Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anticonvulsant, trimethadione (TMO), was tested for effects on cholinergic responses to iontophoretic application of ACh on identified neurons in Aplysia. TMO (1--10 mM) depressed the amplitudes of depolarizing responses mediated by Na+ and hyperpolarizing responses mediated by Cl- but did not affect hyperpolarizing responses mediated by K+. Such a combination of effects on cholinergic responses distinguishes the action of this anti-absence drug from agents effective against tonic-clonic seizures and from convulsive drugs.
 ...
PMID:Trimethadione effects on cholinergic responses in Aplysia neurons. 626 Mar 3

Glutamate has traditionally been regarded as an excitatory neurotransmitter. Synaptic activation of ionotropic glutamate receptors mediates fast EPSPs in the CNS. Moreover, activation of metabotropic glutamate receptors (mGluRs), which are coupled to second messenger effector systems via GTP-binding proteins (G-proteins), results in the expression of slow EPSPs. We have now examined the response of basolateral amygdala (BLA) neurons to activation of postsynaptic mGluRs. In approximately 78% of BLA neurons examined, activation of postsynaptic mGluRs results in membrane hyperpolarization and an associated decrease in membrane input resistance or a hyperpolarization followed by a depolarization associated with an increase in input resistance. The purpose of this study was to address the mechanisms underlying the membrane hyperpolarization. Here, we report that the ACPD-induced hyperpolarization is insensitive to TTX, is dependent on extracellular K+ concentrations, and has a reversal potential (-84 mV) close to that estimated from the Nernst equation for an increase in a K+ conductance. In addition, the ACPD response is resistant to (1) intracellular chloride loading, (2) the GABAB receptor antagonist CGP55845A, (3) the ACh receptor antagonist atropine, and (4) the ionotropic glutamate receptor antagonists CNQX and APV. These data suggest that the hyperpolarization results from a direct activation of postsynaptic mGluRs on neurons of the BLA. Furthermore, we performed studies that suggest that the hyperpolarization is G-protein mediated and results from activation of a TEA-sensitive, calcium-dependent potassium conductance. The sensitivity of this conductance to thapsigargin further suggests that this response requires the release of calcium from intracellular stores. In summary, these data suggest a role for glutamate as an inhibitory transmitter in the BLA during periods of metabotropic glutamate receptor activation. In nuclei such as the BLA that are exquisitely sensitive to seizure induction, an inhibitory response to glutamate may act to delay the onset of epileptogenesis.
 ...
PMID:Activation of postsynaptic metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurons of the basolateral amygdala. 796 9

Intracerebral-ventricular (icv) injection of 4-aminopyridine (4-AP) 8 micrograms to rabbits generated convulsions and epileptic discharges in electrocorticogram (ECoG). With 40 rabbits, the occurrence of convulsion at this dose level was 100%. The results from five rabbits showed that seizures may break out repeatedly at intervals of 1-5 min and such state may last about 1.5 h. Antiepileptic drugs, such as phenytoin sodium, phenobarbital sodium and diazepam, were found to effectively control the seizures provoked by icv 4-AP. Sodium valproate was less effective than the foregoing drugs. The icv 4-AP-induced convulsion appeared to have some merits as compared with the old epilepsy models, such as those induced by electric stimulation, cardiazol, or icv ferrous sulfate. We feel that it may be recommended as a model for the preliminary screening of antiepileptic drugs. The seizures provoked by icv 4-AP were shown to be antagonized by scopolamine, haloperidol, phentolamine, or propranolol, but potentiated by l-dopa. It is now recognized that 4-AP can enhance the release of ACh, DA, and NE in the central nervous system. The present results suggest that the convulsion elicited by 4-AP seems to be related to the disturbance of synaptic transmission in the brain.
 ...
PMID:[Intracerebral-ventricular injection of 4-aminopyridine induced convulsion in rabbits]. 800 96

Restriction fragment length polymorphisms (rflps) have been identified for the nicotinic ACh receptor subunit genes alpha 5 and alpha 7 between two mouse strains (C3H/2ibg and DBA/2ibg) that differ in sensitivity to the convulsant effects of nicotine. In the study reported here, F2 animals derived from these two parental stains were tested for their sensitivity to the convulsant effects of nicotine as measured by seizure frequency and overall sensitivity score. Subsequently, the animals were genotyped for the alpha 5 and alpha 7 rflps. In addition, levels of alpha-bungarotoxin (alpha-BTX) binding were measured in four brain regions (colliculi, hippocampus, hypothalamus and striatum) to determine whether there is a correlation among alpha-BTX binding levels, sensitivity to nicotine and nicotinic ACh receptor subunit genotype. A significant relationship was observed between alpha 5 and alpha 7 genotype and sensitivity to nicotine. In addition, the alpha 7 rflp significantly correlated with levels of alpha-BTX binding in hippocampus, colliculi and striatum. The alpha 5 rflp did not correlate with alpha-BTX binding levels in any brain region. Levels of alpha-BTX binding did not correlate with nicotine-induced seizure sensitivity or overall nicotine sensitivity score in any of the four brain regions examined.
 ...
PMID:Sensitivity to the seizure-inducing effects of nicotine is associated with strain-specific variants of the alpha 5 and alpha 7 nicotinic receptor subunit genes. 949 72

1. We constructed rat homologues (S252F and +L264) of two human alpha4 nicotinic mutations - alpha4(S248F) and alpha4(777ins3) - that have been linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and co-expressed them with wild-type rat beta2 subunits in Xenopus oocytes. 2. The S252F and +L264 mutations had three common effects on the ACh response. First, they caused use-dependent potentiation of the response during a train of brief 100 nM ACh pulses. Second, they delayed the rise times of the 5-15 nM (+L264) and 30 nM (S252F) ACh responses. Third, they reduced extracellular Ca2+-induced increases in the 30 microM ACh response. 3. Beside these shared effects, the S252F mutation also reduced the channel burst duration measured from voltage-jump relaxations, enhanced steady-state desensitization and reduced the single-channel conductance. In contrast, the +L264 mutation prolonged the channel burst duration, did not affect desensitization and slightly increased single-channel conductance. Neither mutation affected the number of surface receptors measured by antibody binding but the S252F mutation reduced the maximum ACh response. 4. The ACh concentration dependence of use-dependent potentiation and the delay in the rising phase of the mutant ACh response suggest that these effects are caused by a slow unblocking of the closed mutant receptors. Use-dependent potentiation of the mutant response during a series of high-frequency cholinergic inputs to the presynaptic terminal could trigger ADNFLE seizures by suddenly increasing nicotinic-mediated transmitter release.
 ...
PMID:Two mutations linked to nocturnal frontal lobe epilepsy cause use-dependent potentiation of the nicotinic ACh response. 982 8

We tested the effects of the acetylcholinesterase inhibitor eserine (10 microM), an indicator of the activity of endogenous ACh, on the generation of epileptiform discharges during blockade of inhibitory GABA(A)-mediated potentials by bicuculline (10 microM), in the CA3 area of hippocampal slices from postnatal days 4-20 (P4-P20) immature and adult rats. Eserine provoked or significantly increased the frequency of spontaneous synchronous epileptiform discharges, in 6/22 (27%) P4-P10 slices, 34/35 P11-P20 slices and 18/18 adult slices, an epileptogenic effect. In immature slices, spontaneous discharges showed a stable frequency throughout perfusion with eserine, while in 5/11 adult slices an initial fast frequency was followed by a slower steady-state one. The cholinergic agonist carbachol (CCh, 25 microM) provoked only transient or no spontaneous synchronous discharges in adult slices (n=8), thus suggesting that massive activation of cholinergic receptors may lead to suppression of epileptiform activity in adult brain. Stimulus-induced excitatory CA3 responses, were depressed by eserine in approximately half of 20 P4-P10, 45 P11-P20 and 11 adult slices. The depression consisted of a decrease in the amplitude, duration, and number of population spikes of the field potentials by about 30%, a minor neuroprotective effect, which did not change with maturation. The different developmental profiles of the epileptogenic and neuroprotective effects of endogenous ACh suggest that they are mediated by different mechanisms. These experiments demonstrate that, endogenous ACh is sufficient to induce epileptogenesis during a decrease or failure of GABAergic inhibition, in both >/=P10 immature and in adult hippocampus. We therefore suggest that clinical or behavioral conditions which raise the concentration of endogenous ACh may lower the threshold to seizures.
 ...
PMID:Epileptiform activity generated by endogenous acetylcholine during blockade of GABAergic inhibition in immature and adult rat hippocampus. 1041 85

Acetylcholine functions as a neuromodulator in the mammalian brain by binding to specific receptors and thus bringing about profound changes in neuronal excitability. Activation of muscarinic receptors often results in an increased excitability of cortical cells. It is, however, unknown whether such an action is present in the subiculum, a limbic structure that may be involved in cognitive processes as well as in seizure propagation. Most rat subicular neurons are endowed of intrinsic membrane properties that make them fire action potential bursts. Using intracellular recordings from these bursting cells in a slice preparation, we report here that application of the cholinergic agonist carbachol (CCh, 30-100 microM) to medium containing ionotropic excitatory amino acid receptor antagonists reduces burst-afterhyperpolarizations (burst-AHPs) and discloses depolarizing plateau potentials that outlast the triggering current pulses by 140-2,800 ms. These plateau potentials appear with CCh concentrations >50 microM and are dependent on the resting membrane potential and on the intensity/duration of the triggering pulse; are recorded during application of tetrodotoxin (1 microM, n = 5 neurons); but are markedly reduced by replacing 82% of extracellular Na(+) with equimolar choline (n = 6). Plateau potentials also are abolished by Co(2+) (2 mM; n = 5) or Cd(2+) (1 mM; n = 2) application and by recording with electrodes containing the Ca(2+) chelator bis(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (0.2 M; n = 6). CCh-induced burst-AHP reduction and plateau potentials are reversed by the muscarinic antagonist atropine (0.5 microM, n = 7). In conclusion, our findings demonstrate a powerful muscarinic modulation of the intrinsic excitability of subicular bursting cells that is predominated by the appearance of plateau potentials. These changes in excitability may contribute to physiological processes such as learning or memory and play a role in the generation of epileptiform depolarizations. We propose that, as in other limbic structures, muscarinic plateau potentials in the subiculum are mainly due to a Ca(2+)-dependent nonselective cationic conductance.
 ...
PMID:Muscarinic receptor activation induces depolarizing plateau potentials in bursting neurons of the rat subiculum. 1056 29

Generalized tonic-clonic convulsions were induced on 2 consecutive days by pentylenetetrazol (PTZ) in immature rats (postnatal days 10 and 20), and hippocampal slices were prepared at different intervals post-injection. The anticholinesterase eserine provoked interictal-like discharges in the CA3 area of PTZ-injected rats (19/33), but not in controls (0/15), an effect mimicked by carbachol and reversed by atropine. This enhanced response to eserine was recorded in slices from 25-100% of the PTZ-injected rats, the percentage varying with the age at injection and post-injection interval. These results suggest that seizures in immature brain may have long-term consequences in cholinergic neurotransmission, converting a rise in endogenous ACh into an epileptogenic stimulus, which in turn would presumably facilitate the recurrence of seizures.
 ...
PMID:Immature rat convulsions and long-term effects on hippocampal cholinergic neurotransmission. 1071 7

N-tert-butyl-alpha-phenylnitrone (PBN), a widely used nitrone-based free radical trap was recently shown to prevent acetylcholinesterase (AChE) inhibitors induced muscle fasciculations and brain seizures while being ineffective against glutamergic or cholinergic receptor agonist induced seizures. In the present study we compared the effects on AChE activity of four free radical spin traps PBN, alpha-(4-pyridil-1)-N-tert-butyl nitrone (POBN), N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO). The kinetics of AChE inhibition were studied in vitro using a spectrophotometric kinetic assay with AChE from rat brain, diaphragm, electric eel and mouse brain. Spin trapping compounds S-PBN and DEPMPO, in concentrations up to 3 mM did not inhibit hydrolysis of ACh, while PBN and POBN inhibited hydrolysis of ACh in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ACh concentrations at each inhibitor concentration were linear and generally indicated mixed type inhibition. PBN was the most potent inhibitor of mouse AChE with Ki and Ki' of 0.58 and 2.99 mM, respectively, and the weakest inhibitor of electric eel AChE. In contrast, POBN showed the highest affinity for electric eel enzyme, with Ki and Ki' values of 1.065 and 3.15 mM, respectively. These findings suggest that the effect of PBN and POBN on AChE activity does not depend on trapping of damaging reactive oxygen and that in addition to their antioxidant action other pharmacological effects of these compounds should be considered when neuroprotective actions of PBN or POBN are investigated.
 ...
PMID:Atypical effect of some spin trapping agents: reversible inhibition of acetylcholinesterase. 1071 41

Specific defects in neuronal ion channel proteins have recently been identified in some forms of hereditary epilepsy. A deletion of 300 amino acids from the COOH terminal of the K+ channel reduces the electrical stability of the neuron in subjects with benign familial neonatal seizures. Defects in the protein subunits of the Na+ channel may prolong neuronal depolarization in children with generalized epilepsy with febrile convulsions. A point mutation in one of the ACh receptor subunits may reduce the function of inhibitory interneurons in subjects with autosomal dominant nocturnal frontal lobe epilepsy. Finally, several different defects in the Ca2+ channel amino acid sequence have been identified in various types of epilepsy in mice in which symptoms and EEG show similarities to those in human petit mal. This remarkable progress in the precise localization of ion channel defects in epilepsy provides a novel basis for the development of more differentiated diagnosis and pharmacological therapy.
 ...
PMID:[Molecular defects may cause epilepsy. New discoveries can provide better possibilities for directional diagnostics and treatment]. 1111 87


<< Previous 1 2 3 4 Next >>