Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of the gamma-aminobutyric acid type A receptor (GABA(A)R) is maintained by endogenous phosphorylation. We have shown that the corresponding kinase is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using the locally produced glycolytic ATP. In addition, using cerebral tissue obtained during curative surgery for epilepsy, we showed that both the endogenous phosphorylation and the GABA(A)R function are significantly reduced in the "epileptogenic" cerebral cortex when compared to "control" tissue. This dysfunction likely contributes to seizure generation and/or transition from the interictal to the ictal state. Glucose utilization is decreased in the epileptogenic cortex of patients with partial epilepsy in the interictal state, but the relationship to the disorder remains unclear. We propose that this hypometabolism is related to the deficiency in the endogenous phosphorylation of GABA(A)R and the resulting greater lability of GABAergic inhibition. Several lines of evidences indeed suggest that GABAergic inhibition is costly in terms of metabolic consumption. The deficiency of this glycolysis-dependent mechanism may thus link epileptogenicity to glucose hypometabolism. The antiepileptic effect of ketogenic diets may be mediated by the subsequent rise in the NADH/NAD(+) index, which favors GABA(A)R endogenous phosphorylation and should contribute to restoration of GABAergic inhibition in the epileptogenic zone.
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PMID:Lability of GABAA receptor function in human partial epilepsy: possible relationship to hypometabolism. 1904 98

The effect of seizures on brain blood flow and metabolism has been extensively studied. However, few studies have focused on mitochondria. We used near infrared spectroscopy (NIRS) to study hemoglobin and cytochrome oxidase changes during seizures, induced by the GABA antagonist bicuculline, in the adult rat. A broadband spectroscopy system was used with the optodes placed across the rat head. We focused on the initial seizures post-bicuculline addition during which oxyhemoglobin (HbO2) increased, deoxyhemoglobin (HHb) decreased and total hemoglobin (Hbtot) increased. The NIRS signal associated with the oxidised CuA centre of mitochondrial cytochrome c oxidase (oxCCO) decreased. At the highest bicuculline doses (0.25 mg/animal) the maximum values recorded were: delta HbO2 = +19 +/- 7 microM; delta HHb = -12 +/- 4 microM; delta Hbtot = +7 +/- 4 microM, delta oxCCO = - 1.7 +/- 0.3 microM. These results are broadly in line with other NIRS studies. However, previous measurements of NADH fluorescence indicate oxidation of the mitochondrial redox chain under these conditions. The changes induced by bicuculline provide an interesting challenge to the physics and biochemistry of using NIRS to study mitochondrial redox states in vivo and we explore the possible spectroscopic and/or biochemical meaning of these apparent anomalies.
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PMID:Bicuculline-induced seizures: a challenge for optical and biochemical modeling of the cytochrome oxidase CuA NIRS signal. 1922 61

The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), specific to neurons and muscle, supplies aspartate to the cytosol and, as a component of the malate-aspartate shuttle, enables mitochondrial oxidation of cytosolic NADH, thought to be important in providing energy for neurons in the central nervous system. We describe AGC1 deficiency, a novel syndrome characterized by arrested psychomotor development, hypotonia, and seizures in a child with a homozygous missense mutation in the solute carrier family 25, member 12, gene SLC25A12, which encodes the AGC1 protein. Functional analysis of the mutant AGC1 protein showed abolished activity. The child had global hypomyelination in the cerebral hemispheres, suggesting that impaired efflux of aspartate from neuronal mitochondria prevents normal myelin formation.
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PMID:AGC1 deficiency associated with global cerebral hypomyelination. 1996 69

Nitric oxide (NO) has been implicated in the neuronal hyperexcitability hence its involvement in the pathophysiology of epilepsy is clear. However, some studies indicate that NO has anticonvulsant effects while others present its convulsive effects. In the present study we tested the involvement of NO in pentylenetetrazol (Metrazol) induced Status Epilepticus (SE) rats, using the nonspecific inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) and the neuronal-specific inhibitor, 7-nitroindazole (7N1). The effects of NOS (NO synthase) inhibitors were tested, within the seizures and between them, using the Multiparametric Assembly (MPA) which continuously monitored Cerebral Blood Flow (CBF) by Laser Doppler flowmetry, mitochondrial NADH redox state by the fluorometric technique, extracellular K(+) and H(+) levels using selective mini-electrodes and electrical activity (DC potential and ECoG) using special electrodes. Between seizures a trend of increase in CBF with oxidation of NADH was seen, with no change in K(+) and H(+) extracellular levels. Pre-treatment with L-NAME prevented this trend of increase in CBF whereas the injection of 7NI even decreased CBF between seizures. Within seizures, CBF increased and mitochondrial NADH was oxidized at the first seizures, while in the last seizure NADH was reduced. The use of NOS inhibitors significantly increased the degree of NADH oxidation at the latest convulsions. In conclusion our results demonstrated beneficial effect of NOS inhibitors on the brain cortex under SE induced by Metrazol, implying that they may serve as anticonvulsant drugs.
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PMID:The evaluation of nitric oxide involvement in metrazol induced status epilepticus using multiparametric monitoring. 2123 45

Seizure activity can lead to energy failure and neuronal injury, resulting in neurological and cognitive sequelae. Moreover, mutations affecting genes encoding for proteins that maintain energy homeostasis within the cell often result in an epileptic phenotype, implying that energy failure can contribute to epileptogenesis. Indeed, there is evidence to indicate that the efficacy of the ketogenic diet, a treatment for refractory epilepsy, can be partly explained by its effect on increasing energetic substrates. The ATP level, reflecting the energy level of a cell, is maintained by the potential gradient across the mitochondrial membrane. This potential gradient is maintained by NADH/H(+) equivalents, produced by reactions within the tricarboxylic acid cycle (TCA-cycle). Anaplerosis, the replenishment of TCA-cycle substrates, therefore represents an appealing strategy to address energy failure such as occurs in seizures. There is accumulating evidence that pyruvate, a classical anaplerotic substrate, has seizure suppressive effects and protects against seizure induced cell death. This review summarizes the evidence for the contribution of TCA cycle deficits in generating seizures. We highlight the role for TCA substrate supplementation in protecting against seizures and seizure induced cell death, and propose that these are important targets for future translational research addressing energy depletion in seizures. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.
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PMID:Energy depletion in seizures: anaplerosis as a strategy for future therapies. 2265 85

The present study was aimed to investigate the potential beneficial effect of curcumin, a polyphenol with pleiotropic properties, on mitochondrial dysfunctions, oxidative stress and cognitive deficits in a kindled model of epilepsy. Kindled epilepsy was induced in rats by administering a sub-convulsive dose of pentylenetetrazole (PTZ, 40 mg/kg body weight) every alternate day for 30 days. PTZ administered rats exhibited marked cognitive deficits assessed using active and passive avoidance tasks. This was accompanied by a significant decrease in NADH:cytochrome-c reductase (complex I) and cytochrome-c oxidase (complex IV) activities along with an increase in ROS, lipid peroxidation and protein carbonyls. The levels of glutathione also decreased in the cortex and hippocampus. Electron micrographs revealed disruption of mitochondrial membrane integrity with distorted cristae in PTZ treated animals. Histopathological examination showed pyknotic nuclei and cell loss in the hippocampus as well as in the cortex of PTZ treated animals. Curcumin administration at a dose of 100 mg/kg, p.o. throughout the treatment paradigm was able to ameliorate cognitive deficits with no significant effect on seizure score. Curcumin was able to restore the activity of mitochondrial complexes. In addition, significant reduction in ROS generation, lipid peroxidation and protein carbonyls was observed in PTZ animals supplemented with curcumin. Moreover, glutathione levels were also restored in PTZ treated rats supplemented with curcumin. Curcumin protected mitochondria from seizure induced structural alterations. Further, the curcumin supplemented PTZ rats had normal cell morphology and reduced cell loss. These results suggest that curcumin supplementation has potential to prevent mitochondrial dysfunctions and oxidative stress with improved cognitive functions in a chronic model of epilepsy.
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PMID:Curcumin supplementation improves mitochondrial and behavioral deficits in experimental model of chronic epilepsy. 2511 10

The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.
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PMID:From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. 2558 28

The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.
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PMID:The ketogenic diet compensates for AGC1 deficiency and improves myelination. 2640 95

Evaluating cerebral energy metabolism at microscopic resolution is important for comprehensively understanding healthy brain function and its pathological alterations. Here, we resolve specific alterations in cerebral metabolism in vivo in Sprague Dawley rats utilizing minimally-invasive 2-photon fluorescence lifetime imaging (2P-FLIM) measurements of reduced nicotinamide adenine dinucleotide (NADH) fluorescence. Time-resolved fluorescence lifetime measurements enable distinction of different components contributing to NADH autofluorescence. Ostensibly, these components indicate different enzyme-bound formulations of NADH. We observed distinct variations in the relative proportions of these components before and after pharmacological-induced impairments to several reactions involved in glycolytic and oxidative metabolism. Classification models were developed with the experimental data and used to predict the metabolic impairments induced during separate experiments involving bicuculline-induced seizures. The models consistently predicted that prolonged focal seizure activity results in impaired activity in the electron transport chain, likely the consequence of inadequate oxygen supply. 2P-FLIM observations of cerebral NADH will help advance our understanding of cerebral energetics at a microscopic scale. Such knowledge will aid in our evaluation of healthy and diseased cerebral physiology and guide diagnostic and therapeutic strategies that target cerebral energetics.
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PMID:Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo. 2866 79

Ultrastructural evaluation of skin biopsies has been utilized for diagnosis of mitochondrial disease. This study investigates how frequently skin biopsies reveal mitochondrial abnormalities, correlates skin and muscle biopsy findings, and describes clinical diagnoses rendered following the evaluation. A retrospective review of surgical pathology reports from 1990 to 2015 identified skin biopsies examined by electron microscopy for suspected metabolic disease. A total of 630 biopsies were included from 615 patients. Of these patients, 178 also underwent a muscle biopsy. Of the 630 skin biopsies, 75 (12%) showed ultrastructural abnormalities and 34 (5%) specifically showed mitochondrial abnormalities including increased size (n=27), reduced or abnormal cristae (n=23), dense matrices (n=20), and increased number (n=8). Additional findings included lysosomal abnormalities (n=13), lipid accumulation (n=2) or glycogen accumulation (n=1). Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n=2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n=1), or ultrastructural findings including large mitochondrial size (n=5), abnormal mitochondrial structure (n=5), and increased mitochondrial number (n=4). The most common presenting symptoms were intellectual disability (n=13), seizures (n=12), encephalopathy (n=9), and gastrointestinal disturbances (n=9). At last known follow-up, 12 patients had a definitive diagnosis of a mitochondrial disorder. One patient each had Complex I deficiency, Complex III deficiency, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, and Phelan-McDermid syndrome. Our results suggest that skin biopsy sometimes yields diagnostic clues suggestive of a mitochondrial cytopathy in cases with a negative muscle biopsy.
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PMID:Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results. 2880 41


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