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)

Protein kinase C (PKC) comprises a family of kinases consisting of nine subspecies that are differentially distributed in the central nervous system. This implies distinct functions. Its involvement is suggested in cellular and molecular mechanisms by which the hippocampus exerts influence on information processing. In this study, it was questioned whether abnormal activity in the neuronal substrate, particularly the hippocampal formation, induced by amygdala kindling indeed impairs spatial memory performance and correlated alpha, beta I/II, and gamma PKC subspecies expression. Rats were trained in a spatial discrimination task (SDT) and simultaneously kindled in the amygdala to induce abnormal, epileptiform activity. Control rats were only trained in the holeboard, a "free choice" maze, in which working (WM) and reference memory (RM) were simultaneously examined. Halfway through and at the end of the experiments the influence of kindling and SDT training on the immunoreactivity for PKC subspecies alpha, beta I/II, and gamma was evaluated in the hippocampal formation. Kindling resulted in a gradual increase in afterdischarge duration and motor seizure (MS) severity. Repeated SDT training ultimately resulted in an asymptotic level of WM and RM performance. As soon as generalized MSs developed, kindled rats failed to improve RM, whereas WM was not influenced. Compared to untrained rats, in trained controls PKC gamma but not PKC alpha beta I/II immunoreactivity was elevated in CA1 pyramidal and dentate gyrus granular cells. Generalized but not partial MSs abolished these alterations in PKC gamma immunoreactivity. The present data indicate that repeated training in a SDT affects the expression of PKC subspecies gamma but not of alpha or beta in the rat hippocampus. Generalized epileptiform activity impair both acquisition of new spatial RM information and PKC gamma expression. It is argued that PKC gamma plays a role in cellular mechanisms through which pathological brain activity impairs certain aspects of spatial memory.
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PMID:Amygdala kindling-induced seizures selectively impair spatial memory. 1. Behavioral characteristics and effects on hippocampal neuronal protein kinase C isoforms. 130 96

Administration of phorbol 12-myristate,13-acetate (PMA, 10 fmol-10 nmol) or phorbol 12,13-dibutyrate (PDB, 0.2-495 nmol) (i.c.v.) to mice induced: hindlimb scratching, tremor, myoclonic jerks, hyperlocomotion, clonic seizure, followed by death or recovery. CD50 values for clonic seizures for PMA and PDB were 1.0 pmol and 1.2 nmol. 4-alpha-Phorbol (68-686 nmol) was inactive. The effects of PDB (24-247 nmol) were reduced by pretreatment with staurosporine (30 nmol, i.c.v.). Protein kinase C activators are potent convulsants in vivo.
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PMID:The protein kinase C activators, phorbol 12-myristate,13-acetate and phorbol 12,13-dibutyrate, are convulsant in the pico-nanomolar range in mice. 149 48

Protein kinase C (PKC) activity was measured in samples of neocortex, cerebellum, and hippocampus from adult rats receiving a series of 10 electroconvulsive seizures (ECS). Rats were sacrificed immediately and at various intervals from 15 min to 24 h after the last seizure. From 77 to 84% of total PKC activity was found in the cytosol versus the membrane fraction. PKC activity in cerebellum was significantly higher than in neocortex (15%, P less than 0.05). Repeated ECS treatment did not affect total PKC activity nor its distribution between membrane and cytosolic fractions when compared with sham ECS controls. This finding is in keeping with reports that adrenergic-stimulated phosphoinositol turnover is not altered 24 h following repeated ECS.
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PMID:Protein kinase C activity and subcellular distribution in rat brain following repeated electroconvulsive seizures. 173 74

Protein kinase C (PKC) activity, Western blot analysis of PKC alpha, beta, gamma, epsilon and zeta with isozyme-specific antibodies, endogenous substrate protein phosphorylation, and Western blot analysis of neuromodulin, were studied in mouse brain after repeated electroconvulsive shock. The PKC isozymes and endogenous substrates in the crude cytosolic and membrane fractions were partially purified on DE-52 columns eluted with buffer containing 100 or 200 mM KCl. The kinase activity assayed by phosphorylation of exogenous histone was increased in the 200 mM KCl eluates of both the cytosol and membrane fractions from electroshocked mice. Further analysis by immunoblotting demonstrated that this increased activity was due to an increase in the PKC gamma isozyme. The level of the novel type isozymes, epsilon and zeta, was not altered in electroshocked mice. An in vitro phosphorylation study showed that the endogenous substrate, 17 kDa neurogranin, was mostly eluted by 100 mM KCl. In contrast, the 43 kDa neuromodulin only appeared in the 200 mM KCl eluate, according to autoradiography, SDS-PAGE and Western blot analysis; its level was found to be increased in the membrane fraction of electroshocked mice, as demonstrated by in vitro phosphorylation studies. Therefore, an increase in both PKC gamma and neuromodulin contributed to the increased phosphorylation of neuromodulin during electroshock seizure.
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PMID:Alterations of protein kinase C isozyme and substrate proteins in mouse brain after electroconvulsive seizures. 792 28

Protein kinase C (PKC) activity in hippocampus and amygdala was measured during kindled seizures and 30 min, 3, 24, and 48 h, and 2 weeks after seizures in amygdaloid-kindled rats. Sham-operated rats not subjected to kindling were used as controls. During kindled seizures, membrane-bound PKC activity in bilateral hippocampi was significantly increased, with a slight reduction in cytosolic PKC activity, but there was no change in either membrane-bound or cytosolic PKC activity in bilateral amygdala. Thirty minutes after seizures, PKC activity in both fractions was significantly increased in bilateral hippocampi and amygdala. Three hours after seizures, PKC activity in both fractions was markedly decreased in bilateral hippocampi. In bilateral amygdala, a similar and significant decrease in membrane-bound PKC activity was noted, with no marked change in the cytosolic fraction. Twenty-four hours after seizures, a significant decrease in membrane-bound PKC activity in bilateral hippocampi and amygdala was again noted, although cytosolic PKC activity was unchanged. Forty-eight hours after the seizures, PKC activity in both fractions had returned to control levels. Two weeks after the last seizure, there was no significant change in PKC activity in either fraction in any region, except for a slight increase in membrane-bound PKC activity in unilateral hippocampus contralateral to the kindled amygdala. These results suggest that kindled amygdaloid seizures cause an immediate and transient increase in PKC activity in limbic structures, followed by suppression of enzyme activity, and that PKC in hippocampus responds to kindled seizures more readily and preferentially than it does in amygdala.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kindled amygdaloid seizures in rats cause immediate and transient increase in protein kinase C activity followed by transient suppression of the activity. 808 33

Kainate-induced seizure activity causes persistent changes in the hippocampus that include synaptic reorganization and functional changes in the mossy fibers. Using in situ hybridization histochemistry, the expression of PKC alpha, PKC beta, PKC gamma, PKC delta and PKC epsilon mRNAs was investigated in the hippocampus of adult rats following seizures induced by a s.c. injection of kainic acid. In CA1 and CA3, we found a significant decrease in PKC gamma mRNA 1 day after kainic acid which persisted for a 2nd day in CA1. None of the other PKC isoform mRNAs were altered in CA1 or CA3. In granule cells, a significant up-regulation specific to PKC epsilon mRNA was observed. One week after kainic acid administration, a marked increase in PKC epsilon immunoreactivity was found that persisted 2 months after kainic acid administration. PKC epsilon immunoreactivity was found associated with mossy fibers projecting to the hilus of the dentate gyrus and to the stratum lucidum of the CA3 field and presumably with the newly sprouted mossy fibers projecting to the supragranular layer. These data provide the first evidence for a long-lasting increase of the PKC epsilon in the axons of granule cells caused by kainate-induced seizures and suggest that PKC epsilon may be involved in the functional and/or structural modifications of granule cells that occur after limbic seizures.
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PMID:Selective up-regulation of protein kinase C epsilon in granule cells after kainic acid-induced seizures in rat. 938 78

Protein kinase C (PKC) consists of a family of Ca2+/phospholipid-dependent isozymes that has been implicated in the delayed neurotoxic effects of glutamate in vitro. In the present study, we assessed the effect of the glutamate analogue kainic acid (KA) on the subcellular expression of PKC isozymes in the hippocampus (HPC) in the period preceding (0.5, 1.5, 12, and 24 h) and during (120 h) hippocampal necrosis using western blot analysis and PKC isozyme-specific antibodies. Before subcellular fractionation (cytosol + membrane), hippocampi were microdissected into "HPC" (fields CA1-CA3) and "dentate gyrus" (DG; granule cells + hilus) regions. Four general patterns of alterations in PKC isozyme expression/distribution were observed following KA treatment. The first pattern was a relative stability in expression following KA treatment and was most apparent for cytosol PKCalpha (HPC + DG) and membrane (HPC) and cytosol (DG) PKCbetaII. The second pattern, observed with PKCgamma and PKCepsilon, was characterized by an initial increase in expression in both membrane and cytosolic fractions before seizure activity (0.5 h) followed by a gradual decrease until significant reductions are observed by 120 h. The third pattern, exhibited by PKCdelta, involved an apparent translocation, increasing in the membrane and decreasing in the cytosol, followed by down-regulation in both fractions and subsequent recovery. The fourth pattern was observed with PKCzeta only and entailed a significant reduction in expression before and during limbic motor seizures followed by a dramatic fivefold increase in the membrane fraction during the period of hippocampal necrosis (120 h). Although these patterns did not segregate according to conventional PKC isozyme classifications, they do indicate dynamic isozyme-specific regulation by KA. The subcellular redistribution of PKC isozymes may contribute to the histopathological sequelae produced by KA in the hippocampus and may model the pathogenesis associated with diseases involving glutamate-induced neurotoxicity.
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PMID:Differential subcellular redistribution of protein kinase C isozymes in the rat hippocampus induced by kainic acid. 1009 84

Kainate receptors (KARs) on CA1 pyramidal cells make no detectable contribution to EPSCs. We report that these receptors have a metabotropic function, as shown previously for CA1 interneurons. Brief kainate exposure caused long-lasting inhibition of a postspike potassium current (I(sAHP)) in CA1 pyramidal cells. The pharmacological profile was independent of AMPA receptors or the GluR5 subunit, indicating a possible role for the GluR6 subunit. KAR inhibition of I(sAHP) did not require ionotropic action or network activity, but was blocked by the inhibitor of pertussis toxin-sensitive G proteins, N-ethylmaleimide (NEM), or the PKC inhibitor calphostin C. These data suggest how KARs, putatively containing GluR6, directly increase excitability of CA1 pyramidal cells and help explain the propensity for seizure activity following KAR activation.
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PMID:Metabotropic-mediated kainate receptor regulation of IsAHP and excitability in pyramidal cells. 1193 45

Primary generalized epilepsy may be the result of maldevelopment of central nervous system and each seizure may be the consequence of a neuronal maladaptation to an unknown stimulus using the paleospinothalamical tract due to an overexpression of brain-derived neurotrophic factor and neurotrophin-3. The subsequent protein kinase C epsilon (PKC-epsilon) activation and intracellular Ca(2+) release causes a nociceptive hypersensitization and an increased cortical hyperexcitability because of increased frequency of synchronous Ca(2+) oscillations, cortical maldevelopment at the level of synapses and an attenuation of GABA(A) receptor mediated responses in reticular thalamic nucleus. Valproate may exert its antiepileptic effect as a PKC-epsilon inhibitor, and using with a PKC-epsilon activator that cannot pass blood brain barrier, its side effects may become avoidable.
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PMID:The epsilon theory: a novel synthesis of the underlying molecular and electrophysiological mechanisms of primary generalized epilepsy and the possible mechanism of action of valproate. 1560 53

Systemic administration of pilocarpine preceded by lithium induces status epilepticus (SE) that results in neurodegeneration and may lead to the development of spontaneous recurrent seizures. We investigated the effect of Li/pilocarpine-induced SE on phosphorylation of the NMDA receptor in rat hippocampus. Phosphorylation of NR1 by PKC on Ser890 was decreased to 45% of control values immediately following 1 h of SE. During the first 3 h following the termination of SE, phosphorylation of Ser890 increased 4-fold before declining to control values by 24 h. Phosphorylation of NR1 by PKA was also depressed relative to controls immediately following SE and transiently increased above control values upon the termination of SE. SE was accompanied by a general increase in tyrosine phosphorylation of hippocampal proteins that lasted for several hours following the termination of seizures. Tyrosine phosphorylation of the NR2A and NR2B subunits of the NMDAR increased 3-4-fold over control values during SE, continued to increase during the first hour following SE and then declined to control levels by 24 h. SE resulted in the activation of Src and Pyk2 associated with the postsynaptic apparatus, suggesting a role for these enzymes in the SE-induced increase in tyrosine phosphorylation. Changes in phosphorylation of the NMDA receptor may play a role in the pathophysiological consequences of SE.
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PMID:Changes in phosphorylation of the NMDA receptor in the rat hippocampus induced by status epilepticus. 1574 56


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