Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of seizures on phosphoinositide hydrolysis and protein kinase C activity was measured in rat hippocampus and cerebral cortex, primarily using a model in which generalized convulsive status epilepticus was induced by administration of LiCl (3 mmole/kg) 20 hr prior to pilocarpine (30 mg/kg). A short (5 min) period of seizures reduced phosphoinositide hydrolysis in hippocampal slices stimulated by norepinephrine or ibotenate, but did not alter the responses to carbachol, 50 mM K+, or NaF. Induction of seizures with diisopropylfluorophosphate caused a similar reduction in the response to norepinephrine without altering carbachol-stimulated phosphoinositide hydrolysis. The inhibition of norepinephrine-stimulated phosphoinositide hydrolysis after seizures generated by lithium plus pilocarpine administration was apparently not due to inhibitory influences of quisqualate or activation of protein kinase C since both of these treatments caused similar inhibitions in slices from control and treated rats. Seizures induced by lithium plus pilocarpine or by kainate did not alter the activity of protein kinase C or the distribution of protein kinase C between membrane and cytosolic fractions. Thus, seizures cause a neurotransmitter-selective impairment of phosphoinositide hydrolysis, and this response may play a role in the severity or duration of seizure activity.
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PMID:Seizures selectively impair agonist-stimulated phosphoinositide hydrolysis without affecting protein kinase C activity in rat brain. 133 19

At 4 h during pilocarpine-induced status epilepticus (DPISE) in rat, protein kinase C (PKC)beta1, PKCbeta2, and PKCgamma were induced at the border between the stratum oriens and alveus (O/A border) of CA1 in the hippocampus. Induced PKCgamma was colocalized with metabotropic glutamate receptor alpha (mGluR alpha). By intracerebroventricular injection of mGluR1alpha antagonists, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), PKCbeta1, PKCbeta2, and PKCgamma immunoreactive products decreased dramatically; however, intracerebroventricular injection of saline did not change the expression of PKCbeta1, PKCbeta2, and PKCgamma, suggesting that these three PKC isoforms might be involved in mGluR1alpha-related excitoneurotoxicity. One day after pilocarpine-induced status epilepticus (APISE), PKCdelta was induced in microglial cells. At this time point, both PKCgamma and PKCepsilon immunopositive products decreased in the inner molecular layer of upper blade of the stratum granulosum. At 7-31 days APISE, induced PKCbeta1, PKCdelta, PKCeta, and PKCzeta positive astrocytes were demonstrated in all parts of hippocampus, suggesting that they may be involved in gliosis. By this time, both PKCgamma and PKCepsilon immunopositive products in the inner molecular layer had almost disappeared, suggesting that they may be involved in the inhibition of granule cells by controlling neurotransmitter release presynaptically in the dentate gyrus of normal rats.
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PMID:Expression of different isoforms of protein kinase C in the rat hippocampus after pilocarpine-induced status epilepticus with special reference to CA1 area and the dentate gyrus. 1505 86

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

Altered function of gamma-aminobutyric acid type A receptors (GABA(A)Rs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABA(A)R subunits, including alpha4, and may play a role in epileptogenesis. The majority of GABA(A)Rs that contain alpha4 subunits are extra-synaptic due to lack of the gamma2 subunit and presence of delta. However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of alpha4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant alpha4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition.
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PMID:Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor alpha 4 subunits in hippocampal neurons. 1690 9

The unbalanced excitatory/inhibitory neurotransmitter function in the neuronal network afflicted by seizures is the main biochemical and biophysical hallmark of epilepsy. The aim of this work was to identify changes in the signaling mechanisms associated with neuropeptide Y (NPY)-mediated inhibition of glutamate release that may contribute to hyperexcitability. Using isolated rat hippocampal nerve terminals, we showed that the KCl-evoked glutamate release is inhibited by NPY Y2 receptor activation and is potentiated by the stimulation of protein kinase C (PKC). Moreover, we observed that immediately after status epilepticus (6 h postinjection with kainate, 10 mg/kg), the functional inhibition of glutamate release by NPY Y2 receptors was transiently blocked concomitantly with PKC hyperactivation. The pharmacological blockade of seizure-activated PKC revealed again the Y2 receptor-mediated inhibition of glutamate release. The functional activity of PKC immediately after status epilepticus was assessed by evaluating phosphorylation of the AMPA receptor subunit GluR1 (Ser-831), a substrate for PKC. Moreover, NPY-stimulated [35S]GTPgammaS autoradiographic binding studies indicated that the common target for Y2 receptor and PKC on the inhibition/potentiation of glutamate release was located downstream of the Y2 receptor, or its interacting G-protein, and involves voltage-gated calcium channels.
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PMID:Protein kinase C activity blocks neuropeptide Y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus. 1716 71

Status epilepticus (SE) is a progressive and often lethal human disorder characterized by continuous or rapidly repeating seizures. Of major significance in the pathology of SE are deficits in the functional expression of GABA(A) receptors (GABA(A)Rs), the major sites of fast synaptic inhibition in the brain. We demonstrate that SE selectively decreases the phosphorylation of GABA(A)Rs on serine residues 408/9 (S408/9) in the beta3 subunit by intimately associated protein kinase C isoforms. Dephosphorylation of S408/9 unmasks a basic patch-binding motif for the clathrin adaptor AP2, enhancing the endocytosis of selected GABA(A)R subtypes from the plasma membrane during SE. In agreement with this, enhancing S408/9 phosphorylation or selectively blocking the binding of the beta3 subunit to AP2 increased GABA(A)R cell surface expression levels and restored the efficacy of synaptic inhibition in SE. Thus, enhancing phosphorylation of GABA(A)Rs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE.
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PMID:Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. 1818 80

There is evidence suggesting that protein kinase C (PKC) activation can prevent the enhanced network excitability associated with status epilepticus and group I metabotropic glutamate receptor (mGluR)-induced epileptogenesis. However, we observed no suppression of mGluR-induced burst prolongation in the guinea pig hippocampal slice when applied in the presence of the PKC activator phorbol-12,13-dibutyrate (PDBu). Furthermore, PDBu alone converted picrotoxin-induced interictal bursts into ictal-length discharges ranging from 2 to 6s in length. This effect could not be elicited by the inactive analog 4-alpha-PDBu and was suppressed with the PKC inhibitor chelerythrine, indicating PKC dependence. PKC activation can enhance neurotransmitter release, and both glutamate and acetylcholine are capable of eliciting similar prolonged synchronized discharges. However, neither mGluR1 nor NMDA receptor antagonist suppressed PDBu-driven burst prolongation, suggesting that increased glutamate release alone is unlikely to account for the PKC-induced expression of ictaform discharges. Similarly, atropine, a broad-spectrum muscarinic receptor antagonist, had no effect on PKC-induced burst prolongation. By contrast, AMPA/kainate receptor antagonist abolished PKC-induced burst prolongation, and mGluR5 antagonist significantly blunted the maximum burst length induced by PKC. These data suggest that PKC-induced prolongation of epileptiform bursts is dependent on changes specific to mGluR5 and AMPA/kainate receptors and not mediated simply by a generalized increase in transmitter release.
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PMID:Impact of protein kinase C activation on epileptiform activity in the hippocampal slice. 1871 54

While it is generally accepted that phospholipase C (PLC) and protein kinase C (PKC) are down-stream proteins involved in metabotropic glutamate receptor 5 (mGluR5)-related signal transduction, we still do not know which subtype of PLC or PKC is specifically regulated after mGluR5 activation. In the present study in mGluR5 wild-type (mGluR5+/+) mice, we showed induced PKCbeta2 or PKCgamma expression at the border between the stratum oriens and alveus (O/A border) at 2h during pilocarpine induced status epilepticus (SE), and in the stratum pyramidale in CA1 area at 1 day after pilocarpine induced SE; at 1 day, induced expression of PLCbeta4 in the stratum pyramidale of CA1 area was observed. Furthermore, double labeling revealed the co-localization of induced PKCbeta2 or PKCgamma with mGluR5 or with induced PLCbeta4 in the stratum pyramidale of CA1 area. These induced expression, however, were not found in mGluR5 mutant (mGluR5-/-) mice. It suggests that induced PLCbeta4-PKCbeta2/PKCgamma at 1 day after pilocarpine induced SE in pyramidal neurons or PKCbeta2 or PKCgamma in interneurons at O/A border at 2h during pilocarpine induced SE may be specifically linked to the activation of mGluR5. When compared to mGluR5+/+ mice, significant shorter latency (from pilocarpine injection to the occurrence of status epilepticus) and maintenance period (from beginning to the end of status epilepticus) for status epilepticus in mGluR5-/- mice were also demonstrated. It is possible that mGluR5 may play a negative role in initiation of status epilepticus by interacting with muscarinic acetylcholine receptor in mGluR5+/+ mice.
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PMID:mGluR5-PLCbeta4-PKCbeta2/PKCgamma pathways in hippocampal CA1 pyramidal neurons in pilocarpine model of status epilepticus in mGluR5+/+ mice. 1877 62

We investigated the protein expression of different protein kinase C (PKC) isoforms (PKC-alpha, PKC-beta1, PKC-beta2, PKC-gamma, PKC-delta, PKC-epsilon, PKC-eta and PKC-zeta) in the hippocampus of normal control mice and progressive changes in PKC isoforms expression during and after pilocarpine induced status epilepticus (PISE). We showed the reduced expression of PKC-delta, PKC-eta and PKC-zeta in interneurons in the CA1 area and in the hilus of the dentate gyrus during or after PISE. Increased expression of PKC-alpha and PKC-beta1 was demonstrated in the stratum pyramidale of CA3 area, and PKC-epsilon was up-regulated in the stratum lucidum of the CA3 area during or after PISE. Our results suggest that hippocampal PKC isoforms may play different roles in seizure generation, and be targets for development of anti-convulsive drugs.
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PMID:Pilocarpine-induced status epilepticus alters hippocampal PKC expression in mice. 2173 Oct 76

There is a growing concern about the effects of chemicals on the developing nervous system. Chemical exposure at critical periods of development can be associated with effects ranging from subtle to profound on the structure and/or function of the nervous system. Understanding critical biological molecular targets, which underlie chemical-induced neurotoxicity, will provide a scientific basis for risk assessment. Cell signaling molecules such as protein kinase C (PKC) have been shown to play critical roles in motor activity, development of the nervous system, and in learning and memory. PKC also has been shown to be associated with several neurological disorders including Alzheimer's disease, status epilepticus, and cerebellar ataxia. In the literature, there is abundant information linking PKC to cognitive function, long-term potentiation, or brain structural changes. Here, we show the relationship between changes in PKC (as assayed using radioactive material or by western blots) and the neurotoxic effects caused by environmental chemicals in vitro and in vivo.
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PMID:Cell signaling and neurotoxicity: protein kinase C in vitro and in vivo. 2181 75


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