic disorders and neurodegeneration in mice fed a high-fat diet (HFD). Three groups of mice were fed with a standard diet (STD), HFD or HFD supplemented with honey (HFD-H) for 16 weeks. Biochemical, histological, Western blotting, RT-PCR and Profiler PCR array were performed to assess metabolic parameters, peripheral and central insulin resistance and neurodegeneration. Daily honey intake prevented the HFD-induced glucose dysmetabolism. In fact, it reduced plasma fasting glucose, insulin and leptin concentrations and increased adiponectin levels. It improved glucose tolerance, insulin sensitivity and HOMA index without affecting plasma lipid concentration. HFD mice showed a significantly higher number of apoptotic nuclei in the superficial and deep cerebral cortex, upregulation of Fas-L, Bim and P27 (neuronal pro-apoptotic markers) and downregulation of Bcl-2 and BDNF (anti-apoptotic factors) in comparison with STD- and HFD-H mice, providing evidence for honey neuroprotective effects. PCR-array analysis showed that long-term honey intake increased the expression of genes involved in insulin sensitivity and decreased genes involved in neuroinflammation or lipogenesis, suggesting improvement of central insulin resistance. The expressions of p-AKT and p-GSK3 in HFD-H mice, which were decreased and increased, respectively, in HFD mouse brain, index of central insulin resistance, were similar to STD animals supporting the ability of regular honey intake to protect brain neurons from insulin resistance. In conclusion, the present results provide evidence for the beneficial preventative impact of regular honey ingestion on neuronal damage caused by HFD.
    Keywords:  HFD mice; honey; insulin resistance; neurodegeneration; obesity
    DOI:  https://doi.org/10.3390/nu14040756
  45. Free Radic Biol Med. 2022 Feb 17. pii: S0891-5849(22)00059-4. [Epub ahead of print]182 23-33
    C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration.
    Changjuan Shao, Julia Zhu, Xiaopin Ma, Sandra L Siedlak, Mark L Cohen, Alan Lerner, Wenzhang Wang.
      Mitochondrial membrane protein-associated with neurodegeneration (MPAN) is a rare genetic disease characterized by aggressive neurodegeneration and massive iron accumulation in patients' brains. Genetics studies identified defects in C19orf12 locus being associated with MPAN which likely caused loss of function although underlying pathogenic mechanism(s) remain elusive. In the present study, we investigated C19orf12 knockout (KO) M17 neuronal cells and primary skin fibroblasts from MPAN patients with C19orf12 homozygous G58S or heterozygous C19orf12 p99fs*102 mutations as cellular models of MPAN. C19orf12 KO cells and MPAN fibroblast cells demonstrated mitochondrial fragmentation and dysfunction, iron overload and increased oxidative damage. Antioxidant NAC and iron chelator DFO rescued both oxidative stress and mitochondrial deficits. Moreover, C19orf12 KO cells and MPAN fibroblast cells were susceptible to erastin- or RSL3-induced ferroptosis which could be almost completely prevented by pretreatment of iron chelator DFO. Importantly, we also found mitochondrial fragmentation and increased ferroptosis related oxidative damage in neurons in the biopsied cortical tissues from an MPAN patient. Collectively, these results supported the notion that iron overload and ferroptosis likely play an important role in the pathogenesis of MPAN.
    Keywords:  C19orf12; Ferroptosis; Iron accumulation; MPAN; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.006
  46. Cells. 2022 Feb 14. pii: 666. [Epub ahead of print]11(4):
    Research Progress on Neuroprotection of Insulin-like Growth Factor-1 towards Glutamate-Induced Neurotoxicity.
    Lijun Ge, Shuyuan Liu, Limor Rubin, Philip Lazarovici, Wenhua Zheng.
      Insulin-like growth factor-1 (IGF-1) and its binding proteins and receptors are widely expressed in the central nervous system (CNS), proposing IGF-1-induced neurotrophic actions in normal growth, development, and maintenance. However, while there is convincing evidence that the IGF-1 system has specific endocrine roles in the CNS, the concept is emerging that IGF-I might be also important in disorders such as ischemic stroke, brain trauma, Alzheimer's disease, epilepsy, etc., by inducing neuroprotective effects towards glutamate-mediated excitotoxic signaling pathways. Research in rodent models has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 was administered by different routes, and several clinical studies have shown safety and promise of efficacy in neurological disorders of the CNS. Focusing on the relationship between IGF-1-induced neuroprotection and glutamate-induced excitatory neurotoxicity, this review addresses the research progress in the field, intending to provide a rationale for using IGF-I clinically to confer neuroprotective therapy towards neurological diseases with glutamate excitotoxicity as a common pathological pathway.
    Keywords:  animal models; clinical trials; glutamate-mediated excitotoxicity; insulin-like growth factor-1; neuroprotection; signaling pathways
    DOI:  https://doi.org/10.3390/cells11040666
  47. Metabolites. 2022 Jan 21. pii: 101. [Epub ahead of print]12(2):
    TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS.
    Suvithanandhini Loganathan, Bryce A Wilson, Sara B Carey, Ernesto Manzo, Archi Joardar, Berrak Ugur, Daniela C Zarnescu.
      Amyotrophic lateral sclerosis (ALS) is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a Drosophila model of ALS based on TDP-43 expression in motor neurons that recapitulates hallmark features of motor neuron disease including TDP-43 aggregation, locomotor dysfunction, and reduced lifespan. To gain insights into metabolic changes caused by TDP-43, we performed global metabolomic profiling in larvae expressing TDP-43 (WT or ALS associated mutant variant, G298S) and identified significant alterations in several metabolic pathways. Here, we report alterations in multiple metabolic pathways and highlight upregulation of Tricarboxylic acid (TCA) cycle metabolites and defects in neurotransmitter levels. We also show that modulating TCA cycle flux either genetically or by dietary intervention mitigates TDP-43-dependent locomotor defects. In addition, dopamine levels are significantly reduced in the context of TDP-43G298S, and we find that treatment with pramipexole, a dopamine agonist, improves locomotor function in vivo in Drosophila models of TDP-43 proteinopathy.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Tricarboxylic acid (TCA) cycle; dopamine; glutamine; metabolic alterations; pramipexole; pyruvate
    DOI:  https://doi.org/10.3390/metabo12020101
  48. Int J Mol Sci. 2022 Feb 12. pii: 2032. [Epub ahead of print]23(4):
    Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review.
    Bruno Pinto, Tiago Conde, Inês Domingues, M Rosário Domingues.
      Major depressive disorder (MDD), also called depression, is a serious disease that impairs the quality of life of patients and has a high incidence, affecting approximately 3.8% of the world population. Its diagnosis is very subjective and is not supported by measurable biomarkers mainly due to the lack of biochemical markers. Recently, disturbance of lipid profiling has been recognized in MDD, in animal models of MDD or in depressed patients, which may contribute to unravel the etiology of the disease and find putative new biomarkers, for a diagnosis or for monitoring the disease and therapeutics outcomes. In this review, we provide an overview of current knowledge of lipidomics analysis, both in animal models of MDD (at the brain and plasma level) and in humans (in plasma and serum). Furthermore, studies of lipidomics analyses after antidepressant treatment in rodents (in brain, plasma, and serum), in primates (in the brain) and in humans (in plasma) were reviewed and give evidence that antidepressants seem to counteract the modification seen in lipids in MDD, giving some evidence that certain altered lipid profiles could be useful MDD biomarkers for future precision medicine.
    Keywords:  depression; inflammation; lipidomics; major depressive disorder; mass spectrometry; oxidative stress
    DOI:  https://doi.org/10.3390/ijms23042032
  49. Psychiatry Res Neuroimaging. 2022 Feb 10. pii: S0925-4927(22)00020-8. [Epub ahead of print]321 111459
    Glutamate and N-Acetylaspartate Alterations Observed in Early Phase Psychosis: A Systematic Review of Proton Magnetic Resonance Spectroscopy Studies.
    J N Bissonnette, A M Francis, S MacNeil, C E Crocker, P G Tibbo, D J Fisher.
      Glutamate and N-acetylaspartate have been investigated in the neuropathology of chronic schizophrenia, with fewer studies focusing on early phase psychosis. Additionally, there has been little review and synthesis of the literature focused on multiple brain regions. This systematic review aims to provide a clear report of the current state of research on glutamate and n-acetylaspartate concentrations in early phase psychosis (defined as the first five years following psychosis onset) in multiple brain regions. Existing literature was searched systematically to compile reports of glutamate/glutamate+glutamine (Glx) and n-acetylaspartate absolute levels and ratios in both male and female individuals with early phase psychosis. Reports on glutamate/Glx concentrations in the medial prefrontal region and thalamus were varied, but the majority of reports suggested no alterations in EPP. No studies reported glutamate alterations in the hippocampus or cerebellum. There was no evidence for n-acetylaspartate alterations in the caudate, basal ganglia, and medial prefrontal cortex, and minimal evidence for NAA reductions in the thalamus, anterior cingulate cortex, and hippocampus. Future research should focus on the regions that are less commonly reported, and should aim to explore possible confounds, such as medication status and substance use.
    Keywords:  glutamate; n-acetylaspartate; neuropathology
    DOI:  https://doi.org/10.1016/j.pscychresns.2022.111459
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