UMLS:C0036572 - FACTA Search

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)

It has been hypothesized that the Long-Sleep and Short-Sleep mouse lines were bidirectionally selected for high and low brain excitability, and further, that these differences are mediated by the benzodiazepine/gamma-aminobutyric acid (GABA) receptor-chloride channel complex. Hence, mice from both lines were administered seven convulsants (bicuculline, pentylenetetrazol, 3-carbomethoxy-beta-carboline, picrotoxin, caffeine, flurothyl and strychnine) and myoclonic and clonic seizure latencies recorded. Supporting the original hypothesis, the results show that the two lines were differentiated by all of the convulsants and that in response to the drugs, three distinct convulsive patterns were found. Nevertheless, a simple genetic model accounting for these results was not evident. To further clarify these susceptibility patterns, a convulsant representing each of these patterns (bicuculline, pentylenetetrazol or caffeine) was administered in conjunction with the anticonvulsant-barbiturate phenobarbital or the benzodiazepine antagonist Ro 15-1788. Irrespective of the convulsant given, phenobarbital attenuated both myoclonus and clonus subsequent to all convulsants, while Ro 15-1788 had a more discrete anticonvulsant profile.
...
PMID:Patterns of convulsive susceptibility in the long-sleep and short-sleep selected mouse lines. 250 42

The behavioral and biochemical effects of ethanol in man and animals have been investigated for a long time. A role of catecholamines in the central stimulatory action and during withdrawal has been envisaged, but more recent observations have revealed the involvement of inhibitory synaptic transmitter, GABA, in the actions of ethanol. Ethanol-induced motor incoordination, hypnosedation, antianxiety, and anticonvulsant actions are reported to be GABA-mediated. Involvement of the GABA system has been implicated in ethanol withdrawal-induced seizures in animals. More direct evidences using Cl- influx studies in synaptoneurosomes and spinal neuronal culture studies confirm such a mode of action of ethanol, probably influencing the chloride channel modulation at the GABA-benzodiazepine receptor ionophore complex. RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-Oxo-4H-imidazo [1,5-alpha], [1,4] benzodiazepine-3-carboxylate), a novel imidazobenzodiazepine, an analogue of the classical benzodiazepine antagonist is reported to possess alcohol antagonistic properties. RO15-4513 reverses both the behavioral and biochemical effects of ethanol, including the action of GABA-induced Cl- fluxes. But its potential clinical application may be restricted due to its inverse agonistic property. The present review focuses on the GABA-linked behavioral and biochemical actions of ethanol and discusses the potential of RO15-4513 as an alcohol antagonist.
...
PMID:Molecular interactions of ethanol with GABAergic system and potential of RO15-4513 as an ethanol antagonist. 284 47

Recent findings suggest that steroids with sedative-hypnotic properties interact specifically with the gamma-aminobutyric acidA/benzodiazepine receptor-chloride ionophore complex (GBRC). They show positive heterotropic cooperativity by allosterically enhancing the binding of GABA agonists and the clinically useful benzodiazepines (BZs) to their respective recognition sites. These steroids have stringent structural requirements for activity at the GBRC, with the essential requirements for high potency being a 3 alpha-hydroxyl group and a 5 alpha-reduced A-ring. Some of these steroids are naturally occurring metabolites of progesterone and deoxycorticosterone and have nanomolar potencies as potentiators of chloride channel conductance. These 3 alpha-hydroxylated, 5 alpha-reduced steroids do not act through any known sites on the GBRC. Thus, the exact site and mechanism of action remain to be determined. Together with the observation that physiological levels of these metabolites are sufficient to influence the function of the GBRC, the evidence clearly suggests a role for these steroids in the normal regulation of brain excitability by potentiating the postsynaptic effects of gamma-aminobutyric acid (GABA). Pharmacological studies of the GBRC-active steroids show that they possess anxiolytic and anticonvulsant activities. The potential therapeutic application of these steroids in the treatment of mood disorders and catamenial exacerbation of seizures associated with the menstrual cycle is discussed. Collectively, the evidence from the studies of these steroids imply that another mechanism by which the endocrine system influences brain function has been identified. Its characterization will provide important insight into how steroids modulate brain excitability under normal and pathophysiological states.
...
PMID:Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore. 285 77

Aromatic and heterocyclic esters of 1-methyl-4-piperidinol and 1,4-dimethyl-4-piperidinol and aromatic esters of (dialkylamino)alkanols were prepared and evaluated for antiepileptic activity by the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for minimal central neurotoxicity by the rotorod ataxia test. The most potent compound, namely the 2-phenylbenzoate (57) of 3-(diethylamino)propanol, was slightly more potent than diphenylhydantoin in the MES assay, while the 2-phenylbenzoate (24) of 1-methyl-4-piperidinol and the 2-phenylbenzoate (56) of (diethylamino)ethanol displayed activity comparable to that of diphenylhydantoin. The 2-phenethylbenzoate ester (6) of 1-methyl-4-piperidinol exhibited one-third the activity of diphenylhydantoin. The 2,4,5-trimethylbenzoate 40 and 2,4,6-trimethylbenzoate 41 of 1-methyl-4-pieridinol were even less potent, but did display activity in the phenobarbital-methsuximide range. Certain compounds interact with sites associated with the GABA receptor-chloride channel complex, but their potencies as anticonvulsant agents do not correlate with interaction at sites on the channel complex. Certain analogues antagonize binding of a batrachotoxin analogue to sodium channel sites, a property indicative of local anesthetic activity. There are structural similarities between 2-phenylbenzoates 57, 56, and 24 and diphenylhydantoin, and the latter anticonvulsant also antagonizes binding of the batrachotoxin analogue.
...
PMID:Anticonvulsant activity of piperidinol and (dialkylamino)alkanol esters. 301 69

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.
...
PMID:Dose pipecolic acid interact with the central GABA-ergic system? 302 50

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) lines of mice have been genetically selected based on the severity of handling-induced convulsions after identical chronic ethanol exposure. The present experiments showed that naive WSP mice were more sensitive than WSR mice to a subconvulsant dose of picrotoxin, bicuculline or pentylenetetrazole as measured by the ability of these drugs to exacerbate handling-induced convulsions. This may reflect a difference between lines in the GABA-chloride channel. The density and affinity of [35S]t-butylbicyclophosphorothionate (TBPS) binding sites, a cage convulsant which binds to the picrotoxin site on the GABA-chloride channel, was measured in the frontal cortex, remainder of the cortex, cerebellum and hippocampus. The binding properties of [3H]flunitrazepam and the potency of gamma-aminobutyric acid (GABA) to enhance flunitrazepam binding was characterized in whole brain samples. There were no differences between lines. The behavioral results suggest a role for the GABA-chloride channel in the differential ethanol withdrawal seizure behavior of WSR and WSP mice, but this is not due to changes in receptor densities or affinities.
...
PMID:Differences in GABA activity between ethanol withdrawal seizure prone and resistant mice. 322 35

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese-containing compound which is used as an additive in unleaded gasoline. One neurotoxic effect of MMT in mice is seizure activity. In this study, seizures were observed in mice treated with MMT in propylene glycol or corn oil. The LD50 associated with seizure activity was lower in mice receiving MMT in propylene glycol (152 mg/kg) than in those receiving MMT in corn oil (999 mg/kg). Manganese concentrations in the brains of mice which showed seizure activity due to MMT were higher than in those that did not (2.45 micrograms/g vs. 1.14 micrograms/g for MMT treated in propylene glycol and 3.25 micrograms/g vs. 1.63 micrograms/g for MMT in corn oil). Mice treated with manganese chloride (MnCl2) showed increases in brain manganese comparable to those of the mice showing seizure activity due to MMT, but exhibited no sign of seizure activity. MMT in non-lethal seizure-inducing doses had no effect on the accumulation of 4-aminobutyric acid (GABA) in mouse brain. However, MMT inhibited the binding of t-[3H]t-butylbicycloorthobenzoate [3H]-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse brain membranes with an IC50 value of 22.8 microM. The data suggest that MMT (organic manganese) or a closely related metabolite and not elemental manganese itself is responsible for the seizure activity observed. The seizure activity may be the result of an inhibitory effect of MMT at the GABA-A receptor linked chloride channel.
...
PMID:Neurotoxic effects of methylcyclopentadienyl manganese tricarbonyl (MMT) in the mouse: basis of MMT-induced seizure activity. 360 84

The intrinsic processes involved in the initiation and arrest of seizures are not completely understood. Cortical and cerebellar inhibitory mechanisms, accumulation of metabolic products, and glial uptake of extracellular potassium (K+o), anions, and released neurotransmitters are all important processes that limit focal firing and terminate a seizure once it has been initiated. Of these, the intrinsic cortical inhibitory mechanisms--i.e., recurrent and surround inhibition--appear to be the most important. Active cation and anion transport processes are two metabolic events that have yet to be elucidated but clearly could be involved in terminating a seizure discharge. For example, without an active mechanism to transport chloride, opening of the chloride channel by the inhibitory transmitter GABA would not result in increased chloride permeability. The transient hypoxia and hypercapnia and lactic acidosis that follows a severe tonic-clonic seizure produces a mixed systemic metabolic and respiratory acidosis. In experimental animals, the hypercapnia that results is sufficient to block seizure discharges. Increasing the CO2 concentration significantly reduces the extension to flexion (E/F) ratio of mice given maximal electroshock seizures (MES) and increases the time required for 50% of the animals to recover sufficiently from a first MES to be able to have another MES. The decreased E/F ratio and the increased recovery time (RT50) are both indicative of a decrease in seizure activity. Since the extent to which CO2 is allowed to accumulate in the brain is regulated by the glial specific enzyme carbonic anhydrase (CA), it follows that the glial cell has an integral role in the mechanisms involved in arresting seizure activity. In contrast, hypoxia increased the E/F ratio and decreased the RT50, evidence that seizure activity was enhanced. Another metabolic factor affecting duration of seizure activity, susceptibility to seizures, and recovery from seizures is glucose. Recovery from seizures depends in part on an adequate supply of this energy source. An inverse correlation (R = 0.95) between RT50 and blood sugar was found when the blood sugar was altered experimentally by treatments that altered the endocrine status (pancreatectomy, treatment with alloxan, cortisol, insulin, glucagon, and dextrose). Since glial cells contain (as glycogen) the small amount of glucose present in the brain, they probably hasten the ability of the brain to recover normal function following a seizure.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Role of glial cation and anion transport mechanisms in etiology and arrest of seizures. 370 23

Many models of epileptiform activity have been developed using in vitro slices, particularly the in vitro hippocampal slice preparation. Using this preparation, investigators have elucidated some of the intrinsic neuronal and synaptic properties that appear to be involved in the generation of burst activity and hyperexcitability typical of epileptic brain. A variety of potassium and calcium conductances, in dendritic as well as somatic membrane, have been found in hippocampal neurons that produce burst discharges; appropriate channel blockers can modulate the firing patterns of these neurons. Receptor antagonists, particularly those which interact with the gamma-aminobutyric acid (GABA) receptor-chloride channel complex, have also been found to be very effective in producing epileptiform activity in the reduced central nervous system (CNS) slice preparation. In most acutely produced epileptogenic slice tissues, it appears that blockade of inhibition, intrinsic mechanisms of excitability, and recurrent excitatory synaptic connections interact to synchronize the cell population. Slice preparations of brain tissue taken from epileptic foci induced in chronic animals have been studied. The kainic acid model, kindling model, and other chronic models of epileptiform activity (alumina gel, freeze lesions) have been studied in vitro; results of these studies suggest that in these tissues there is an alteration in PSP efficacy. Seizure sensitivity in immature CNS tissue may also be produced, in part, by a late development of inhibitory postsynaptic potentials (IPSPs). Studies of cortical slices taken from human epileptic brain during surgery for intractable seizures have begun to reveal some interesting clues about cellular mechanisms underlying discharge in abnormal tissue. Spontaneous, rhythmic post-synaptic potential (PSP) activity has been recorded particularly in slices taken from mesial temporal lobe structures involved in epileptic foci. It is still unclear, however, whether such activity is a reflection of epileptogenicity of this tissue, or is rather characteristic of even normal tissue from mesial temporal cortex. We have learned much about the cellular and synaptic properties of CNS neurons using the in vitro slice preparation and have developed a variety of animal preparations in which we can model epileptiform activity. However, it is still unclear if any of these preparations accurately model human epileptiform abnormalities. A major challenge for modern epilepsy research is to build a bridge between experimental animal models of epilepsy and the epilepsies that occur in the clinical human population.
...
PMID:Hippocampal slices in experimental and human epilepsy. 370 29

Benzodiazepine receptors were investigated in the cerebral cortex, the hippocampus, the brainstem, and the cerebellum of audiogenic seizure (AGS)-susceptible and seizure-resistant (ER) control rats. In AGS-susceptible rats of Sprague-Dawley descent, muscimol (10-6 M and 3 x 10-5 M) activated the binding of 3H-diazepam (0.4 nM) significantly less than in ER-rats. This finding may be strain selective, since it was not observed in AGS-susceptible rats of Wistar descent. Specific binding of the convulsant benzodiazepine receptor ligand methyl 6,7-dimethoxy-4-ethyl carboline-3-carboxylate (3H-DMCM), the benzodiazepine receptor ligand 3H-diazepam and the chloride channel directed cage convulsant t-butylbicyclophosphorothionate 35S-TBPS were not significantly changed in AGS-susceptible as compared to control rats. Our findings indicate that a disturbance at the level of the benzodiazepine receptor/GABA receptor/chloride channel complex is not a likely general aetiological factor for audigenic seizures in rats.
...
PMID:A study on benzodiazepine receptor binding in audiogenic seizure-susceptible rats. 609 92

<< Previous 1 2 3 4 5 6 Next >>