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)

Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.
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PMID:Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic seizures in status epilepticus in rat. 131 99

Anticonvulsants are neuronal stabilizing compounds that exhibit multiple clinical effects, including anticonvulsant, anxiolytic, sedative, and muscle-relaxant properties. This complex therapeutic picture complicates the treatment of seizure disorders in individuals with mental and developmental disorders, and frequently impairs the routine integration into society for these individuals. In order to improve the therapeutic effectiveness of these compounds, it is necessary to identify their precise molecular actions on the neuronal membrane and their effects on neuronal function. We have identified two major classes of low-affinity BZ binding sites that seem to function as generalized anticonvulsant receptors and that may mediate the anticonvulsant and sedative effects produced by these compounds. The identification of these binding sites and their anticonvulsant binding profile may clarify the complex picture of anticonvulsant mechanisms and elucidate the site(s) at which anticonvulsants produce their inhibition of MES-induced seizures and sedative effects. We will continue to examine the physiological changes induced by anticonvulsant binding at these BZ binding sites that may be a foundation for understanding the molecular basis of sedation and MES-induced seizure inhibition. Specifically, we will investigate the specific membrane components associated with the inhibition of Ca2+ channels, Na+ channel rectification, and CaM kinase II. If these goals can be achieved, then model systems could be developed to screen potential anticonvulsant or sedative compounds in the search for more effective therapeutic drugs.
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PMID:A molecular approach to the development of anticonvulsants. 243 83

A type II calmodulin-dependent protein kinase (CaM kinase II) has been characterized in the synaptic region and may mediate some of the effects of Ca2+ on neuronal excitability. The activity of CaM kinase II is inhibited by anticonvulsant compounds and may be the molecular basis of their neuro-modulatory effects. The direct injection of purified CaM kinase II into invertebrate neurons has demonstrated that this kinase can directly alter specific ion conductances and neuronal activity. A long-lasting decrease in CaM kinase II activity is associated with septal kindling, an experimental model of epilepsy and long-term memory. In summary, CaM kinase II appears to be a central mediator of the effects of Ca2+ on neuronal function. Further investigation of this enzyme and its effects on neuronal activity may provide a molecular insight into an endogenous mechanism for modulating some of the effects of Ca2+ on neuronal excitability and may increase our understanding of the complex regulatory mechanisms that underlie the pathogenesis of seizure discharge and its regulation by anticonvulsant compounds.
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PMID:Molecular mechanisms of neuronal excitability: possible involvement of CaM kinase II in seizure activity. 282 86

Excessive bilirubin levels in newborn infants result in long-term neurologic deficits that remain after bilirubin levels return to normal. Much of the observed neurologic deficits can be attributed to bilirubin-induced, delayed neuronal cell death. Inhibition of calcium/calmodulin-dependent kinase II (CaM kinase II) activity that precedes cell death is observed in conditions such as seizure activity, stroke, and glutamate excitotoxicity. Because neonatal bilirubin exposure results in neuronal loss in developing brain systems, we tested whether bilirubin exposure would induce an immediate inhibition of CaM activity, in vitro. P-81 filtration assay of basal and calcium-stimulated kinase activity was performed under standard kinase assay conditions. Bilirubin and/or albumin was added to the reaction vessels to determine the effect of these agents on kinase activity. Bilirubin exposure resulted in a concentration-dependent inhibition of CaM kinase II activity (IC50 = 16.78 microM). At concentrations above 50 microM, bilirubin exposure resulted in a 71 +/- 8% (mean +/- SD) inhibition of kinase activity (p < 0.001, t test, n = 10). Bilirubin exposure did not result in kinase inhibition if excessive bilirubin was removed by albumin binding before stimulation of kinase activity (106.9 +/- 9.6% control activity, n = 5). However, removal of bilirubin by binding with albumin after calcium addition did not restore kinase activity. (36.1 +/- 3.8% control activity, n = 5). Thus, once inhibition was observed, the activity could not be restored by addition of albumin. The data suggest that bilirubin exposure resulted in a calcium-dependent inhibition of CaM kinase II activity that, once induced, was not reversible by removing bilirubin by the addition of albumin. Because inhibition of CaM kinase II activity has been correlated with delayed neuronal cell death in many neuropathologic conditions, bilirubin-induced inhibition of this enzyme may be a cellular mechanism by which bilirubin exposure results in delayed neuronal cell death in developing brain.
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PMID:Bilirubin induces a calcium-dependent inhibition of multifunctional Ca2+/calmodulin-dependent kinase II activity in vitro. 861 99

This study evaluated hippocampal inhibitory function and the level of expression of gamma-aminobutyric acid type A (GABAA) receptor mRNA in an in vivo model of epilepsy. Chronic recurrent limbic seizures were induced in rats using injections of pilocarpine. Electrophysiological studies performed on hippocampal slices prepared from control and epileptic animals 1 to 2 months after pilocarpine injections demonstrated a significant hyperexcitability in the epileptic animals. Reduced levels of mRNA expression for the alpha 2 and alpha 5 subunits of the GABAA receptors were evident in the CA1, CA2, and CA3 regions of the hippocampus of epileptic animals. No decrease in mRNA encoding alpha 1, beta 2, or gamma 2 GABAA receptor subunits was observed. In addition, no change in the mRNA levels of alpha CaM kinase II was seen. Selective decreases in mRNA expression did not correlate with neuronal cell loss. The results indicate that selective, long-lasting reduction of GABAA subunit mRNA expression and increased excitability, possibly reflecting loss of GABAergic inhibition, occur in an in vivo model of partial complex epilepsy.
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PMID:Long-lasting reduction of inhibitory function and gamma-aminobutyric acid type A receptor subunit mRNA expression in a model of temporal lobe epilepsy. 879 Mar 88

We studied levels of mRNA for the alpha- and beta-subunits of calmodulin (CaM) kinase II using the amygdaloid kindling model of epilepsy. There were significant increases in mRNA for the beta-subunit of CaM kinase II in the hippocampus 4-24 h after stage 5-kindled seizures. Moreover, this mRNA was significantly increased by 20.0-26.5% in the bilateral dentate gyrus 8 to 24 h after kindled seizures. The beta-subunit mRNA was also significantly increased by 13.5-19.0% in the CA3 on the side ipsilateral to the stimulation, 4 to 8 h after kindled seizures. mRNA for the alpha-subunit of CaM kinase II was not significantly changed in the regions examined for up to 24 h after the kindled seizures. These results suggest that CaM kinase II mediates the molecular processes that follow kindled seizures. It is possible that increases in CaM kinase II-dependent protein phosphorylation are associated with the plastic changes in kindling.
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PMID:Increased levels of mRNA for beta- but not alpha-subunit of calmodulin kinase II following kindled seizures. 924 40

Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) activity was evaluated in a well-characterized in vitro model of epileptiform activity. Long-lasting spontaneous recurrent seizure (SRS) activity was induced in hippocampal neuronal cultures by exposure to low Mg2+ media for 3 h. Analysis of endogenous Ca2+/calmodulin-dependent phosphorylation revealed a significant long-lasting decrease in 32P incorporation into the alpha (50 kDa) and beta (60 kDa) subunits of CaM kinase II in association with the induction of SRS activity in this preparation. Ca2+/calmodulin-dependent substrate phosphorylation of the synthetic peptides, Autocamtide-2 and Syntide II, was also significantly reduced following the induction of SRSs and persisted for the life of the neurons in culture. The decrement in CaM kinase II activity associated with low Mg2+ treatment remained significantly decreased when values were corrected for changes in levels of alpha subunit immunoreactivity and neuronal cell loss. Addition of the protein phosphatase inhibitors, okadaic acid and cyclosporin A, to the phosphorylation reaction did not block the SRS-associated decrease in substrate phosphorylation, indicating that enhanced phosphatase activity was not a contributing factor to the observed decrease in phosphate incorporation. The findings of this study demonstrate that CaM kinase II activity is decreased in association with epileptogenesis observed in these hippocampal cultures and may contribute to the production and maintenance of SRSs in this model.
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PMID:Long-lasting decrease in neuronal Ca2+/calmodulin-dependent protein kinase II activity in a hippocampal neuronal culture model of spontaneous recurrent seizures. 1064 28

The development of symptomatic epilepsy is a model of long-term plasticity changes in the central nervous system. The rat pilocarpine model of epilepsy was utilized to study persistent alterations in calcium/calmodulin-dependent kinase II (CaM kinase II) activity associated with epileptogenesis. CaM kinase II-dependent substrate phosphorylation and autophosphorylation were significantly inhibited for up to 6 weeks following epileptogenesis in both the cortex and hippocampus, but not in the cerebellum. The net decrease in CaM kinase II autophosphorylation and substrate phosphorylation was shown to be due to decreased kinase activity and not due to increased phosphatase activity. The inhibition in CaM kinase II activity and the development of epilepsy were blocked by pretreating seizure rats with MK-801 indicating that the long-lasting decrease in CaM kinase II activity was dependent on N-methyl-D-aspartate receptor activation. In addition, the inhibition of CaM kinase II activity was associated in time and regional localization with the development of spontaneous recurrent seizure activity. The decrease in enzyme activity was not attributed to a decrease in the alpha or beta kinase subunit protein expression level. Thus, the significant inhibition of the enzyme occurred without changes in kinase protein expression, suggesting a long-lasting, post-translational modification of the enzyme. This is the first published report of a persistent, post-translational alteration of CaM kinase II activity in a model of epilepsy characterized by spontaneous recurrent seizure activity.
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PMID:Chronic inhibition of Ca(2+)/calmodulin kinase II activity in the pilocarpine model of epilepsy. 1096

This study was conducted to characterize the post-pubertal developmental aspects on seizure susceptibility and severity as well as calcium/calmodulin protein kinase type II (CaM kinase II) activity in status epilepticus (SE). Thirty- to ninety-day-old rats, in 10-day increments, were studied. This corresponds to a developmental age group that has not received thorough attention. The pilocarpine model of SE was characterized both behaviorally and electrographically. Seven criteria were analyzed for electrographical characterization: seizure severity, SE susceptibility, the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death. After 1 h of SE, specific brain regions were isolated for biochemical study. Phosphate incorporation into a CaM kinase II-specific substrate, autocamtide III, was used to determine kinase activity. There was no developmental effect on the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death; however, there was a significant effect on SE probability and seizure severity. Once SE was expressed, all animals showed a decrease in both cortical and hippocampal CaM kinase II activities. Conversely, seizure activity in the absence of SE did not result in a decrease in CaM kinase II activity. The data suggest that there is a gradual age-dependent modulation of SE susceptibility and seizure severity within the developmental stages studied. Additionally, once status epilepticus is observed at any age, there is a corresponding SE-induced inhibition of CaM kinase II.
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PMID:Age dependence of pilocarpine-induced status epilepticus and inhibition of CaM kinase II activity in the rat. 1586 29