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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pivaloyloxymethyl esters 4 and 5 of the amino acid GABA uptake inhibitors guvacine and nipecotic acid, respectively, were synthesized as potential prodrugs. The half-lives of 4 and 5 for conversion into the parent amino acids were determined under approximate physiological conditions in the presence or absence of human serum. Under the former conditions the half-lives for 4 and 5 were 6.3 hr and 0.8 hr, and, in the absence of serum, 15.5 hr and 1.2 hr, respectively. The compounds 4 and 5 were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) to DBA/2 mice and their effects on audiogenic seizures determined. In agreement with earlier findings for 5, all phases of the seizure response of the animals were suppressed by compound 4 at doses above 2mmol/kg i.p. At anticonvulsant doses of compound 4, as well as of 5, side effects such as sedation and impairments of motor activities were observed. The ethyl and pivaloyloxymethyl esters 9 and 11 of cis-4-acetoxynipecotic acid, designed as 'double' ester prodrugs of the GABA uptake inhibitor cis-4-OH-nipecotic acid, were synthesized and shown to have very weak anticonvulsant effects. Compounds 9 and 11 did, however, show a broad spectrum of cholinergic side effects. These apparent interactions of 9 and 11 with muscarinic cholinergic receptors have been explained on the basis of the similarity of the structures of 9 and 11 to that of the muscarinic agonist 1-methyl-4-acetoxypiperidine. Furthermore, the structural similarity of 9 and the muscarinic agonist nipecotic acid ethyl ester may, to some extent, underlie the cholinergic profile of 9.
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PMID:GABA uptake inhibitors. Synthesis and effects on audiogenic seizures of ester prodrugs of nipecotic acid, guvacine and cis-4-hydroxynipecotic acid. 350 45

The postnatal development of susceptibility to the convulsant effects of Ro5-4864 (4'-chlorodiazepam) was characterized in two inbred mouse strains (DBA/2J and BALB/c ByJ) which as adults differ markedly in their response to this convulsant. Onset of susceptibility to a dose of Ro5-4864 which caused a high frequency of clonic seizures in adults was observed at 10 days of age in DBA/2 mice, but not until 35 days in BALB/c By mice. At 14 days of age an abrupt increase in susceptibility to Ro5-4864-induced tonic seizures was found in DBA/2 but not BALB/c By mice. Both the peak of tonic seizure susceptibility (21 days) and the time course of its subsequent age-dependent decline closely paralleled the change in audiogenic seizure susceptibility in the DBA/2 strain. PK11195 (40 mg/kg) blocked Ro5-4864 (25 mg/kg)-induced, age-dependent tonic seizures but had no effect on clonic seizure induction in the same mice. These observations establish that both the susceptibility to Ro5-4864 in adult mice and the postnatal time course for development of susceptibility to this convulsant are inherently different in these two strains of mice. The lack of coincidence between the developmental onset of susceptibility to Ro5-4864-induced seizures and the onset of supersensitivity to Ro5-4864-induced tonic seizures during the period of peak audiogenic seizure susceptibility in DBA/2 mice implies that more than one neurochemical mechanism is involved in the ability of Ro5-4864 to induce seizures in this strain. However, the blockade of Ro5-4864-induced tonic seizures by PK11195 suggests that peripheral type benzodiazepine receptors may mediate this effect.
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PMID:Ontogeny of susceptibility to the convulsant, Ro 5-4864, and its relationship to audiogenic seizure susceptibility in inbred mice. 356 Nov 51

We examined the inbred mouse strains DBA/2Ibg, C57BL/6Ibg, and C3H/2Ibg for differences in susceptibility to bicuculline-induced seizures, as well as to bicuculline-induced epileptiform activity recorded in the CA1 pyramidal cell layer of hippocampal slices. For susceptibility to seizure onset the strain rank order was (most to least susceptible): C3H = DBA greater than C57. The rank order for sensitivity to effects of bicuculline on tonic seizure latency and on hippocampal epileptiform activity were identical: C3H greater than DBA = C57. It is suggested that mechanisms underlying the development of bicuculline-induced epileptiform events in the hippocampal slice may be similar to those involved in the development of tonic seizures measured in vivo.
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PMID:Differential sensitivity to bicuculline in three inbred mouse strains. 360 31

RO 15-4513, an imidazodiazepine that has been reported to reverse some of the behavioral effects of ethanol, was given to DBA/2 mice. Although no animals treated with a 6 mg/kg dose of this drug had seizures, 20% of animals given 20 mg/kg of this drug had tonic seizures. Ethanol withdrawal was induced in DBA/2 mice treated with 4-methyl pyrazole using an inhalation paradigm. Mice were more likely to have a seizure during ethanol withdrawal if treated with RO 15-4513 (6 mg/kg) than if they received the vehicle. These data suggest administering RO 15-4513 as an alcohol antagonist to alcoholic subjects may increase the incidence of seizures.
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PMID:RO 15-4513 induces seizures in DBA/2 mice undergoing alcohol withdrawal. 367 63

We have examined if the age-related susceptibility of DBA/2J mice to audiogenic seizures is the result of an abnormality in the number or sensitivity of brain adrenoceptors. The binding of alpha 1-, alpha 2-, and beta-adrenoceptor ligands to membranes prepared from whole brain or regions of brain of DBA/2J mice was measured at various ages, corresponding to the periods before, during, and after the maximal sensitivity to audiogenic seizures. For comparison, we have studied concurrently age-matched C57 Bl/6 mice, a strain resistant to audiogenic seizures at all ages. There was no difference in the binding of alpha 2- or beta-adrenoceptor ligands to whole brain membranes between the two strains of mice at any age. The maximal number of alpha 1-adrenoceptor binding sites was lower in whole brains of DBA/2J mice than of C57 Bl/6 mice at all ages studied except 13-15 days of age. The differences were small (maximally 17%) but were statistically significant at 21-23 days of age, the time of maximal sensitivity of DBA/2J mice to audiogenic seizures. No difference between the two strains was found in the number or affinity of alpha 1- or alpha 2-adrenoceptor binding sites at any age in any of the brain regions studied. The age-related susceptibility of DBA/2J mice to audiogenic seizures is not the result of an abnormality in number or sensitivity of alpha 2- or beta-adrenoceptor binding sites, but a reduced number of alpha 1-adrenoceptor binding sites may be involved.
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PMID:Brain adrenoceptor binding sites in mice susceptible (DBA/2J) and resistant (C57 Bl/6) to audiogenic seizures. 371 97

Mice of two inbred strains, DBA and C3H, were pretreated with mecamylamine before challenge with nicotine. Mecamylamine blocked nicotine-induced seizures, enhanced startle, and alterations in respiratory rate, Y-maze activity, heart rate and body temperature. Mecamylamine blocked nicotine-induced seizures and enhanced startle with IC50 values of less than 0.1 mg/kg. The other nicotine effects were blocked by mecamylamine with IC50 values between 0.8 and 2.3 mg/kg. Strain differences in sensitivity to mecamylamine blockade were also detected. These results suggest that nicotine elicits its effects at two receptors, which may be those labeled with [125I]-alpha-bungarotoxin and with [3H]-nicotine.
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PMID:Mecamylamine blockade of nicotine responses: evidence for two brain nicotinic receptors. 373 41

Following the intraperitoneal administration of the adenosine analogues, 2-chloro-adenosine (1-4 mg/kg) or 5'-N-ethylcarboxamidoadenosine (NECA; 0.01-0.5 mg/kg) to audiogenic DBA/2 mice, there is a potent protection against sound-induced seizures and a simultaneous large (2-5 degrees) reduction in body temperature. The anticonvulsant potency of the adenosine analogues is almost completely abolished by pretreatment with methylxanthines or warming the mice to prevent the adenosine-induced temperature decrease. Adenosine (0.01-1 mM), 2-chloro-adenosine (0.1-1 mM) and NECA (0.1 mM) also significantly inhibit potassium-evoked release of 3H-D-aspartate from rat hippocampal slices. This inhibition is not affected by theophylline (1 mM).
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PMID:Adenosine analogues. The temperature-dependence of the anticonvulsant effect and inhibition of 3H-D-aspartate release. 374 84

delta-Aminolevulinic acid, an intermediate in heme formation, is elevated in certain human disorders including acute intermittent porphyria, tyrosinemia, and lead poisoning. It has been implicated in the central nervous system manifestations of these disorders via interactions with the GABAergic system. This potential interaction was examined by testing whether or not delta-aminolevulinic acid could alter the latency to seizure in mice. Seizures were induced in a variety of inbred strains of mice including C57BL, C3H, DBA mice and in a heterogeneous stock of mice. Flurothyl and 3-mercaptopropionic acid were used to induce seizures in the presence and absence of delta-aminolevulinic acid administered either i.p. (0.5 and 1.5 mmol/kg), or i.c.v. (4.5 and 450 nmol). delta-Aminolevulinic acid increased the latency to myoclonic and clonic seizures induced by flurothyl when administered i.p.; i.c.v. injections also delayed clonic seizures induced by flurothyl, and increased the latency to tonic seizures induced by 3-mercaptopropionic acid. The degree to which delta-aminolevulinic acid altered seizure latency in all tests was dependent on strain of mouse tested. These data support the conclusion that delta-aminolevulinic acid can act as an anticonvulsant agent, and mimic the effects of GABA. Moreover, there is genetic variation in the sensitivity of the various strains of mice to delta-aminolevulinic acid.
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PMID:Genetic differences in the effects of delta-aminolevulinic acid on seizure latency in mice. 377 Jan 19

A classical F2 and backcross genetic design was used to examine the relationship between sensitivity to nicotine-induced seizures and hippocampal nicotinic receptors. Nicotine was administered by i.v. infusion through cannulas implanted in the right jugular veins of mice from the C3H and DBA mouse strains and their derived F1, F2 and backcross (F1 X C3H and F1 X DBA) generations. Nicotine-induced seizure sensitivity was assessed by infusing nicotine at a 2.0 mg/kg/min concentration until the onset of a clonic seizure. After seizure testing, mice were sacrificed and the binding of alpha-bungarotoxin (BTX) was determined in three brain regions: cortex, midbrain and hippocampus. The pattern of results for the six generations for seizure sensitivity was similar to that observed for hippocampal BTX binding. Genetic analyses indicate that receptor concentrations in the hippocampus and seizure sensitivity are both influenced by a relatively simple genetic system which involves one or more genes acting in an additive fashion. In addition, the genetic correlation which is indicative of the extent to which two characters are influenced by the same genes, supports the relationship between nicotine-induced seizure sensitivity and hippocampal BTX binding. The results suggest that those animals which are sensitive to nicotine-induced seizures have a greater concentration of nicotinic receptors as determined by the binding of BTX than animals which are less sensitive to the convulsant effects of nicotine.
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PMID:Genetic analysis of nicotine-induced seizures and hippocampal nicotinic receptors in the mouse. 379 45

The effects of natural and synthetic sauvagine on locomotor activity and ECS-induced seizures were studied in DBA/2 mice. A dose-dependent activity depression was evident following the administration of both compounds. Moreover they exerted a protective effect against ECS-induced seizures. This effect was naloxone-reversible, suggesting the involvement of endogenous opioids. In both series of experiments natural sauvagine was more effective than the synthetic compound.
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PMID:Effects of sauvagine on behavioural arousal of mice. 383 73


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