Picrotoxin-induced Convulsions In Rats Research Articles

Anticonvulsant activity of Rudraksha (Elaeocarpus angustifolius Blume) bark against picrotoxin-induced convulsions in rats

Anticonvulsant activity of Rudraksha (Elaeocarpus angustifolius Blume) bark against picrotoxin-induced convulsions in rats

Developmental characteristics of picrotoxin-induced convulsions in rats with genetic absence epilepsy

Adult rats with genetic absence epilepsy (GAERS) were shown to be hyperresponsive to convulsions induced by picrotoxin compared to nonepileptic controls (NERs). In contrast, young GAERS aged 22–26 days were less responsive than NERs to picrotoxin-induced convulsions. Around 30 days of age, when spontaneous spike-wave discharges develop in GAERS, the sensitivity of both strains did no longer differ. After 40 days of age, GAERS appeared definitely more prone than NERs to convulse in response to picrotoxin injection. A developmental imbalance in excitation/inhibition may parallel the occurrence of SWDs.

The effect of N-nitro- l-arginine methyl ester posttreatment on the anticonvulsant effect of phenobarbitone and diazepam on picrotoxin-induced convulsions in rats

The present study has investigated the effect of posttreatment of the nonspecific inhibitor of nitric oxide (NO) synthase (NOS), N-nitro- l-arginine methyl ester ( l-NAME), on the anticonvulsant effect of phenobarbitone and diazepam on picrotoxin-induced convulsions in rats. Phenobarbitone, which is known to inhibit convulsions by potentiating γ-aminobutyric acid (GABA) activity in the brain, did not inhibit the convulsive action of picrotoxin in l-NAME-posttreated animals. l-NAME produced no such interaction with diazepam, which inhibits convulsions through GABA potentiation as well as by a GABA-independent mechanism. l-arginine, the precursor of NO, increased the protective effect of both phenobarbitone and diazepam. These results suggest that a decreased synthesis of NO in the brain by the nonspecific inhibitors of NOS is likely to result in an impairment of the anticonvulsant effect of antiepileptics that inhibit convulsions solely by potentiating GABA activity in the brain.

Evidence for the involvement of l-citrulline but not nitric oxide in the proconvulsant action of the precursor l-arginine on picrotoxin-induced convulsions in rats

To determine the role of the metabolites of l-arginine in its actions on picrotoxin-induced convulsions in rats, the concentrations of nitric oxide (NO) and l-citrulline were measured in the brain 30 and 60 min after the administration of l-arginine (1000 and 2000 mg/kg) or of N-nitro- l-arginine methyl ester ( l-NAME, 30 mg/kg), an inhibitor of NO synthase. Animals treated similarly were challenged 30 and 60 min later with picrotoxin (5 mg/kg), and the time of onset of myoclonus and clonic convulsions and the frequency of convulsions were determined. These parameters were also determined 30 and 60 min after administering l-arginine in l-NAME-pretreated (30 min) animals. Thirty minutes after the administration of l-arginine, the concentrations of both NO and l-citrulline were raised, the onset of myoclonus and clonic convulsions was delayed, and the frequency of convulsions was decreased, indicating the anticonvulsant property of l-arginine. A 60-min treatment of l-arginine produced a further increase in the concentration of l-citrulline but not that of NO and promoted the frequency of picrotoxin-induced convulsions. Pretreatment with l-NAME prevented l-arginine from raising the concentrations of both NO and l-citrulline; it also promoted the anticonvulsant actions and prevented the proconvulsant actions of l-arginine. These results lead to the conclusion that NO has no involvement in the time-dependent anti and proconvulsant actions of l-arginine on the picrotoxin convulsion model, and that l-citrulline seems to have a role in the proconvulsant action of l-arginine.

Evidence for an involvement of nitric oxide and gamma aminobutyric acid in the anticonvulsant action of l-arginine on picrotoxin-induced convulsions in rats

Five, 30, and 60 min pretreatment of 1000 mg/kg and not 500 mg/kg of l-arginine inhibited convulsions induced by picrotoxin. The concentrations of nitric oxide (NO) and gamma aminobutyric acid (GABA) were increased in the brain 5, 30, and 60 min after administration of 1000 mg/kg and not 500 mg/kg of l-arginine. A much higher dose of l-arginine (2000 mg/kg), 30 min after administration, produced a lesser anticonvulsant and NO and GABA increasing actions as compared to that produced by 1000 mg/kg of l-arginine. The same dose of l-arginine, 60 min after administration, decreased the concentrations of both NO and GABA and increased the convulsion frequency of picrotoxin. An NO decreasing dose of nitric oxide synthase (NOS) inhibitor, N-nitro- l-arginine methyl ester ( l-NAME) decreased brain GABA concentration and increased the convulsant action of picrotoxin. Further, l-NAME pretreatment prevented l-arginine (1000 mg/kg) from producing anticonvulsant and NO and GABA increasing effects. An interpretation of these results suggests that NO synthesized from systemically administered l-arginine inhibits convulsions by increasing the concentration of GABA in the brain. However, the effects of l-arginine are reversible, if it is administered at a higher dose (2000 mg/kg) 60 min prior to the test. It is concluded that l-arginine produces anticonvulsant or proconvulsant action depending upon the dose and time of its administration-related changes in the concentrations of NO and GABA in the brain.

Evidence for an involvement of the ammonia-decreasing action of L-arginine in suppressing picrotoxin-induced convulsions in rats and its additive action with diazepam

The effects of pre- (30 min before challenge) and post-treatment (5 min after challenge) of L-arginine (840 mg kg-1) were tested on picrotoxin-induced increase in ammonia concentrations in brain regions (cerebral cortex, brain stem and cerebellum) and the accompanying convulsive responses in adult male rats. The effect of pre- and post-treatment of L-arginine was tested on the action of diazepam against picrotoxin-induced convulsions. Picrotoxin-induced increase in ammonia concentrations in the brain regions was reverted partially by L-arginine pre-treatment. However, L-arginine pre-treatment failed to inhibit convulsions independently and concurrently with diazepam. On the other hand, L-arginine posttreatment reverted ammonia to control level in all brain regions. A partial but significant inhibition of convulsions was found in these animals. The effect produced concurrently by L-arginine and diazepam post-treatment was much greater than that produced by these agents independently. These results suggest that brain ammonia has a partial but significant participation in the convulsant action of picrotoxin. L-arginine has produced a partial protection of picrotoxin-induced convulsions by reverting brain ammonia to control level. The data further suggest that the duration of action of L-arginine is considerably short and that L-arginine has an additive anticonvulsant action with diazepam. [Neurol Res 2001; 23: 622-626]

Seizure-protecting effects of kyotorphin and related peptides in an animal model of epilepsy

Administration of peptides kyotorphin (KT), neokyotorphin (NKT), and d-ser-2-NKT into the lateral brain ventricle (10 nmol increased the latency and attenuated the severity of picrotoxin-induced convulsions in rats. Anticonvulsive effects of the peptides were also observed after their administration into the CA1 hippocampi (2.5, 5, 10 nmol, with the order of potency d-ser-2-NKT → NKT → KT. When injected into the substantia nigra reticulata, the 10 nmol dose of NKT and d-ser-2-NKT displayed equal seizure-protecting effect, which was higher than that for KT. It is concluded that kyotorphin and its analogs provide structure-dependent, dose-dependent, and target site-dependent antiepileptic effect.

Are GABA B receptors involved in the pharmacological effects of ethanol?

The interaction of ethanol with GABA B-receptor system and the selectivity of phaclofen for GABA-receptor subtypes were investigated by employing an in vitro model of 36Cl-influx assay in mammalian cultured neurons and also in vivo models of picrotoxin- and NMDA-induced convulsions in rats. Ethanol (20 mM), without having any effect per se, potentiated the effect of GABA on 36Cl-influx, whereas at concentration 50 mM, ethanol activated Cl −-channels directly in mice spinal cord cultured neurons. In contrast, (−)baclofen (100 μM) did not modify the effects of GABA or ethanol on 36Cl-influx. Similarly, phaclofen (500 μM), as well as pertussis toxin (140 ng/ml, overnight incubation) did not modify these effects. Interestingly, phaclofen (200 μg i.c.v.) reversed the anticonvulsant effect of ethanol, but not that of pentobarbital or diazepam or progabide, against picrotoxin-induced convulsions in rats. However, phaclofen failed to modify the anticonvulsant effect of ethanol against NMDA-induced convulsions. These observations indicate that phaclofen is devoid of GABA A-receptor blockade property, and the anticonvulsant effect of ethanol against picrotoxin may be mediated through the activation of both GABA-receptor subtypes.

Comparison of anticonvulsant effect of ethanol against NMDA-, kainic acid- and picrotoxin-induced convulsions in rats

The anticonvulsant effect of ethanol against N-methyl-D-aspartic acid-(NMDA), kainic acid-, and picrotoxin-induced convulsions was studied in rats. Ethanol (2 g/kg, ip) offered protection against these agents, and it was most effective against picrotoxin and least effective against kainic acid. MK801, NMDA receptor antagonist, also provided protection against these agents. However, it was most effective against NMDA and least effective against kainic acid. Ineffective doses of MK801 (0.1 mg/kg, ip) and ethanol (0.5 g/kg, ip), when administered concurrently, had a facilitatory anticonvulsant effect, thereby providing protection against mortality following severe convulsions induced by NMDA or picrotoxin, but not against kainic acid. The protective effect of ethanol against NMDA- and kainic acid-induced neurotoxicity, in contrast to picrotoxin-induced toxicity, was not reversed by imidazodiazepine, Ro 15-4513, an ethanol antagonist. Furthermore, Ro 15-4513 did not produce any proconvulsant effect with NMDA or kainic acid. These findings suggested that the anticonvulsant actions of ethanol may be attributed to its ability to antagonize NMDA-mediated excitatory responses and facilitate the GABAergic transmission.

RO15-4513 but not FG-7142 reverses anticonvulsant effects of ethanol against bicuculline- and picrotoxin-induced convulsions in rats.

The reversal of anticonvulsant effect of ethanol against chemoconvulsions by RO15-4513 was investigated in rats as this novel imidazobenzodiazepine (ethyl-8 azido-5, 6-dihydro-5-methyl-6-Oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate) is reported to antagonize the acute behavioral and biochemical effects of ethanol in animals. Reversal of ethanol effects on onset of myoclonic jerks, tonic extensor phase, mortality time and percent protection against mortality were compared with not only other anticonvulsant pentobarbital but also with another inverse agonist FG-7142. Pretreatment with RO15-4513 (4 mg/kg) reversed the protective effect of ethanol against bicuculline-induced tonic extensor phase and mortality (87%). This response was sensitive to reversal by RO15-1788 (10 mg/kg). However, onset of myoclonic jerks and duration of clonus were not significantly altered. It also reversed the effect against picrotoxin but the reversal against mortality was up to 50%. As compared to ethanol, RO15-4513 reversed partially the protective effect of pentobarbital against bicuculline- and picrotoxin-induced convulsions. FG-7142 failed to reverse the protective effect of ethanol and pentobarbital against bicuculline-induced tonic extensor phase although it reversed the effect against onset and mortality. It had no effect on the protective effect against picrotoxin-induced convulsions. Both RO15-4513 and FG-7142 possessed proconvulsant effects against bicuculline but not against picrotoxin. These observations suggest that RO15-4513 has a more preferential action against ethanol effects as compared to the other inverse agonist.

Interaction between GABAergic anticonvulsants and the NMDA receptor antagonist MK 801 against MES- and picrotoxin-induced convulsions in rats

The interaction between GABAergic (barbiturates, diazepam, ethanol) and other (phenytoin) anticonvulsants and the N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 in protecting rats against maximal electroshock (MES)- and picrotoxin-induced (10 mg/kg) convulsions was studied. MK 801 (0.1 to 5 mg/kg) showed anticonvulsant responses against MES-induced convulsions in a dose dependent manner, higher doses showing severe muscle relaxation, motor incoordination, and anticonvulsant action. It also produced stereotypic head movement, circling behavior, and affected locomotion. When subanticonvulsant dose (1 mg/kg) of MK 801 was simultaneously administered with subprotective doses of GABAergic anticonvulsants, it significantly potentiated the effects of barbiturates, as compared to other agents. At 1 mg/kg, MK 801 did not offer protection against tonic convulsions though protected (100%) the animals from mortality due to picrotoxin-induced convulsions. It potentiated the effect of a subprotective dose (5 mg/kg) of pentobarbital, but not of diazepam, against tonic convulsions. However, no mortality was observed in either group. The antiglutamate action of barbiturates, particularly that of pentobarbital, may contribute to the observed potentiating response between pentobarbital and MK 801.

Dihydroergotoxine and the Seizure Threshold1

Dihydroergotoxine administration shortened the latency of allylglycine-and picrotoxin-induced convulsions in rats and increased the incidence of convulsions elicited by picrotoxin, i.e., it lowered ED50 for picrotoxin. The same drug (0.1-10.0 mg/kg) decreased the levels of gamma-aminobutyric acid (GABA) in the caudate nucleus and cingulate cortex, but enhanced the aminooxyacetic acid induced accumulation of GABA indicating an increased synthesis of GABA in these brain regions. The concentrations of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, noradrenaline, and dopamine in the whole rate brain were not affected with doses of dihydroergotoxine up to 10.0 mg/kg, but this dose of the drug slowed down the turnover of dopamine, as evidenced by a diminished disappearance of dopamine induced by alpha-methyl-p-tyrosine administration. The results suggest that dihydroergotoxine decreases GABA-ergic transmission and, therefore, presumably lowers the seizure threshold.