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)

Phenytoin (diphenylhydantoin) inhibits the calcium-dependent increases in guanosine 3':5'-monophosphate (cGMP) produced by high potassium depolarization and by muscarinic receptor activation in N1E-115 neuroblastoma cells. The inhibition of the cGMP response to depolarization is half-maximal at 40 microM, similar to the plasma concentration associated with an optimal therapeutic response. The cGMP increase produced by the cationophore A23187 is insensitive to phenytoin blockade, indicating that the enzymatic machinery responsible for calcium-stimulated cGMP accumulation is not affected. The calcium concentration-response curve for the cGMP response to high potassium showed that phenytoin acted primarily to reduce the maximal response. The corresponding curve for the cGMP response to acetylcholine showed apparent competitive inhibition by phenytoin whereas the acetycholine concentration-response curve showed noncompetitive inhibition by phenytoin. The results suggest that phenytoin inhibits cGMP responses by blocking calcium influx. The ability to block the depolarization-induced cGMP response is shared by other anticonvulsants which are effective against generalized tonic-clonic and cortical focal seizures but not by those effective against absence seizures.
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PMID:Phenytoin inhibition of cyclic guanosine 3':5'-monophosphate (cGMP) accumulation in neuroblastoma cells by calcium channel blockade. 625 31

Barrel rotation is a motor response observed in rats in which the animal twists about its long axis and rolls laterally. This response was first described following intracerebroventricular injection of somatostatin. The pharmacologic specificity of the response has been questioned, and its physiologic basis is unknown. Recently, barrel rotation following intraventricular injection of quaternary chlorpromazine, chlorpromazine methiodide (CPZMI), has been reported. We have studied the specificity and pharmacologic basis of CPZMI-induced barrel rotation. The response was not induced by 26 compounds injected as controls, and was induced by 6 anti-muscarinic compounds. Dose-response relationships for onset, duration and magnitude of CPZMI-induced barrel rotation response were studied; number of rotations increased linearly with CPZMI dose up to 20 micrograms, after which number of rotations decreased and toxic effects (sedation, seizures) occurred. CPZMI barrel rotation was inhibited by intraventricular injection of the muscarinic agonist carbachol and enhanced by intraventricular or systemic atropine. Muscarinic and dopamine receptor studies indicated that CPZMI has high affinity for the muscarinic cholinergic receptor and low affinity for the spiperone binding site. Modified Scatchard analysis of CPZMI displacement of [3H]QNB at the muscarinic receptor is consistent with muscarinic antagonist properties. We conclude that CPZMI-induced barrel rotation has a specific pharmacologic basis, that of muscarinic cholinergic antagonism.
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PMID:Chlorpromazine methiodide-induced barrel rotation: an antimuscarinic effect. 713 12

Previous investigations have indicated that soman-induced convulsions involve the inositol lipid signalling system. We previously reported that 10 min after the onset of seizures, inositol 1,4,5-triphosphate (IP3) build-up was coupled to activation of non-muscarinic receptor subtypes. In the present study, we demonstrate that (1) in addition to muscarinic receptors, histamine H1 subtypes and glutamate metabotropic receptors contribute to the first IP3 increase (first 10 min of seizures) and (2) the histamine H1 subtype and glutamate metabotropic receptors are also involved in the second step of inositol phosphate response (after 10 min of seizures). alpha 1-adrenoceptor and 5-HT2 receptors, known to be coupled to phosphoinositide turnover, did not participate in soman-induced IP3 response. Neurochemical interactions between cholinergic, histamine H1 and glutamate metabotropic systems, responsible of the phosphoinositide hydrolysis under soman are envisaged.
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PMID:Involvement of non-muscarinic receptors in phosphoinositide signalling during soman-induced seizures. 762 3

We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pilocarpine-induced convulsions in rats: evidence for muscarinic receptor-mediated activation of locus coeruleus and norepinephrine release in cholinolytic seizure development. 768 35

Hippocampal levels of mRNA encoding nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are rapidly induced by enhanced neuronal activity following seizures and glutamate or muscarinic receptor activation. However, the levels of neurotrophin-3 (NT-3) mRNA acutely decrease after limbic seizures suggesting that a different mode of regulation may exist for these neurotrophins. Here we show that BDNF and neutrotrophin-4 (NT-4), but not NT-3 itself, up-regulate NT-3 mRNA in cultured hippocampal neurons. In the rat hippocampus, the muscarinic receptor agonist, pilocarpine increased BDNF mRNA levels rapidly and those of NT-3 with a delay of several hours. Injection of BDNF into neonatal rats elevated NT-3 mRNA in the hippocampus which demonstrates that BDNF is able to enhance NT-3 expression in vivo. The regulation of NT-3 by BDNF and NT-4 enlargens the neurotrophic spectrum of these neurotrophins to include neuron populations responsive primarily to NT-3.
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PMID:Brain-derived neurotrophic factor and neurotrophin-4 increase neurotrophin-3 expression in the rat hippocampus. 774 1

We have used the pilocarpine-induced seizure model in mice and i.c.v. injection of subtype-specific receptor antagonists to investigate the muscarinic receptor subtype specificity of cholinergically-activated seizures. The rank order potencies of antagonists for inhibition of pilocarpine-induced seizures are atropine = telenzepine > 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP) > pirenzepine with ID50's of 8.6, 12.0, 29.9, and 83.0 nmol/mouse, respectively. The M3-specific antagonists hexahydrosila-difenidol and its p-fluoro analog showed no effect on pilocarpine-induced seizures. The M2-specific antagonists gallamine and methoctramine cause seizures in mice in the absence of a pilocarpine injection. These seizures could be inhibited by coinjection of methoctramine with the M1-specific antagonist, pirenzepine. These data suggest a role of muscarinic M1 receptors in mediating pilocarpine-induced seizures and a role of the muscarinic M2 receptors in modulating neuronal activity.
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PMID:Assessment of the muscarinic receptor subtypes involved in pilocarpine-induced seizures in mice. 802 81

The present study was designed to determine the types of acetylcholine receptors involved in the initiation of epileptic seizures from the zona incerta and surrounding structures by cholinergic stimulation in rats. Unilateral intracerebral microinjection of the mixed muscarinic and nicotinic agonist carbachol (3 micrograms) produced generalized seizures in 12 of 20 rats studied. Local pretreatment with equimolar doses of acetylcholine receptor antagonists was used as a method of determining the receptor type involved in the initiation of cholinergically induced seizures in the rat diencephalon. Pretreatment with the M1 muscarinic receptor antagonist, pirenzepine (7 micrograms), abolished carbachol-induced seizures in 91% of the animals tested. The M2 muscarinic receptor antagonist, methoctramine (12 micrograms) and the nicotinic receptor antagonist, mecamylamine (3 micrograms), were relatively ineffective in antagonizing seizures in 9% and 27%, respectively. The results suggest that M1 muscarinic receptors are preferentially involved in the initiation of generalized epileptic seizures in the basal diencephalon of the rat.
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PMID:Involvement of M1 muscarinic receptors in the initiation of cholinergically induced epileptic seizures in the rat brain. 803 10

Wistar rats of a selected strain show spontaneous generalized non-convulsive seizures with bilateral synchronous spike-wave discharges on the cortical electroencephalograph (EEG). The 7 to 9 c/s spike-wave discharges occur predominantly in waking states of inactivity. The effects of cholinergic drugs on the cumulated duration of spike-wave discharges were investigated in this rat model of absence epilepsy. I.p. injections of drugs which potentiate cholinergic neurotransmission, namely the acetylcholinesterase inhibitor, physostigmine (0.1-0.5 mg/kg), the muscarinic receptor agonists, oxotremorine (0.25-1 mg/kg) and pilocarpine (0.125-2 mg/kg), and the nicotinic receptor agonist, nicotine (0.062-2 mg/kg), suppressed discharges in a dose-dependent manner and induced an arousal-like cortical EEG. The muscarinic receptor antagonist, scopolamine, increased the spike-wave discharges at doses below 0.05 mg/kg; at higher doses (0.05-1 mg/kg) it decreased discharges and induced a sleep-like EEG. The nicotinic receptor antagonist, mecamylamine (0.5-6 mg/kg), had no effect on spike-wave discharges or the EEG. These results suggest that cholinergic activity accounts for the preferential occurrence of absence seizures in states of reduced arousal.
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PMID:Effects of cholinergic drugs on genetic absence seizures in rats. 838 12

Pharmacological data have shown that the cholinergic transmission participates in the control of spike-and-wave discharges in rats with genetic absence epilepsy. The corticothalamic circuitry which generates spontaneous spike-and-wave discharges, the electroencephalographic expression of absence seizures, receives important cholinergic inputs from two distinct sources: (i) the nucleus basalis projecting mainly to the cortex and (ii) the pedunculopontine and laterodorsal tegmental nuclei providing cholinergic afferents to the thalamus. In the present study, the involvement of the cholinergic mesopontothalamic projections in the control of spike-and-wave discharges was investigated. Activation of cell bodies in the pedunculopontine and laterodorsal tegmental nuclei, by local microinjections of non-toxic doses of kainate (20 pmol/side) or picrotoxin (66 pmol/side), suppressed spike-and-wave discharges. Similar effects were produced by direct cholinergic activation of the ventrolateral part of the thalamus: intrathalamic microinjections of carbachol (0.7-2.8 pmol/side), a cholinergic receptor agonist, resulted in a dose-dependent suppression of spike-and-wave discharges. This suppression was partially reversed by a simultaneous microinjection of an equimolar dose of scopolamine, a muscarinic receptor antagonist. Electrolytic or neuroexcitotoxic lesions of the pedunculopontine and laterodorsal tegmental nuclei did not modify spike-and-wave discharges. These results suggest that the cholinergic mesopontine projection to the thalamus exerts a phasic inhibitory control of generalized non-convulsive epileptic seizures.
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PMID:Mesopontine cholinergic control over generalized non-convulsive seizures in a genetic model of absence epilepsy in the rat. 884 6

Sensitivity of brain muscarinic acetylcholine receptors to the agonists was examined in nicotine tolerant animals which were developed by acutely repeated injections of nicotine. In conscious rats, the dose-response curves of muscarinic agonists arecoline and pilocarpine, cholinesterase inhibitors soman and physostigmine rather than GABA receptor antagonist pentylenetetrazol or glycine receptor antagonist strychnine for producing EEG seizures were shifted leftwards by acutely repeated injections of nicotine. This phenomenon could be prevented by nicotinic antagonist mecamylamine. Similar results were obtained in acute nicotine tolerant mice and rabbits. In other experiments, the dose-response curve of arecoline-induced convulsions or oxotremorine-induced tremors was also shifted leftwards, and the durations of arecoline- and oxotremorine-induced tremors were prolonged in acute nicotine tolerant mice. In addition, the effects of arecoline for producing down-regulation of muscarinic receptors of rat cerebrum and hippocampus rather than brain stem were potentiated in acute nicotine tolerant rats. It is concluded that the sensitivity of brain muscarinic receptor to its agonists is increased in acute nicotine tolerant rats, mice and rabbits.
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PMID:Regulatory effects of acutely repeated nicotine treatment towards central muscarinic receptors. 889 Sep 20


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