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 convulsant profile of lindane was investigated in OF1 and NMRI mice lines in relation to other convulsants acting at the GABAA and NMDA receptor complexes. Thus, a specific GABA-gated chloride channel blocker, PTX, a GABAA receptor antagonist, PTZ, and an excitatory amino acid receptor agonist, NMDA, were used. Antagonism of the convulsant effects of each of these drugs was investigated with (+)MK-801, a blocker of the NMDA-operated cation channel, and with nifedipine, a voltage-dependent calcium channel antagonist. While no differences in potency for PTX or PTZ to induce seizures were observed between OF1 and NMRI mice, lindane was approximately 80 and 90% more potent in its ability to induce seizures and lethality, respectively, in OF1 than in NMRI mice. Brain lindane concentrations at the moment of convulsion, measured after ED100 doses of lindane (400 and 200 mg/kg for NMRI and OF1 mice, respectively), did not differ between OF1 and NMRI mice, suggesting that the different potency of lindane between these mouse lines is a consequence of pharmacokinetic factors. Furthermore, (+)MK-801 antagonized seizures induced by either lindane, PTX or PTZ with similar potencies in both mouse lines. These results, coupled with the different pharmacokinetics of lindane in OF1 and NMRI mice, suggest that the distinct effects of lindane in these mice are not mediated by different activities at either NMDA or GABAA receptor complexes. Nonetheless, nifedipine antagonized lindane-induced seizures with a three-fold higher potency in NMRI than in OF1 mice. In contrast, nifedipine failed to antagonize PTX and PTZ convulsions in both OF1 and NMRI mice. These results suggest that besides the GABAA receptor complex other mechanisms related to calcium mobilization may be involved in the convulsant action of lindane.
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PMID:Lindane-induced convulsions in NMRI and OF1 mice: antagonism with (+)MK-801 and voltage-dependent calcium channel blockers. 128 May 23

Our understanding of the pathophysiological mechanisms underlying the childhood epilepsies is rudimentary at this time. However, results of recent studies in animal models have lead to a number of important hypotheses concerning age-dependent alterations in seizure susceptibility. In area CA3 of hippocampus it appears that during a critical period when this brain area is particularly prone to electrographic seizures, an overabundance of recurrent excitatory synapses may exist. At the same time the synapses themselves appear to be functionally different than their mature counterpart. Age-dependent differences in the properties of postsynaptic NMDA receptors seem to contribute to enhanced seizure susceptibility. In recent years significant progress has been made in unravelling the fundamental processes that underlie the formation of connections between developing neurons. Over-production of early-formed axon collaterals appears to be common-place in the CNS. Moreover, the selection of appropriate patterns of connectivity appear to be dependent in large part on the patterning of neurophysiologic activity. In this regard the NMDA receptor seems to play a pivotal role in synapse consolidation. Based on these observations and the central role recurrent excitation appears to play in hippocampal seizures, it seems entirely plausible that excessive abnormal neuronal discharging that occurs during seizures early in life could result in the consolidation of abnormal numbers of recurrent excitatory synapses. This miswiring of hippocampal networks might be responsible for the marked seizure susceptibility into adulthood and might even contribute to complex partial epilepsy in individuals with a history of childhood seizures.
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PMID:The ontogeny of hippocampal local circuits and focal epileptogenesis. 128 4

Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
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PMID:Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms. 129 67

The alpha 2-antagonist, yohimbine has been shown to dose-dependently induce clonic seizures in mice. The convulsant effects of yohimbine are not due to alpha 2-antagonism, as other alpha 2-antagonists, such as rauwolscine and idazoxan, did not produce seizures at doses up to 100 mg/kg. Since GABAmimetic and excitatory amino acid antagonist agents attenuate yohimbine-induced seizures, the respective contribution of these systems to the production of yohimbine seizures was investigated. The CD50 dose of yohimbine (dose required to produce clonic seizures in 50% of the mice) was determined to be 25.5 mg/kg (s.c.). The CD15 dose of N-methyl-DL-aspartic acid (NMDLA), bicuculline and methyl-6,7-dimethoxy-4 ethyl-beta carboline-3-carboxylate (DMCM) significantly potentiated the convulsant effects of yohimbine, such that the CD50 dose was decreased from 25.5 mg/kg to 1.6, 10.9 and 9.9 mg/kg, respectively. Furthermore, the potentiation in the presence of NMDLA was significantly greater than either bicuculline or DMCM. These results suggest that yohimbine-induced seizures are not only mediated through the impairment of GABAergic transmission but moreover, by a possible endogenous enhancement of excitatory amino acid transmission. In addition, the effects of GABAmimetic agents, competitive and non-competitive NMDA receptor antagonists and strychnine-insensitive glycine receptor antagonists were compared in the yohimbine-, bicuculline- and NMDLA-induced seizure assays.
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PMID:Yohimbine-induced seizures involve NMDA and GABAergic transmission. 132 92

A study was performed to examine the specific binding of excitatory amino acid (EAA) receptor subtypes in 5 brain regions of rats kindled from the amygdala or hippocampus, using extensively washed and Triton X-100-treated membranes. Seven days after the last amygdala kindled seizure, [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine maleate ([3H]MK-801) binding, which labels N-methyl-D-aspartate (NMDA)-sensitive receptor-linked cation channels, decreased significantly only in the amygdala of kindled rats compared to that of controls under equilibrium assay conditions. There was no significant change in [3H]MK-801 binding in the amygdala or hippocampus 7 days after the last hippocampal kindled seizure, or 28 days after the last amygdala kindled seizure. Nor was there a significant change in NMDA-sensitive [3H]glutamate, strychnine-insensitive [3H]glycine, [3H]spermidine, [3H]kainate or [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA) binding in any brain region 7 days after the last amygdala kindled seizure, or in the hippocampus 28 days after the last amygdala kindled seizure. These results indicate that [3H]MK-801 binding sites labeling NMDA-sensitive receptor-linked cation channels in the amygdala undergo downregulation only transiently, but that none of the subcomponents of the NMDA receptor macromolecular complex exhibit enduring changes at steady state following the completion of amygdala kindling.
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PMID:Ionotropic excitatory amino acid receptors in discrete brain regions of kindled rats. 132 75

In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.
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PMID:[Effects of agonists and antagonists of benzodiazepine, GABA and NMDA receptors, on caffeine-induced seizures in mice]. 132 1

Injection of N-methyl-D-aspartate (NMDA, 7.5 micrograms) kainate (1 microgram) or quisqualate (2 micrograms) into the rat dorsal hippocampus induced wet-dog shakes and convulsions. As shown by an in situ immunohistochemical analysis, 3 h after the excitatory amino acids injections the rats displayed a bilateral profound elevation of the proenkephalin and prodynorphin mRNA levels in dentate gyrus granule cells (2-3 or 1.5-2 fold higher than control levels, respectively). Pretreatment of rats with D-amino-phosphonovalerate (D-APV, 10 micrograms), a selective antagonist of NMDA receptor, prevented the behavioral and biochemical changes evoked by NMDA. The changes in the behavior and gene expression evoked by kainate or quisqualate were diminished in rats which received 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX, 2 micrograms), a putative antagonist of quisqualate and kainate receptors. The study demonstrated that activation of NMDA, quisqualate or kainate receptors in the hippocampus induced seizures associated with a marked increase in the proenkephalin (PENK) and the prodynorphin (PDYN) gene expression in the rat dentate gyrus.
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PMID:The effects of excitatory amino acids on proenkephalin and prodynorphin mRNA levels in the hippocampal dentate gyrus of the rat; an in situ hybridization study. 134 33

Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites (determined by NMDA displaced glutamate), competitive antagonist sites (CGP 39653), noncompetitive antagonist sites (MK801) as well as the non-NMDA glutamate receptors for kainate and AMPA (using kainate and CNQX, respectively) were measured using autoradiographic procedures. Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus. The density of noncompetitive NMDA antagonist sites, however, was decreased in the dentate gyrus by estradiol treatment. Ovarian steroids had no effect on the density of kainate or AMPA receptors in any region of the hippocampus examined. These data indicate that the agonist and antagonist binding sites on the NMDA receptor/ion channel complex are regulated independently by an as yet unidentified mechanism, and that this regulation exhibits regional specificity in the hippocampus. The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity.
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PMID:Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. 135 42

The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.
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PMID:Weak anticonvulsant activity of CGP 37849 and CGP 39551 against kindled seizures following systemic administration. 135 38

Biosynthesis of the polyamines spermidine and spermine and their precursor putrescine is controlled by the activity of the two key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). In the adult brain, polyamine synthesis is activated by a variety of physiological and pathological stimuli, resulting most prominently in an increase in ODC activity and putrescine levels. The sharp rise in putrescine levels observed following severe cellular stress is most probably the result of an increase in ODC activity and decrease in SAMDC activity or an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Spermidine and spermine levels are usually less affected by stress and are reduced in severely injured areas. Changes of polyamine synthesis and metabolism are most pronounced in those pathological conditions that induce cell injury, such as severe metabolic stress, exposure to neurotoxins or seizure. Putrescine levels correlate closely with the density of cell necrosis. Because of the close relationship between the extent of post-stress changes in polyamine metabolism and density of cellular injury, it has been suggested that polyamines play a role in the manifestation of structural defects. Four different mechanisms of polyamine-dependent cell injury are plausible: (1) an overactivation of calcium fluxes and neurotransmitter release in areas with an overshoot in putrescine formation; (2) disturbances of the calcium homeostasis resulting from an impairment of the calcium buffering capacity of mitochondria in regions in which spermine levels are reduced; (3) an overactivation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during ischemia or after ischemia and prolonged recirculation in the tissue surrounding severely damaged areas; (4) an overproduction of hydrogen peroxide resulting from an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Insofar as a sharp activation of polyamine synthesis is a common response to a variety of physiological and pathological stimuli, studying stress-induced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.
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PMID:Polyamine metabolism in different pathological states of the brain. 135 85


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