Effect of propofol in altering pentylenetetrazol induced seizure threshold in rats

The present study was undertaken to evaluate the role of propofol in altering pentylenetetrazol induced seizure threshold in rats. Total 42 Wistar rats were used to evaluate different parameters (onset of action, duration of seizure, seizure severity score and number of seizure) following propofol injection. The present results showed that there was significant reduction in the time required for onset of seizure in propofol treated groups following PTZ treatment. If treated with propofol alone (2 and 5 mg/kg), there was no significant difference as compared to controls. In seizure severity score assessment, there was no significant difference with various doses of propofol alone treated groups, but the difference was observed in propofol (2 and 5 mg/kg) treated groups following PTZ treatment. Duration of seizure also significantly increased in propofol (5 mg/kg) treated group, but at 2 mg/kg of propofol treatment, no significant difference was observed. The present results showed that propofol ameliorate seizure threshold and caused prolongation of duration of seizure. However, further study and trials are needed to confirm the present results.     

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system

Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.     

The comparative effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol seizure threshold in the rabbit.

The anticonvulsant effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol (PTZ) seizure threshold were studied and compared in the rabbit. The PTZ seizure threshold determined in various rabbit groups during the control phase of conducted experiments, was found to be in the range of 10.1 +/- 2.0 to 13.5 +/- 3.7 mg/kg. Intravenous administration of comparable doses of propofol, thiopental, and diazepam resulted in marked and significant increases in PTZ seizure threshold. At all administered doses (1.25-10.0 mg/kg), propofol was found to be more effective than thiopental in increasing the PTZ threshold dose. However, the anticonvulsant effects of diazepam were more marked than those of propofol, except at a dose of 10 mg/kg where both agents exhibited equipotent activities. These data demonstrate that propofol enjoys a considerable degree of anticonvulsant activity in the rabbit. This anticonvulsant action is greater than that of thiopental at doses ranging from 2.5 to 10 mg/kg and equipotent with diazepam at the 10 mg/kg dose.     

Age related increased threshold for electroshock seizure in BDF1 mice

The thresholds for inducing the minimal and maximal electroshock seizures were examined in relation to age in BDF1 mice of both sexes. The 50 percent effective intensities for the maximal electroshock seizure (tonic hindlimb extensor component) were lowest in the youngest age groups (6-month-old) for both male (10.68 mA) and female (9.18 mA) animals. The threshold increased with age and became significantly higher at 24 months (14.00 mA, 12.70 mA for male and female mice respectively). There was also a further increase in threshold at 30 months for both sexes. Similarly, the threshold for inducing the minimal seizure also increased with age but the differences in mean threshold levels between the youngest and oldest groups were much smaller in comparison to the maximal seizure. It was concluded that the threshold for inducing electroshock seizures significantly increases with age in mice of both sexes.     

Age-dependent increase in the threshold for pentylenetetrazole induced maximal seizure in mice

The thresholds for inducing the maximal seizure by pentylenetetrazole (PTZ) were compared for BDF1 mice of both sexes with varying ages after intraperitoneal administration of various doses of PTZ. The minimal effective PTZ concentrations (MECs) in the brain for inducing the maximal seizure were significantly higher in 24-month or older mice than in 6-month-old animals of both sexes. Some mice of 30 months did not demonstrate the maximal seizure but died within the 15-min observation period, a phenomenon never observed in mice of 24 months or younger. The relationship between plasma and brain concentrations of PTZ changed little during aging. It was concluded that the brain becomes less sensitive to PTZ with age in regard to its convulsant activity, as was previously shown for electroshock by the authors. This observation, coupled with our earlier observations on anticonvulsants, appears to support the classical hypothesis that age has a dual effect on drug sensitivity i.e. a decrease for stimulants but an increase for sedative (or depressant) drugs.     

Genetic and environmental interactions determine seizure susceptibility in epileptic EL mice

Gene identification has progressed rapidly for monogenic epilepsies, but complex gene-environmental interactions have hindered progress in gene identification for multifactorial epilepsies. We analyzed the role of environmental risk factors in the inheritance of multifactorial idiopathic generalized epilepsy in the EL mouse. Seizure susceptibility was evaluated in the EL (E) and seizure-resistant ABP/LeJ (A) parental mouse strains and in their AEF1 and AEF2 hybrid offspring using a handling-induced seizure test. The seizure test was administered in three environments (environments I, II and III) that differed with respect to the number of seizure tests administered (one test or four tests) and the age of the mice when tested (young or old). The inheritance of seizure susceptibility appeared dominant after repetitive seizure testing in young or old mice, but recessive after a single test in old mice. Heritability was high (0.67-0.77) in each environment. Significant quantitative trait loci (QTL) that were associated with environments I and III (repetitive testing) were found on chromosomes 2 and 9 and colocalized with previously mapped El2 and El4, respectively. The El2 QTL found in environment I associated only with female susceptibility. A novel QTL, El-N, for age-dependent predisposition to seizures was found on proximal chromosome 9 only in environment II. The findings indicate that environmental risk factors determine the genetic architecture of seizure susceptibility in EL mice and suggest that QTL for complex epilepsies should be defined in terms of the environment in which they are expressed.     

Electroshock raises pentylenetetrazol threshold: Possible role of inosine

A series of 15 single electroshocks administered through electrodes applied to the scalp of mice raised the threshold to pentylenetetrazol-induced seizures as determined by a tail vein infusion method. The same stimulus increased brain inosine and hypoxanthine. Phenytoin, which blocks the increase in inosine produced by this stimulus, reversed the elevation in threshold by electroshock. The effect of electroshock on threshold may be mediated by inosine.     

Effect of tryptophol on pentylenetetrazol and picrotoxin induced convulsion in mice.

The effect of treatment of mice with tryptophol (TOL), a neutral metabolite of tryptophan, on drug-induced convulsion was studied. TOL effectively suppressed both pentylenetetrazol and picrotoxin induced convulsion. Diphenylhydantoin (DPH), a potent inhibitor of brain aldehyde reductase, significantly reduced the anticonvulsant effect of TOL, however, TOL level in brain of DPH-treated mice was rather higher than that of control one. These results strongly suggest that the manifestation of the anticonvulsant effect of TOL requires the conversion of TOL to its active metabolite, indoleacetaldehyde.     

Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1

We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6xD2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility.     

Effect of inferior olive lesion on seizure threshold in the rat

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.     

Cannabinoid-serotonin interactions in alcohol-preferring vs. alcohol-avoiding mice

Because cannabinoid and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether cannabinoid 1 (CB1) and 5-HT(1A) receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6 J and DBA/2 J, with marked differences in native alcohol preference. When offered progressively (3-10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (approximately 70%) in DBA/2 J than in C57BL/6 J mice. In DBA/2 J mice, chronic treatment with the cannabinoid receptor agonist WIN 55,212-2 increased alcohol intake. WIN 55,212-2 effect was prevented by concomitant, chronic CB1 receptor blockade by rimonabant or chronic 5-HT(1A) receptor stimulation by 8-hydroxy-2-(di-n-propylamino)-tetralin, which, on their own, did not affect alcohol intake. In C57BL/6 J mice, chronic treatment with WIN 55,212-2 had no effect but chronic CB1 receptor blockade or chronic 5-HT(1A) receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN 55,212-2 significantly decreased 5-HT(1A)-mediated [35S]guanosine triphosphate-gamma-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6 J mice. These results show that cannabinoid neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT(1A) interactions. However, the differences between C57BL/6 J and DBA/2 J mice indicate that such modulations of alcohol intake are under genetic control.     

Quantitative trait loci for electrical seizure threshold mapped in C57BLKS/J and C57BL/10SnJ mice

We mapped the quantitative trait loci (QTL) that contribute to the robust difference in maximal electroshock seizure threshold (MEST) between C57BLKS/J (BKS) and C57BL10S/J (B10S) mice. BKS, B10S, BKS × B10S F1 and BKS × B10S F2 intercross mice were tested for MEST at 8-9 weeks of age. Results of F2 testing showed that, in this cross, MEST is a continuously distributed trait determined by polygenic inheritance. Mice from the extremes of the trait distribution were genotyped using microarray technology. MEST correlated significantly with body weight and sex; however, because of the high correlation between these factors, the QTL mapping was conditioned on sex alone. A sequential series of statistical analyses was used to map QTLs including single-point, multipoint and multilocus methods. Two QTLs reached genome-wide levels of significance based upon an empirically determined permutation threshold: chromosome 6 (LOD = 6.0 at ～69 cM) and chromosome 8 (LOD = 5.7 at ～27 cM). Two additional QTLs were retained in a multilocus regression model: chromosome 3 (LOD = 2.1 at ～68 cM) and chromosome 5 (LOD = 2.7 at ～73 cM). Together the four QTLs explain one third of the total phenotypic variance in the mapping population. Lack of overlap between the major MEST QTLs mapped here in BKS and B10S mice and those mapped previously in C57BL/6J and DBA/2J mice (strains that are closely related to BKS and B10S) suggest that BKS and B10S represent a new polygenic mouse model for investigating susceptibility to seizures.     

Phospholipid interactions in model membrane systems. II. Theory.

We describe statistical thermodynamic theory for the lateral interactions among phospholipid head groups in monolayers and bilayers. Extensive monolayer experiments show that at low surface densities, PC head groups have strong lateral repulsions which increase considerably with temperature, whereas PE interactions are much weaker and have no significant temperature dependence (see the preceding paper). In previous work, we showed that the second virial coefficients for these interactions can be explained by: (a) steric repulsions among the head groups, and (b) a tilting of the P-N+ dipole of PC so that the N+ end enters the oil phase, to an extent that increases with temperature. It was also predicted that PE interactions should be weaker and less temperature dependent because the N+ terminal of the PE head-group is hydrophilic, hence, it is tilted into the water phase, so dipolar contributions among PE's are negligible due to the high dielectric constant of water. In the present work, we broaden the theory to treat phospholipid interactions up to higher lateral surface densities. We generalize the Hill interfacial virial expansion to account for dipoles and to include the third virial term. We show that to account for the large third virial coefficients for both PC and PE requires that the short range lateral attractions among the head groups also be taken into account. In addition, the third virial coefficient includes fluctuating head group dipoles, computed by Monte Carlo integration assuming pairwise additivity of the instantaneous pair potentials. We find that because the dipole fluctuations are correlated, the average triplet interactions do not equal the sum of the average dipole pair potentials. This is important for predicting, the magnitude and the independence of temperature of the third virial coefficients for PC. The consistency of the theory with data of both the second and the third virial coefficients extends the applicability of the head-group model to semiconcentrated monolayers, in agreement with the surface potential data in the foregoing paper.     

Theoretical calculations of base-base interactions in nucleic acids: II. Stacking interactions in polynucleotides.

Base-base interactions were computed for single- and double stranded poly,ucleotides, for all possible base sequences. In each case, both right and left stacking arrangements are energetically possible. The preference of one over the other depends upon the base-sequence and the orientation of the bases with respect to helix-axis. Inverted stacking arrangement is also energetically possible for both single- and double-stranded polynucleotides. Finally, interacting energies of a regular duplex and the alternative structures were compared. It was found that the type II model is energetically more favourable than the rest.     

Cyclosporine lowers seizure threshold in an experimental model of electroshock-induced seizures in Munich-Wistar rats

We have developed a model of cyclosporin A (CsA) central nervous system toxicity in the Munich-Wistar rat in which CsA, 20 mg/kg/day i.p., produces significant EEG abnormalities and mortality. In the present study we used cohorts of Munich-Wistar rats to assess effects of CsA on the threshold for tonic-clonic electroshock-induced seizures. Rat cohorts were begun on cremephore, CsA-10 mg/kg/day, or CsA-20 mg/kg/day. On day 7 and day 14 of the dosing protocol, cohorts of animals were exposed to maximal electroshock (MES) using a minimal staircase method within each cohort. Multiple logistic regression models were used to determine differences between groups on the relative odds of producing a MES-induced seizure while controlling for other variables. Seizure threshold was significantly affected by shock amperage and body weight, but not by SUN, creatinine, bilirubin, sodium, potassium, weight loss or day the shock was delivered. The odds ratios of seizure induction in the CsA-treated groups versus placebo group were 1.91 for CsA-10 mg/kg/day and 3.63 for CsA 20-mg/kg/d, both statistically significant. These results suggest that cyclosporine lowers seizure threshold and probably increases susceptibility to seizures, the etiology of which may be multifactorial clinically.