Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice

Background and Purpose: Sirt5 (Sirtuin 5) desuccinylates multiple metabolic enzymes and plays an important role in maintaining energy homeostasis. The goal of this study was to determine whether Sirt5-mediated desuccinylation restores the energy metabolism and protects brain against subarachnoid hemorrhage (SAH). Methods: Male C57BL/6 or Sirt5 −/− mice were used. The endovascular perforation SAH model was applied. Protein lysine succinylation in the brain cortex was examined using liquid chromatography-tandem mass spectrometry analysis. The brain metabolism was evaluated by measurement of brain pH as well as ATP and reactive oxygen species level. Neuronal cell death and neurobehavioral deficits were assessed 24 hours after SAH. The expression and desuccinylation activity of Sirt5, lysine succinylation of citrate synthase and ATP synthase subunits were investigated by Western blot, immunohistochemistry, and ELISA in SAH mice and patients. Furthermore, the benefits of resveratrol-mediated Sirt5 activation were investigated. Results: A total of 211 lysine succinylation sites were differentially expressed on 170 proteins in mice brain after SAH. Thirty-nine percent of these succinylated proteins were localized in mitochondria and they are related to energy metabolism. SAH caused a decrease of Sirt5 expression and succinylated citrate synthase as well as the subunits of ATP synthase, subsequently lowered brain pH, reduced ATP and increased reactive oxygen species production, leading to neuronal cell death, and neurological deficits. Knockdown of Sirt5 aggravated SAH-induced effects, mentioned above. Administration of resveratrol resulted in activation of Sirt5. The activation was accompanied both with restoration of the mitochondrial metabolism and alleviation of early brain injury as well as with desuccinylating citrate synthase and ATP synthase. Conclusions: Protein lysine succinylation is a biochemical hallmark of metabolic crisis after SAH, and disruption of lysine succinylation through activation of Sirt5 might be a promising therapeutic strategy for the treatment of SAH.

Decreased Brain pH and Pathophysiology in Schizophrenia

Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H+ binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia.

Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions

Microglia, the main immunocompetent cells of the brain regulate neuronal function in health and disease, but their contribution to cerebral blood flow (CBF) remained elusive. Here we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. We show that microglia establish direct purinergic contacts with cells in the neurovascular unit that shape cerebral perfusion in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in the barrel cortex after whisker stimulation. We also reveal that hypercapnia, which is associated with acidification, induces microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Furthermore, the absence or dysfunction of microglia markedly impairs adaptation to hypoperfusion via P2Y12R after transient unilateral common carotid artery occlusion, which is also influenced by CX3CR1-mediated actions. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation with broad implications for common neurological diseases.

Systematic analysis of brain lactate and pH levels in 65 animal models related to neuropsychiatric conditions

Altered brain energy metabolism associated with increase in lactate levels and the resultant decrease in pH have been increasingly implicated in multiple neuropsychiatric disorders, such as schizophrenia, bipolar disorder, autism spectrum disorder and neurodegenerative disorders. Although it is controversial, change of pH/ lactate level as a primary feature of these diseases, rather than a result of confounding factors such as medication and agonal state, has been evidenced. Animal models that can be studied without such confounding factors inherent to humans are a suitable alternative to understand the controversy. However, the knowledge in animal models regarding brain pH and lactate and their relation to behavioral outcomes is limited in the context of neuropsychiatric disease conditions. In this study, we investigated the common occurrence of changes in the pH and lactate levels in the brain in animal models by analyzing 65 animal models related to neuropsychiatric and neurodegenerative diseases with 1,239 animals. Additionally, we evaluated the behavioral phenotypes relative to the chemical changes in the brain. Among the models, 27 and 24 had significant changes in brain pH and lactate levels, respectively, including Shank2 KO mice, Clock mutant mice, serotonin transporter KO mice, mice with a paternal duplication of human chromosome 15q11-13, Fmr1 KO mice, BTBR mice, APP-J20 Tg mice, social defeat stress-exposed mice, corticosterone-treated mice, and streptozotocin-induced diabetic mice. Meta-analysis of the data revealed a highly significant negative correlation between brain pH and lactate levels, suggestive of increased lactate levels causing decreased brain pH. Statistical learning algorithm based on the comprehensive data has revealed that the increased brain lactate levels can be predominantly predicted by the indices for the percentage of correct response in working memory test, with a significant simple, negative correlation. Our results suggest that brain energy metabolism is commonly altered in many animal models of neuropsychiatric and neurodegenerative diseases, which may be associated with working memory performance. We consider our study to be an essential step suggesting that the brain endophenotypes serve as a basis for the transdiagnostic characterization of the biologically heterogeneous and debilitating cognitive illnesses. Based on these results, we are openly accepting collaborations to extend these findings and to test the hypotheses generated in this study using more animal models. We welcome any mice/rat models of diseases with or without any behavioral phenotypes.

Great benefits of Conocarpus erectus

Plants still an important source of omega oils that help to healthy for human and animals. Fresh leaves, stem, flower and fruits samples from Conocarpus erectus family Combretaceae has been analyzed using (GLC) Gas and liquid chromatography. The results indicated high levels of Omega oils which related to growth of nerve cells in brain. PH of fresh leaves determined and alkaloids with 8.2 which could help patients of diabetic type II

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

ABSTRACTBirth asphyxia (BA) is often associated with seizures which emerge during the recovery and may exacerbate the ensuing hypoxic-ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, which commence already during the insult. Here, we introduce a term-equivalent model of BA, in which seizures are triggered after, not during, brain hypoxia. Postnatal day 11-12 rat pups were exposed either to steady asphyxia (15 min; 5 % O2 + 20 % CO2) or to intermittent asphyxia (30 min; three 5+5 min cycles of 9 % and 5 % O2 at constant 20 % CO2). Cortical activity and seizures were recorded in freely-behaving animals. Simultaneous electrode measurements of cortical local field potentials (LFP) and intracortical pH and Po2 were made under urethane-anesthesia. Both protocols decreased blood pH to <7.0 and base excess by 20 mmol/l, and evoked an increase in plasma copeptin (0.2 to 5 nM). Clonic and tonic convulsions were triggered after intermittent but not steady asphyxia, and they were tightly associated with electrographic seizures. During intermittent asphyxia LFP activity was suppressed as brain pH decreased from 7.3 to 6.7. Brain Po2 fell below detection level in 5 % ambient O2 but returned to the baseline level during steps to 9 % O2. Neuronal hyperexcitability and seizures were suppressed in all types of experiments when the post-asphyxia brain pH recovery was slowed down by 5 % CO2. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our knowledge the first one in which, consistent with clinical BA, robust behavioral and electrographic seizures are triggered after and not during the BA-mimicking insult.