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 brain is deficient in oxidative defense mechanisms and hence is at greater risk of damage mediated by reactive oxygen species (ROS) resulting in molecular and cellular dysfunction. Emerging evidence suggesting the activation of glutamate gated cation channels, may be another source of oxidative stress, leading to neuronal degeneration. Oxidative stress has been implicated in the development of neurodegenerative diseases like Parkinsonism, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epileptic seizures, and stroke. Melatonin, the pineal hormone, acts as a direct free radical scavenger and indirect antioxidant. It is suggested that the increase in neurodegenerative diseases is attributable to a decrease in the levels of melatonin with age. Melatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. Additionally, it neutralizes hydoxyl radical, superoxide radical, peroxyl radical, peroxynitrite anion, singlet oxygen, hydrogen peroxide, nitric oxide, and hypochlorous acid. Unlike other antioxidants, melatonin can easily cross all morphophysiological barriers, e.g., the blood brain barrier, and enters cells and subcellular compartments. Though evidence are accumulating to suggest the potential of melatonin in neurodegenerative conditions, much information needs to be generated before the drug can find place in neurology clinics.
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PMID:Neuroprotective role of melatonin in oxidative stress vulnerable brain. 1526 48

Epileptic patients exhibited variably altered status of trace elements, electrolytes, and free radical scavenging enzyme activities. We investigated the effect of epilepsy and long-term antiepileptic drug therapy on the serum level of some trace elements (zinc, selenium, and copper), electrolytes (calcium, magnesium, sodium, and potassium), and antioxidants (glutathione peroxidase, and uric acid) and plasma levels of lipid peroxidation index (malondialdehyde), total antioxidant capacity, and ceruloplasmin. Seventy epileptic patients and fourteen controls were recruited in this study. In the treated group (particularly with valproate), we reported increases in the levels of zinc, calcium, sodium, malondialdehyde, and glutathione peroxidase and decreases in the levels of copper, total antioxidant capacity, and ceruloplasmin with no difference in selenium, magnesium, and potassium. However among untreated epileptics, uric acid level was increased and total antioxidant capacity was markedly lowered. We conclude that the above parameters balance differs in epileptics comparable to controls and hence their correlation to seizures pathophysiology and their degree of control or resistance to antiepileptic drug therapy. Better regulation of the lipid peroxidation and antioxidants and fewer disturbances in mineral metabolism were observed in monotherapy versus polytherapy and with carbamazepine versus valproate therapy.
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PMID:Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. 1559 98

Free radicals have been implicated in the pathogenesis of various neurological disorders including epilepsy. Experimental seizures are often accompanied by the generation of free radicals that cause lipid peroxidation (LPO), which may subsequently cause neurodegeneration observed in certain types of human epilepsy. We recently reported a trigger role for nitric oxide (NO) derived by activation of neuronal isoform of nitric oxide synthase (nNOS) and that the action of conventional antiepileptic drugs (AEDs) was potentiated by inhibition of nNOS. In the present study, we extend our observations to understand the significance of blockade of the nNOS pathway on seizure-induced oxidative stress. Increased NO and LPO levels was observed at the time that corresponded to the onset of generalized seizures in rat brain regions following administration of GABA(A) receptor antagonist, picrotoxin (PCT). Treatment with the selective nNOS inhibitor, 7-nitroindazole (7-NI), decreased NO and LPO levels. The AEDs, diazepam and phenobarbitone also prevented seizure-induced increase in NO and LPO levels. Seizures resulted in a significant increase in the activity of antioxidant enzymes, superoxide dismutase in the frontal cortex and hippocampus. On the other hand, the activity of glutathione peroxidase was decreased in the hippocampus and midbrain. Whereas treatment with 7-NI could minimize the effects of PCT, the AEDs per se did not have any significant impact on the activity of the antioxidant enzymes, though co-treatment with 7-NI and AEDs could significantly decrease seizure-induced alterations in antioxidant enzyme activities. These observations suggest that the AEDs may not have a significant role in modulating the activities of antioxidant enzymes and that their ability to decrease LPO is realized more likely by their ability to prevent free radical formation. In conclusion, the present study demonstrates that NO contributes to LPO observed following seizures induced by PCT. The study also provides evidence for the ability of the AEDs to inhibit seizure-induced increase in LPO levels, the effect being enhanced by co-treatment with 7-NI suggesting that 7-NI and the AEDs together could prevent the neurotoxic cascade induced by oxidative stress.
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PMID:Seizure-induced oxidative stress in rat brain regions: blockade by nNOS inhibition. 1568 Jan 79

The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.
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PMID:Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. 1590 28

The aim of this study was to determine seizure-induced oxidative stress by measuring hippocampal glutathione (GSH) and glutathione disulfide (GSSG) levels in tissue and mitochondria. Kainate-induced status epilepticus (SE) in rats resulted in a time-dependent decrease of GSH/GSSG ratios in both hippocampal tissue and mitochondria. However, changes in GSH/GSSG ratios were more dramatic in the mitochondrial fractions compared to hippocampal tissue. This was accompanied by a mild increase in glutathione peroxidase activity and a decrease in glutathione reductase activity in hippocampal tissue and mitochondria, respectively. Since coenzyme A (CoASH) and its disulfide with GSH (CoASSG) are primarily compartmentalized within mitochondria, their measurement in tissue was undertaken to overcome problems associated with GSH/GSSG measurement following subcellular fractionation. Hippocampal tissue CoASH/CoASSG ratios were decreased following kainate-induced SE, the time course and magnitude of change paralleling mitochondrial GSH/GSSG levels. Cysteine, a rate-limiting precursor of glutathione was decreased following kainate administration in both hippocampal tissue and mitochondrial fractions. Together these changes in altered redox status provide further evidence for seizure-induced mitochondrial oxidative stress.
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PMID:Seizure-induced changes in mitochondrial redox status. 1641 13

Cholinergic and gabaergic systems play an important role generating electroencephalographic activity and regulating vigilance states. Pilocarpine is a cholinergic agonist commonly used to induce seizures and an epilepticus-like state in rodents. A relationship between status epilepticus and reactive oxygen species has been also suggested which could result in seizure-induced neurodegeneration. The aim of this study was to evaluate the existence of oxidative damage as well as the antioxidant enzyme response in cortex and hippocampus after the administration of an intraperitoneal (350 mg/kg) and an intracerebroventricular (360 microg, 1 microl) pilocarpine injection in rats. The GABA agonist muscimol (1 mg/kg, i.p.), with described neuroprotective properties, was used as a negative control. Only systemic pilocarpine induced oxidative damage. Malondialdehyde levels, as a marker of lipid peroxidation (LP), increased in both regions (55-56%). Catalase (52-80%) and superoxide dismutase (53-60%) activities also rose in both regions but glutathione peroxidase activity only increased in cortex (45%). Glutathione reductase and caspase-3 activity did not change. In conclusion, systemic pilocarpine produced oxidative brain damage, whereas local pilocarpine brain injection had no effects. Moreover, the enzymatic determinations performed in this study are a good tool to study brain injury in pharmacological manipulations such as the ones used in short recording EEG studies.
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PMID:Antioxidant response analysis in the brain after pilocarpine treatments. 1664 87

Citrullinemia is an inborn error of the urea cycle caused by deficient argininosuccinate synthetase, which leads to accumulation of L-citrulline and ammonia in tissues and body fluids. The main symptoms include convulsions, tremor, seizures, coma, and brain edema. The pathophysiology of the neurological signs of citrullinemia remains unclear. In this context, we investigated the in vitro effects of L-citrulline and ammonia in cerebral cortex from 30-day-old rats on oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS), chemiluminescence, mitochondrial membrane protein thiol content, intracellular content of hydrogen peroxide, total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) as well as on the activities of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). L-Citrulline significantly diminished TRAP (26%) and TAR (37%), while ammonia decreased TAR (30%). Ammonia increased SOD activity (65%) and L-citrulline did not affect the activities of any antioxidant enzymes. We also observed that L-citrulline and ammonia did not alter lipid peroxidation parameters, levels of hydrogen peroxide, and mitochondrial membrane protein thiol content. Taken together, these results may indicate that L-citrulline and ammonia decreased the antioxidant capacity of the brain, which may reflect a possible involvement of oxidative stress in the neuropathology of citrullinemia.
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PMID:Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro. 1677 71

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.
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PMID:Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. 1695 May 24

GHB is a naturally occurring compound in the central nervous system (CNS) whose tissue concentration are highly increased during drug abuse and in the inherited deficiency of succinic semialdehyde dehydrogenase (SSADH) activity. SSADH deficiency is a neurometabolic-inherited disorder of the degradation pathway of gamma-aminobutyric acid (GABA). It is biochemically characterized by increased concentrations of gamma-hydroxybutyric acid (GHB) in tissues, cerebrospinal fluid (CSF), blood and urine of affected patients. Clinical manifestations are variable, ranging from mild retardation of mental, motor, and language development to more severe neurological symptoms, such as hypotonia, ataxia and seizures, whose underlying mechanisms are practically unknown. In the present study, the in vitro and in vivo effects of GHB was investigated on some parameters of oxidative stress, such as chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), as well as the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in homogenates from cerebral cortex of 15-day-old Wistar rats. In vitro, GHB significantly increased chemiluminescence and TBA-RS levels, while TRAP and TAR measurements were markedly diminished. In contrast, the activities of the antioxidant enzymes SOD, CAT and GPX were not altered by GHB in vitro. Acute administration of GHB provoked a significant enhance of TBA-RS levels and a decrease of TRAP and TAR measurements. These results indicate that GHB induces oxidative stress by stimulating lipid peroxidation and decreasing the non-enzymatic antioxidant defenses in cerebral cortex of young rats. If these effects also occur in humans, it is possible that they might contribute to the brain damage found in SSADH-deficient patients and possibly in individuals who consume GHB or its prodrug gamma-butyrolactone.
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PMID:Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats. 1719 55

Pilocarpine is a cholinergic agonist capable to induce seizures and an epilepticus-like state in rodents. This status epilepticus (SE) is an useful animal model to study the development and understanding of the neuropathology, behavioural and electroencephalographic alterations of human temporal lobe epilepsy. It has been suggested a relationship between SE and reactive oxygen species (ROS) that can result in seizure-induced neurodegeneration. The aim of this study was to evaluate the existence of oxidative damage and the changes in the antioxidant system in cortex after administration of a high pilocarpine dose. Rats were injected with pilocarpine (350 mg/kg i.p.) or with saline as control and 2h after the animals were sacrificed. Malondialdehyde (MDA) levels, as marker of lipid peroxidation, significantly increased (64%) after pilocarpine treatment evidencing oxidative damage. Antioxidant enzyme activities--catalase (CAT), glutathione peroxidase (GP) and superoxide dismutase (SOD)--significantly increased in response to pilocarpine (28%, 28% and 21%, respectively). GP and Mn-SOD gene expression were induced by pilocarpine treatment. Vitamin E concentration in brain cortex decreased (15%) as result of pilocarpine administration. In conclusion, the high dose of pilocarpine, used in the present study, induces oxidative damage and increases antioxidant enzyme activities and expression in brain cortex. Moreover, increased lipid peroxidation produces the consumption of Vitamin E.
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PMID:Antioxidant response and oxidative damage in brain cortex after high dose of pilocarpine. 1720 54


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