Improving Brain Energy Metabolism Research Articles

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Refueling the post COVID-19 brain: potential role of ketogenic medium chain triglyceride supplementation: an hypothesis.

COVID-19 infection causes cognitive changes in the acute phase, but also after apparent recovery. Over fifty post (long)-COVID symptoms are described, including cognitive dysfunction ("brain fog") precluding return to pre-COVID level of function, with rates twice as high in females. Additionally, the predominant demographic affected by these symptoms is younger and still in the workforce. Lack of ability to work, even for six months, has significant socio-economic consequences. This cognitive dysfunction is associated with impaired cerebral glucose metabolism, assessed using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), showing brain regions that are abnormal compared to age and sex matched controls. In other cognitive conditions such as Alzheimer's disease (AD), typical patterns of cerebral glucose hypometabolism, frontal hypometabolism and cerebellar hypermetabolism are common. Similar FDG-PET changes have also been observed in post-COVID-19, raising the possibility of a similar etiology. Ketone bodies (B-hydroxybutyrate, acetoacetate and acetone) are produced endogenously with very low carbohydrate intake or fasting. They improve brain energy metabolism in the face of cerebral glucose hypometabolism in other conditions [mild cognitive impairment (MCI) and AD]. Long-term low carbohydrate intake or prolonged fasting is not usually feasible. Medium chain triglyceride (MCT) is an exogenous route to nutritional ketosis. Research has supported their efficacy in managing intractable seizures, and cognitive impairment in MCI and AD. We hypothesize that cerebral glucose hypometabolism associated with post COVID-19 infection can be mitigated with MCT supplementation, with the prediction that cognitive function would also improve. Although there is some suggestion that post COVID-19 cognitive symptoms may diminish over time, in many individuals this may take more than six months. If MCT supplementation is able to speed the cognitive recovery, this will impact importantly on quality of life. MCT is readily available and, compared to pharmaceutical interventions, is cost-effective. Research shows general tolerability with dose titration. MCT is a component of enteral and parenteral nutrition supplements, including in pediatrics, so has a long record of safety in vulnerable populations. It is not associated with weight gain or adverse changes in lipid profiles. This hypothesis serves to encourage the development of clinical trials evaluating the impact of MCT supplementation on the duration and severity of post COVID-19 cognitive symptoms.

Inhibition of Autophagy Facilitates XY03-EA-Mediated Neuroprotection against the Cerebral Ischemia/Reperfusion Injury in Rats.

Objective L-3-n-Butylphthalide (NBP) is used to treat moderate and severe acute ischemia stroke. A previous screening study indicates that XY03-EA, a novel derivative of NBP, is more potent than NBP in the oxyradical scavenging capacity. In this study, in vivo and in vitro ischemia/reperfusion (I/R) models were used to test whether the XY03-EA offered therapeutic benefits in the ischemic stroke and explore the underlying mechanism of action. Methods For this purpose, behavioral scores, cerebral infarct volume, cerebral blood flow, oxidative stress levels, inflammatory factor expression, energy metabolism levels, and autophagy activation were estimated in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The nonhuman primate MCAO/R model was conducted to validate the therapeutic effect of XY03-EA applied for 3 weeks. The neurological deficit score (NDS) progression rate and the infarct volume were continuously recorded on days 3, 7, 14, and 21. The PC-12 cell OGD/R model was used to assess the cell survival rate, reactive oxygen species (ROS) levels, the expression of autophagy execution molecules, and the activation of autophagy-related signaling pathways. Results XY03-EA decreased the cerebral injuries and NDS by increasing cerebral blood flow, improving brain energy metabolism, accelerating ROS clearance, suppressing inflammatory responses, and inhibiting autophagy in the MCAO/R model rats. In the nonhuman primate MCAO/R model, the treatment of XY03-EA for 3 weeks could significantly inhibit the NDS progression rate and indicate a positive trend to reduce the infarct volume in a dose-dependent way. Mechanistically, XY03-EA inhibited ROS-dependent autophagy activation and thereby protected the PC-12 cells from the autophagic cell death induced by OGD/R. Conclusions In this study, we found that XY03-EA alleviated the cerebral I/R injuries in rats and nonhuman primates. Our results demonstrated that XY03-EA exerted neuroprotective effects against the ROS-mediated autophagic neurocyte death and had great potential for the treatment of ischemic stroke.

The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

L-Carnitine and Acetyl-L-Carnitine: Potential Novel Biomarkers for Major Depressive Disorder.

The lack of biomarkers greatly limits the diagnosis and treatment of major depressive disorder (MDD). Endogenous L-carnitine (LC) and its derivative acetyl-L-carnitine (ALC) play antidepressant roles by improving brain energy metabolism, regulating neurotransmitters and neural plasticity. The levels of ALC in people and rodents with depression are significantly reduced. It is necessary to determine whether serum LC and ALC might be used as novel biomarkers for the diagnosis of MDD. Here, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentration of LC and ALC in the serum of healthy controls and patients with MDD; among the latter, in patients who were responsive (effective group) and non-responsive (ineffective group) after 2 weeks of treatment. The diagnostic value of serum LC and ALC for MDD was assessed. Compared with healthy controls, the serum LC and ALC concentrations in patients with MDD were significantly decreased (P < 0.001). Pearson correlation analysis shows that the HDRS-24 score was negatively associated with serum ALC (r = −0.325, P = 0.007). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.801 with 83.1% sensitivity and 66.3% specificity for LC, and an AUC of 0.898 with 88.8% sensitivity and 76.4% specificity for ALC, differentiating patients with MDD from healthy controls. Furthermore, the concentration of LC and ALC in patients with depression was significantly increased in the effective treatment group, and no significant change was observed in the ineffective treatment group. These results suggest that serum LC and ALC may be novel biomarkers for the diagnosis of MDD.

Hydrogen-rich water ameliorates neuropathological impairments in a mouse model of Alzheimer's disease through reducing neuroinflammation and modulating intestinal microbiota.

Hydrogen exhibits the potential to treat Alzheimer's disease. Stereotactic injection has been previously used as an invasive method of administering active hydrogen, but this method has limitations in clinical practice. In this study, triple transgenic (3×Tg) Alzheimer's disease mice were treated with hydrogen-rich water for 7 months. The results showed that hydrogen-rich water prevented synaptic loss and neuronal death, inhibited senile plaques, and reduced hyperphosphorylated tau and neurofibrillary tangles in 3×Tg Alzheimer's disease mice. In addition, hydrogen-rich water improved brain energy metabolism disorders and intestinal flora imbalances and reduced inflammatory reactions. These findings suggest that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer's disease. This study was approved by the Animal Ethics and Welfare Committee of Shenzhen University, China (approval No. AEWC-20140615-002) on June 15, 2014.

Energy Metabolism Impairment in Migraine.

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.

Modulation of brain insulin signaling in Alzheimer’s disease: New insight on the protective role of green coffee bean extract

Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.

Total glycosides of Paeony shows Neuroprotective effects against Semen Strychni-induced neurotoxicity by recovering secretion of hormones and improving brain energy metabolism.

In this study, we investigated the protective effect of total glycosides of paeony against Semen Strychni-induced neurotoxicity and discussed some probably mechanisms. Levels of estrone, estradiol, estriol and growth hormone in male rats' serum were determined by ELISA, levels of ATP and substances associated with energy metabolism in rats' brain were determined by HPLC and levels of progesterone was determined by a UPLC-MS/MS method. The results showed that neurotoxicity induced by Semen Strychni could cause a significant decrease (p<0.05, compare to the blank group) in secretion of estrogens and GH and disorder brain energy metabolism at the same time. While, rats with total glycosides of paeony pre-protection (orally administrated with total glycosides of paeony for 15days before administrating Semen Strychni extract) showed a much better condition in the secretion of hormones and brain energy metabolism, and showed no significant changes in most of those associated substances when comparing to the blank group. Our study indicated that total glycosides of paeony have neuroprotective effects on Semen Strychni-induced neurotoxicity. It could recover the disordered hormone secretion and improve the brain energy metabolism. Total glycosides of paeony is potential to be further used in clinic to protect against neurotoxicity induced by other reasons.

Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death

Amyloid-β (Aβ) oligomers are recognized as the primary neurotoxic agents in Alzheimer's disease (AD). Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline in AD. Nicotinamide adenine dinucleotide (NAD+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD+ expression has been linked with a decrease in Aβ toxicity in AD. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN), a product of the nicotinamide phosphoribosyltransferase reaction. To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD+ precursor NMN on Aβ oligomer-induced neuronal death and cognitive impairment were studied in organotypic hippocampal slice cultures (OHCs) and in a rat model of AD. Treatment of intracerebroventricular Aβ oligomer infusion AD model rats with NMN (500mg/kg, intraperitoneally) sustained improvement in cognitive function as assessed by the Morris water maze. In OHCs, Aβ oligomer-treated culture media with NMN attenuated neuronal cell death. NMN treatment also significantly prevented the Aβ oligomer-induced inhibition of LTP. Furthermore, NMN restored levels of NAD+ and ATP, eliminated accumulation of reactive oxygen species (ROS) in the Aβ oligomer-treated hippocampal slices. All these protective effects were reversed by 3-acetylpyridine, which generates inactive NAD+. The present study indicates that NMN could restore cognition in AD model rats. The beneficial effect of NMN is produced by ameliorating neuron survival, improving energy metabolism and reducing ROS accumulation. These results suggest that NMN may become a promising therapeutic drug for AD.

Inhaled 45–50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia

Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia–ischemia we assessed whether inhaled 45–50% Argon from 2–26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia–ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2–26h (n=10); or (ii) Cooling and inhaled 45–50% Argon (Cooling+Argon) from 2–26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia–ischemia. EEG was monitored. At 48h after hypoxia–ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia–ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia–ischemia (p<0.001 for both) and lower 1H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm2 were 23.9 points lower (95% C.I. 7.3–40.5) for the Cooling+Argon versus Cooling. Inhaled 45–50% Argon from 2–26h augmented hypothermic protection at 48h after hypoxia–ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy.

Electroacupuncture Upregulates SIRT1-Dependent PGC-1α Expression in SAMP8 Mice.

BackgroundAbnormalities of brain energy metabolism are involved in Alzheimer disease (AD). Sirtuin 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), which enhances mitochondrial biogenesis and energy homeostasis. Electroacupuncture (EA) has been reported to improve brain energy metabolism in AD. However, the effect of EA on SIRT1 and PGC-1α in AD remains unclear.Material/MethodsATP levels were measured using assay kits in the hippocampus and frontal cortex of senescence-accelerated mouse prone 8 (SAMP8) mice. Western blotting analysis and quantitative real-time RT-PCR were performed to measure the expression of SIRT1 and PGC-1α in the hippocampus of SAMP8 mice. PGC-1α acetylation was analyzed using immunoprecipitation.ResultsCompared with senescence-accelerated resistant mice 1 (SAMR1) mice, SAMP8 mice had a decline in ATP levels and the expression of SIRT1 and PGC-1α. EA treatment improved ATP levels, upregulated the expression of SIRT1 and PGC-1α, and decreased PGC-1α acetylation.ConclusionsThese data suggest that EA improved brain energy metabolism, potentially associated with the upregulation of SIRT1-dependent PGC-1α expression.

Riboflavin and migraine: the bridge over troubled mitochondria.

Brain energy metabolism has been found to be disturbed in migraine. A mitochondrial defect may reduce the threshold for migraine attacks both increasing neuronal excitability and leading migrainous brain to a hyper-responsiveness to triggering stimuli. Riboflavin, a major co-factor in oxidative metabolism, may overcome this impairment. RCT studies in adult confirmed that riboflavin is safe and probably effective in migraine prophylaxis, based on level B evidence. Improving brain energy metabolism may reduce the susceptibility to migraine when brain energy demand increases due to both physiological and biopsychological factors.

Ameliorative effect of Noni fruit extract on streptozotocin-induced memory impairment in mice

This study evaluated the effects of a standardized ethyl acetate extract of Morinda citrifolia L. (Noni) fruit on impairment of memory, brain energy metabolism, and cholinergic function in intracerebral streptozotocin (STZ)-treated mice. STZ (0.5 mg/kg) was administered twice at an interval of 48 h. Noni (50 and 100 mg/kg, postoperatively) was administered for 21 days following STZ administration. Memory function was evaluated using Morris Water Maze and passive avoidance tests, and brain levels of cholinergic function, oxidative stress, energy metabolism, and brain-derived neurotrophic factor (BDNF) were estimated. STZ caused memory impairment in Morris Water Maze and passive avoidance tests along with reduced brain levels of ATP, BDNF, and acetylcholine and increased acetylcholinesterase activity and oxidative stress. Treatment with Noni extract (100 mg/kg) prevented the STZ-induced memory impairment in both behavioral tests along with reduced oxidative stress and acetylcholinesterase activity, and increased brain levels of BDNF, acetylcholine, and ATP level. The study shows the beneficial effects of Noni fruit against STZ-induced memory impairment, which may be attributed to improved brain energy metabolism, cholinergic neurotransmission, BDNF, and antioxidative action.

Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the β-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. β-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B [Akt] and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system.

Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats

In this study, we investigated whether resveratrol could protect against ischemic injury by improving brain energy metabolism and alleviating oxidative stress. Male rats were divided into three groups: sham operation, ischemia treatment, and ischemia combined with resveratrol treatment (resveratrol-treated group, 30 mg/kg intraperitoneally for 7 days). Cerebral ischemia was induced by using the model of middle cerebral artery occlusion. The dialysates in hypothalamus were obtained by brain microdialysis technique. The effects of resveratrol on neurologic functions and histopathologic changes were evaluated. The levels of ATP, ADP, AMP, adenosine, inosine, hypoxanthine and xanthine in microdialysate were monitored by HPLC analysis. The levels of malondialdehyde and the activities of xanthine oxidase in brain tissues were analyzed in three groups. This study shows that the ischemic infarcts were significantly reduced and neurological functions were improved in resveratrol-treated group compared to ischemia group. The analysis results show that resveratrol treatments remarkably enhanced the level of glucose, ATP and energy charge; decreased the levels of lactate during I/R period. Resveratrol treatments significantly increased the basal levels of adesonine and inosine, inhibited the elevations of hypoxanthine and xanthine levels and remarkably decreased xanthine oxidase activity and malondialdehyde levels. This study provides in vivo evidence that resveratrol could exert neuroprotective effect against ischemia injury by improving brain energy metabolism and alleviating oxidative stress via inhibiting xanthine oxidase activity and preventing the production of hypoxanthine, xanthine and oxygen radicals during ischemia/reperfusion.

Metabonomic Studies of Schizophrenia and Psychotropic Medications: Focus on Alterations in CNS Energy Homeostasis

Schizophrenia is a severe neuropsychiatric disorder with a poorly understood etiology and progression. We and other research groups have found that energy metabolic pathways in the CNS are perturbed in many subjects with this disorder. Antipsychotic drugs that generally target neurotransmission are currently used for clinical management of the disorder, although these can also have marked effects on energy metabolism in the CNS and periphery. Recent proteomic and metabonomic studies have shown that molecular pathways associated with brain energy metabolism are altered in both the disorder and by antipsychotic treatments. This review focuses on discussion of these molecular alterations. Increased knowledge in this area could facilitate biomarker identification and drug discovery based on improving brain energy metabolism in this debilitating disorder.

Diffusion Tensor Imaging Supports the Cytotoxic Origin of Brain Edema in a Rat Model of Acute Liver Failure

Brain edema is a severe complication of acute liver failure (ALF) that has been related to ammonia concentrations. Two mechanisms have been proposed in the pathogenesis: vasogenic edema that is secondary to the breakdown of the blood-brain barrier and cytotoxic edema caused by ammonia metabolites in astrocytes. We applied magnetic resonance techniques to assess the intracellular or extracellular distribution of brain water and metabolites in a rat model of devascularized ALF. The brain water content was assessed by gravimetry and blood-brain barrier permeability was determined from the transfer constant of (14)C-labeled sucrose. Rats with ALF had a progressive decrease in the apparent diffusion coefficient (ADC) in all brain regions. The average decrease in ADC was significant in precoma (-14%) and coma stages (-20%). These changes, which indicate an increase of the intracellular water compartment, were followed by a significant increase in total brain water (coma 82.4% +/- 0.3% vs sham 81.6% +/- 0.3%; P = .0001). Brain concentrations of glutamine (6 hours, 540%; precoma, 851%; coma, 1086%) and lactate (6 hours, 166%; precoma, 998%; coma, 3293%) showed a marked increase in ALF that paralleled the decrease in ADC and neurologic outcome. In contrast, the transfer constant of (14)C-sucrose was unaltered. The pathogenesis of brain edema in an experimental model of ALF involves a cytotoxic mechanism: the metabolism of ammonia in astrocytes induces an increase of glutamine and lactate that appears to mediate cellular swelling. Therapeutic measures should focus on removing ammonia and improving brain energy metabolism.

Nimodipine improves brain energy metabolism and blood rheology during ischemia and reperfusion in the gerbil brain

Whether nimodipine improves cerebral blood flow (CBF) and metabolism in cerebral ischemia remains a controversial issue. We investigated the effect of nimodipine on CBF, brain energy metabolism, using a laser-Doppler flowmeter and in vivo 31phosphorus nuclear magnetic resonance (31P NMR) spectroscopy, and blood rheology during forebrain ischemia and reperfusion in gerbils. Eighty-three adult gerbils received nimodipine (1 μg/kg/min), or an equal volume of the vehicle, or saline, over 60 min prior to a transient forebrain ischemia for 60 min. We measured sequential changes in phosphocreatine (PCr) / inorganic phosphate (Pi) ratio, β-ATP/Pi ratio, and intracellular pH (pHi) during ischemia and reperfusion by 31P NMR spectroscopy, and the measurement of whole blood viscosity (WBV) at 60 min after reperfusion. CBF was measured continuously throughout the study by a laser-Doppler flowmeter. During forebrain ischemia, PCr/Pi and β-ATP/Pi ratios were higher significantly in the nimodipine-treated group (p < 0.05 and 0.01) than in the vehicle- or saline-treated groups. During reperfusion, PCr/Pi and β-ATP/Pi ratios recovered significantly only in the nimodipine-treated group (p < 0.05 and 0.01). The WBV at high shear rate (562.5 s−1) lowered significantly in the nimodipine-treated group (p < 0.05) compared with the vehicle- or saline-treated group. CBF was higher significantly only during administration of nimodipine in the nimodipine-treated group (p < 0.01) than other groups. Nimodipine improved brain energy metabolism and blood rheology during forebrain ischemia and reperfusion in the gerbil brain.