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)

Increases in intraneuronal free calcium result in the rapid, transient, induction of the fos and jun proto-oncogenes. In PC12 cells, induction may be elicited either by membrane depolarization or by direct activation of voltage-dependent calcium channels with BAY K 8644 both of which provoke an influx of calcium. The calmodulin pathway appears to link the elevated intracellular calcium to gene induction. In the brain, c-fos and c-jun may be induced by elevated neuronal activity such as occurs during pentylenetetrazole (PTZ) seizures. The N-methyl-D-aspartate (NMDA) form of the glutamate receptor, which can directly gate calcium, plays a role in the induction of c-fos expression in PTZ seizures. In addition, NMDA can directly stimulate c-fos in the brain. Fos and Jun form a noncovalent nucleoprotein complex that binds to the consensus recognition sequence of the AP-1 transcription factor. Thus in a larger picture we envisage Fos and Jun as members of a concerted stimulus-transcription coupling pathway that links alterations in external stimuli to long term adaptive responses. In this context Fos, Jun and the other immediate-early genes should be viewed as third messengers which are regulated by second messengers such as intracellular calcium.
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PMID:Calcium as a modulator of the immediate-early gene cascade in neurons. 314 42

The metabolism of various metal ions and biogenic amines in El mice, an inbred mutant strain susceptible to epilepsy, was investigated as a possible model for seizure mechanism. Serum Na, P, Ca, Mg, Fe and Zn levels in El mice were lower than those in ddY mice, the mother strain of El mice. Conversely, bone Ca, P, Na, Mg and Zn levels in El mice were higher than those in ddY mice. The results obtained by chemical analysis are consistent with radiographic observations. Possible mechanisms for the lower serum metal ion levels seen in El mice include a decrease in availability of these ions from bone. The dopamine (DA) level in El mouse brain was 15% lower than in ddY mice but could be raised by intraventricular administration of CaCl2. This result was supported a decreased ethanol-induced sleeping time in El as compared to ddY mice, with 'normalization' occurring after intraventricular administration of Da or CaCl2. The biogenic amine levels disorder in El mice is discussed on the basis of our pharmacological observation that biogenic amine synthesis is regulated by divalent cations via a calmodulin-dependent system. Our results suggest that the disorders of metal ion metabolism could be a mechanism for epileptic convulsions in El mice.
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PMID:The relationship between metal ion levels and biogenic amine levels in epileptic mice. 367 12

Calmodulin is a major Ca2+ -binding protein that may mediate many Ca2+ -regulated processes in neuronal function. Calmodulin is present in the presynaptic nerve terminal in association with synaptic vesicles and in postsynaptic density fractions. Several calmodulin-regulated synaptic biochemical processes have been identified. These results indicate that calmodulin may modulate some aspects of neuronal excitability. Phenytoin, carbamazepine, and the benzodiazepines inhibit Ca2+ -calmodulin-regulated protein phosphorylation and neurotransmitter release by synaptic vesicles. A saturable, stereospecific membrane binding site has been identified for the benzodiazepines. The potency of the benzodiazepines to bind to these sites correlates with their ability to inhibit maximal electroshock-induced seizures. Phenytoin and carbamazepine can displace benzodiazepine binding from these binding sites. Binding to these "anticonvulsant" sites regulates Ca2+ -calmodulin-stimulated membrane protein phosphorylation and depolarization-dependent Ca2+ uptake in intact synaptosome preparations. These results provide evidence that major anticonvulsant drugs regulate Ca2+ -calmodulin systems at the synapse. Kindling alters Ca2+ -calmodulin protein phosphorylation in brain membrane. In addition, alterations in Ca2+ -calmodulin kinase systems have been associated with some strains of seizure-susceptible mice. Thus, evidence from multiple sources suggests that calmodulin-mediated processes may play a role in the development of altered neuronal excitability and in some forms of seizure disorders.
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PMID:Calmodulin systems in neuronal excitability: a molecular approach to epilepsy. 615 Jun 80

The phosphorylation of both particulate and soluble proteins in the amygdala was examined in electrically kindled rats. In animals receiving electrical stimulation in the left amygdala for 5-6 days that displayed electrical after-discharges but no motor seizures, no changes were observed in the phosphorylation of either particulate or soluble proteins. In animals stimulated for 20-21 days where major motor seizures were produced, the phosphorylation of a protein having a molecular weight of 45,000 ( 45K ) was markedly increased. The phosphorylation of this protein was increased in both the right (unstimulated) and left (stimulated) amygdala. Major motor seizures induced by electroconvulsive shocks, however, did not alter phosphorylation of this protein. Phosphorylation of the 45K protein was stimulated by calcium and calmodulin. The 45K protein is a major phosphoprotein of amygdala, representing 3.2% of the total particulate phosphoproteins in control animals and 7.4% in the kindled animals. In the presence of calcium-calmodulin, 16.2% of net protein phosphorylation was accounted for by the 45K protein.
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PMID:Increased phosphorylation of a membrane protein consequent to amygdaloid kindling. 672 44

The anticonvulsant activity of calmodulin antagonist W-7, was investigated on convulsions induced in mice by the insecticide lindane and by the calcium channel agonist BayK-8644. We also studied the inhibitory effect of W-7 on on c-fos mRNA expression induced by both convulsants. We observed a good correlation between doses and the acute convulsive effects of lindane and BayK-8644. The incidence rate and time to onset were clearly dose-dependent. W-7 antagonized the convulsive effects of lindane and BayK-8644 in all the parameters studied. A significant decrease in the incidence rate and time to onset were observed when they are compared with the values obtained with the ED100 of lindane- and BayK-8644 induced seizures. Both were able to activate the mRNA expression of the proto-oncogene. The pattern of this expression displayed by in situ hybridization was very similar. A dramatic increase was found in dentate gyrus and high levels of mRNA expression also occurring in hippocampal fields and cortical regions. In accordance with the behavioural results, W-7 antagonized also the c-fos expression induced by lindane and BayK-8644. Our results suggest that lindane as BayK-8644 may activate voltage-dependent calcium channels leading to calmodulin activation.
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PMID:Anticonvulsant activity of calmodulin antagonist W-7 in convulsions induced by lindane and BayK-8644: effects in c-fos expression. 753 29

We planned to ascertain whether the administration of the anticholinesterase, tacrine (5 mg/kg i.p.), to rats pretreated 24 h before with lithium chloride (LiCl; 12 mEq/kg i.p.) produced any change in nitric oxide (NO) synthase activity in the hippocampus. A significant increase in hippocampal Ca(2+)-calmodulin-dependent NO synthase activity occurred 15 min after tacrine injection and was blocked by atropine (5 mg/kg i.p. given 15 min before tacrine) and by N omega-nitro-L-arginine methyl ester (300 micrograms given into one lateral cerebral ventricle 10 min before tacrine), a NO synthase inhibitor. A consistent cyclic guanosine 3',5'-monophosphate (cGMP) accumulation was also seen. In conclusion, the present results show that tacrine given to LiCl-pretreated rats produces a significant increase in NO synthase activity in the hippocampus and this may be responsible, at least in part, for seizures and related brain damage elicited by these drugs.
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PMID:Systemic administration of lithium chloride and tacrine increases nitric oxide synthase activity in the hippocampus of rats. 768 71

The anticonvulsant activity of delta-HCH and of a calmodulin antagonist, W-7 were investigated on convulsions induced in mice by lindane (ED100 100 mg/kg), by GABAergic antagonists PTZ (ED100 60 mg/kg) and PTX(ED100 4 mg/kg), by calcium channel agonist BAY-K-8644 (ED100 5 mg/kg), by two agonists of excitatory amino acid receptors, kainic acid (ED100 80 mg/kg) and NMDA (ED100 160 mg/kg and by the atypical benzodiazepine Ro 5-4864 (ED100 40 mg/kg). The anticonvulsant activity of a voltage-dependent calcium channel antagonist, nifedipine was also investigated on convulsions induced by Ro 5-4864, BAY-K-8644, kainic acid and NMDA. delta-HCH antagonized lindane- and BAY-K-8644-induced convulsions (ED50 231 (172-309) mg/kg and 148 (142-154) mg/kg, respectively) and at concentrations up to 300 mg/kg failed to antagonize Ro 5-4864, kainic acid and NMDA convulsions. In contrast delta-HCH potentiated PTX-induced seizures. Nifedipine antagonized BAY-K-8644- and kainic acid-induced convulsions (ED50 6.5 (4.3-9.7) mg/kg and 30 (13-70) mg/kg but at concentrations up to 20 mg/kg failed to antagonize Ro 5-4864 and 25% of protection was observed on NMDA-induced convulsions at the highest dose (20 mg/kg). The ED50 of W-7 to antagonize convulsions induced by lindane and BAY-K-8644 were 12 (8-19) mg/kg and 49 (29-85) mg/kg, respectively. Some anticonvulsant effect was observed against PTZ and NMDA but without any dose-dependent anticonvulsant activity. W-7 did not protect against PTX and kainic acid convulsions and 30% of protection was observed against convulsions at the highest dose of W-7 (75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant activity of delta-HCH, calcium channel blockers and calmodulin antagonists in seizures induced by lindane and other convulsant drugs. 769 69

A possible relationship among cyanide-induced convulsions, calmodulin, nitric oxide and protein kinase C was investigated in mice. The ED50 value of cyanide as measured by induction of tonic seizures was significantly increased in a dose-dependent manner when mercuric chloride (0.5 or 5.0 nmol/body), gangliosides (GGS) (90 nmol/body), a protein kinase C inhibitor or trifluoperazine (TFP) (45 or 90 nmol/body), a calmodulin inhibitor were preinjected intracerebroventricularly (i.v.t.) and NG-nitro-L-arginine (NNA) (300 mg/kg), a nitric oxide (NO) synthase inhibitor was preinjected intraperitoneally (i.p.) in mice. These results suggest that protein kinase C, calmodulin, and NO dependent cyclic guanosine monophosphate (GMP) dependent enzymes may contribute to the induction of convulsions. In contrast, 2,4-dinitrophenol (DNP) (50 nmol/body, intracerebroventricularly (i.v.t.), an uncoupler of oxidative phosphorylation significantly decreased the ED50 value of cyanide. In addition, DNP (100 nmol/body, i.v.t.) produced a severe tonic seizure in all of the treated mice. These indicate that adenosine triphosphate (ATP) depletion may also contribute in part to the development of cyanide-induced convulsions.
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PMID:A hypothesis for cyanide-induced tonic seizures with supporting evidence. 782 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

Activity-mediated gene expression is thought to play an important role in many forms of neuronal plasticities. We have used pentylenetetrazol-induced seizure that produces synchronous and sustained neuronal activity as a model to examine the mechanism(s) of gene activation. The transcription factor CREB (Ca2+/cAMP response element-binding protein) is thought to be necessary for long-term memory formation both in invertebrates and vertebrates. When phosphorylated on Ser133 either by cAMP-dependent protein kinase and/or Ca2+/calmodulin-dependent protein kinases, CREB increases transcription of genes containing the CRE (cAMP response element) sequence. Using an antibody that detects Ser133-phosphorylated CREB protein, we show that CREB phosphorylation is maximal between 3 and 8 min after the onset of seizure activity and declines slowly both in the hippocampus and the cortex. The total amount of CREB protein did not change at the time points examined. The increased phosphorylation of CREB protein is preceded by an increase in the amount of cAMP, suggestive of cAMP-dependent protein kinase activation, in the hippocampus and activation of Ca2+/calmodulin-dependent protein kinases in the cortex. Subsequent to CREB phosphorylation, the expression of the CRE-containing gene, c-fos, and the AP-1 complexes (heterodimers of Fos and Jun family members) is increased. These findings support the role of CREB-mediated gene expression in activity-dependent neuronal plasticities.
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PMID:Neuronal activity increases the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in rat hippocampus and cortex. 866 77


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