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

2021 ◽  
Author(s):  
Hideo Hagihara ◽  
Hirotaka Shoji ◽  
Tsuyoshi Miyakawa ◽  
Keyword(s):  
Working Memory ◽  
Energy Metabolism ◽  
Animal Models ◽  
Negative Correlation ◽  
Confounding Factors ◽  
Brain Ph ◽  
Lactate Levels ◽  
The Brain ◽  
Brain Energy ◽  
Brain Lactate

AbstractAltered 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.

Production and clearance of lactate from brain tissue, cerebrospinal fluid, and serum following experimental brain injury

1988 ◽  
Vol 69 (5) ◽  
pp. 736-744 ◽  
Author(s):  
Suguru Inao ◽  
Anthony Marmarou ◽  
Geoff D. Clarke ◽  
Bruce J. Andersen ◽  
Panos P. Fatouros ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Severe Trauma ◽  
Serum Lactate ◽  
Content Type ◽  
Brain Ph ◽  
Csf Lactate ◽  
Lactate Levels ◽  
The Brain ◽  
Brain Lactate ◽  
Fine Print

✓ Lactate dynamics in the brain, cerebrospinal fluid (CSF), and serum were studied in 20 chloralose-anesthetized cats following fluid-percussion trauma. Brain lactate and brain tissue pH were measured by hydrogen-1 and phophorus-31 magnetic resonance spectroscopy. The CSF, arterial, and cerebrovenous serum lactate levels as well as serum glucose concentration were quantified. In the six sham-operated control animals, brain, CSF, cerebrovenous, and arterial lactate levels as well as brain pH remained at normal values. In the five animals in the mild-trauma group (1.6 atm), brain and CSF lactate levels were moderately elevated, although the brain pH and serum lactate content remained at control values. Severe trauma (3.1 atm) in nine cats produced an 82% increase in the brain lactate index and a reduction in brain tissue pH (7.02 ± 0.02 to 6.95 ± 0.02; mean ± standard error of the mean), indicating brain tissue acidosis caused by excessive lactate accumulation. Brain lactate levels reached a peak 1½ hours after severe trauma, then steadily decreased to normal levels by 8 hours posttrauma. Maximum increases of CSF and arterial lactate levels (from 1.4 ± 0.2 to 4.1 ± 0.4 and from 1.6 ± 0.2 to 4.1 to 0.6 mmol/liter, respectively) were observed 15 minutes after trauma, and the values decreased during the next 2 hours. The response was biphasic, with a secondary rise observed in both CSF and serum lactate levels during the remaining 4 hours of the experiment. The difference between the arterial and venous lactate levels (A-Vlact) gradually increased and reached a peak 2 hours postinjury (from −0.05 ± 0.10 to −0.41 ± 0.09 mmol/liter). The results of this study show that the production of lactate in brain tissue, CSF, and blood increased in proportion to the severity of the injury. The observation that lactate levels in blood and CSF are maximum immediately following impact while brain lactate and A-Vlact are gradually increasing suggests that the brain-tissue production of lactate fails to account for the rapid appearance of lactate in CSF and blood. It is speculated that the initial elevation of CSF lactate values reflects the systemic response of trauma, and the secondary rise of CSF lactate levels following severe trauma is due to slow seepage of lactate produced by brain tissue into the CSF space. These studies are the first to describe the temporal profile of brain lactate production and eventual clearance by CSF and blood in fluid-percussion injury. The results emphasize the need for caution in interpreting elevated CSF lactate levels following head injury.

scholarly journals The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

2012 ◽  
Vol 34 (3) ◽  
pp. 121-128 ◽  
Author(s):  
Rodrigo Barbachan Mansur ◽  
Elisa Brietzke
Keyword(s):  
Bipolar Disorder ◽  
Energy Metabolism ◽  
Energy Supply ◽  
Clinical Implications ◽  
Metabolic Abnormalities ◽  
Compensatory Mechanisms ◽  
High Prevalence ◽  
Brain Theory ◽  
The Brain ◽  
Brain Energy

Metabolic abnormalities are frequent in patients with schizophrenia and bipolar disorder (BD), leading to a high prevalence of diabetes and metabolic syndrome in this population. Moreover, mortality rates among patients are higher than in the general population, especially due to cardiovascular diseases. Several neurobiological systems involved in energy metabolism have been shown to be altered in both illnesses; however, the cause of metabolic abnormalities and how they relate to schizophrenia and BD pathophysiology are still largely unknown. The "selfish brain" theory is a recent paradigm postulating that, in order to maintain its own energy supply stable, the brain modulates energy metabolism in the periphery by regulation of both allocation and intake of nutrients. We hypothesize that the metabolic alterations observed in these disorders are a result of an inefficient regulation of the brain energy supply and its compensatory mechanisms. The selfish brain theory can also expand our understanding of stress adaptation and neuroprogression in schizophrenia and BD, and, overall, can have important clinical implications for both illnesses.

Magnetic Resonance Spectroscopy in Migraine

Cephalalgia ◽  
1995 ◽  
Vol 15 (4) ◽  
pp. 323-327 ◽  
Author(s):  
P Montagna
Keyword(s):  
Energy Metabolism ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Energy Demand ◽  
Low Energy ◽  
Resonance Spectroscopy ◽  
Non Invasive ◽  
Relevant Role ◽  
Brain Ph ◽  
Brain Energy

31-phosphorus Magnetic Resonance Spectroscopy (MRS) is a technique developed for the non-invasive study of energy metabolism in living subjects. It determines the concentrations of high and low energy phosphates in resting and activated conditions, and of intracellular pH. 31P-MRS has been applied to the study of migraine, both during and in between attacks. Intracellular brain pH remains unchanged during the migraine attack, suggesting that ischemia does not play a relevant role in the origin of the neuro-logical signs. During and in-between attacks, migraineurs display abnormalities in energy metabolism of brain and muscle, consisting of reduced levels of phosphocreatine, reduced cellular-free energy and increased rate of ATP biosynthesis. We suggest that these abnormalities in energy metabolism predispose migraineurs to develop an attack under conditions of increased brain energy demand.

scholarly journals Dissociated Expression of Mitochondrial and Cytosolic Creatine Kinases in the Human Brain: A New Perspective on the Role of Creatine in Brain Energy Metabolism

2013 ◽  
Vol 33 (8) ◽  
pp. 1295-1306 ◽  
Author(s):  
Matthew TJ Lowe ◽  
Eric H Kim ◽  
Richard LM Faull ◽  
David L Christie ◽  
Henry J Waldvogel
Keyword(s):  
Energy Metabolism ◽  
Human Brain ◽  
High Energy ◽  
Cellular Energy ◽  
Neuronal Populations ◽  
Neurologic Function ◽  
New Perspective ◽  
The Brain ◽  
Brain Energy

The phosphocreatine/creatine kinase (PCr/CK) system in the brain is defined by the expression of two CK isozymes: the cytosolic brain-type CK (BCK) and the ubiquitous mitochondrial CK (uMtCK). The system plays an important role in supporting cellular energy metabolism by buffering adenosine triphosphate (ATP) consumption and improving the flux of high-energy phosphoryls around the cell. This system is well defined in muscle tissue, but there have been few detailed studies of this system in the brain, especially in humans. Creatine is known to be important for neurologic function, and its loss from the brain during development can lead to mental retardation. This study provides the first detailed immunohistochemical study of the expression pattern of BCK and uMtCK in the human brain. A strikingly dissociated pattern of expression was found: uMtCK was found to be ubiquitously and exclusively expressed in neuronal populations, whereas BCK was dominantly expressed in astrocytes, with a low and selective expression in neurons. This pattern indicates that the two CK isozymes are not widely coexpressed in the human brain, but rather are selectively expressed depending on the cell type. These results suggest that the brain cells may use only certain properties of the PCr/CK system depending on their energetic requirements.

Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias

2021 ◽  
Author(s):  
Chiara Giuseppina Bonomi ◽  
Vincenzo De Lucia ◽  
Alfredo Paolo Mascolo ◽  
Martina Assogna ◽  
Caterina Motta ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Brain Energy Metabolism ◽  
Csf Lactate ◽  
Lactate Levels ◽  
Brain Energy

scholarly journals Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

2022 ◽  
Vol 12 ◽  
Author(s):  
Elidie Beard ◽  
Sylvain Lengacher ◽  
Sara Dias ◽  
Pierre J. Magistretti ◽  
Charles Finsterwald
Keyword(s):  
Energy Metabolism ◽  
Neurodegenerative Diseases ◽  
Critical Role ◽  
Functional Brain Imaging ◽  
Brain Energy Metabolism ◽  
Lactate Shuttle ◽  
Lactate Release ◽  
Brain Functions ◽  
The Brain ◽  
Brain Energy

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

scholarly journals Influence of Blood Glucose Concentration on Brain Lactate Accumulation during Severe Hypoxia and Subsequent Recovery of Brain Energy Metabolism

1982 ◽  
Vol 2 (4) ◽  
pp. 429-438 ◽  
Author(s):  
Mark Gardiner ◽  
Maj-Lis Smith ◽  
Erik Kågström ◽  
Esther Shohami ◽  
Bo K. Siesjö
Keyword(s):  
Blood Glucose ◽  
Energy Metabolism ◽  
Energy Charge ◽  
Lactate Concentration ◽  
Brain Energy Metabolism ◽  
Severe Hypoxia ◽  
Adenylate Energy Charge ◽  
Blood Glucose Concentrations ◽  
Brain Energy ◽  
Brain Lactate

The effects of hypoxaemia on regional cerebral blood flow (CBF) and brain cortical metabolite concentrations were investigated at different blood glucose concentrations in rats under nitrous oxide anaesthesia. Tissue hypoxia of 15-min duration was induced by a combination of arterial hypoxaemia, hypotension, and clamping of the right carotid artery. Blood glucose concentrations were manipulated by varying the food intake in the 24 h before the experiment, and by glucose administration. Cortical CBF doubled during hypoxia on the intact side, but did not differ significantly from control values on the clamped side. In the clamped hemisphere there was a substantial decrease in adenylate energy charge. At brain tissue glucose concentrations of 1 μmol g−1 and above, there was an inverse correlation between adenylate energy charge and brain lactate concentration. In starved animals with mean brain glucose of 0.32 ± 0.00 μmol g−1, lactate concentration was significantly lower, in spite of equally severe disruption of energy state. Recovery of brain adenylate energy charge was worse in fed and glucose-infused groups than in the fasted group. These results demonstrate that limitation of substrate supply during severe hypoxia in the rat allows enhanced recovery of brain energy metabolism following the hypoxic episode.

Energy Metabolism Impairment in Migraine

2019 ◽  
Vol 26 (34) ◽  
pp. 6253-6260 ◽  
Author(s):  
Sabina Cevoli ◽  
Valentina Favoni ◽  
Pietro Cortelli
Keyword(s):  
Energy Metabolism ◽  
Energy Demand ◽  
Energy Production ◽  
Mitochondrial Respiratory Chain ◽  
Migraine Prophylaxis ◽  
Resonance Spectroscopy ◽  
Oxidative Energy Metabolism ◽  
Spectroscopy Studies ◽  
The Brain ◽  
Brain Energy

Migraine is a common disabling neurological disorder which is characterised by a recurring headache associated with a variety of sensory and autonomic symptoms. The pathophysiology of migraine remains not entirely understood, although many mechanisms involving the central and peripheral nervous system are now becoming clear. In particular, it is widely accepted that migraine is associated with energy metabolic impairment of the brain. The purpose of this review is to present an updated overview of the energy metabolism involvement in the migraine pathophysiology. Several biochemical, morphological and magnetic resonance spectroscopy studies have confirmed the presence of energy production deficiency together with an increment of energy consumption in migraine patients. An increment of energy demand over a certain threshold creates metabolic and biochemical preconditions for the onset of the migraine attack. The defect of oxidative energy metabolism in migraine is generalized. It remains to be determined if the mitochondrial deficit in migraine is primary or secondary. Riboflavin and Co-Enzyme Q10, both physiologically implicated in mitochondrial respiratory chain functioning, are effective in migraine prophylaxis, supporting the hypothesis that improving brain energy metabolism may reduce the susceptibility to migraine.

scholarly journals Effect of lactate administration on brain lactate levels during hypoglycemia in patients with type 1 diabetes

2018 ◽  
Vol 39 (10) ◽  
pp. 1974-1982 ◽  
Author(s):  
Evita C Wiegers ◽  
Hanne M Rooijackers ◽  
Cees J Tack ◽  
Bart WJ Philips ◽  
Arend Heerschap ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Sodium Lactate ◽  
Saline Infusion ◽  
Modest Increase ◽  
Impaired Awareness ◽  
Lactate Levels ◽  
Lactate Infusion ◽  
The Brain ◽  
Brain Lactate

Administration of lactate during hypoglycemia suppresses symptoms and counterregulatory responses, as seen in patients with type 1 diabetes and impaired awareness of hypoglycemia (IAH), presumably because lactate can substitute for glucose as a brain fuel. Here, we examined whether lactate administration, in a dose sufficient to impair awareness of hypoglycemia, affects brain lactate levels in patients with normal awareness of hypoglycemia (NAH). Patients with NAH ( n = 6) underwent two euglycemic-hypoglycemic clamps (2.8 mmol/L), once with sodium lactate infusion (NAH w|lac) and once with saline infusion (NAH w|placebo). Results were compared to those obtained during lactate administration in patients with IAH ( n = 7) (IAH w|lac). Brain lactate levels were determined continuously with J-difference editing 1H-MRS. During lactate infusion, symptom and adrenaline responses to hypoglycemia were considerably suppressed in NAH. Infusion of lactate increased brain lactate levels modestly, but comparably, in both groups (mean increase in NAH w|lac: 0.12 ± 0.05 µmol/g and in IAH w|lac: 0.06 ± 0.04 µmol/g). The modest increase in brain lactate may suggest that the excess of lactate is immediately metabolized by the brain, which in turn may explain the suppressive effects of lactate on awareness of hypoglycemia observed in patients with NAH.

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