Effect of diazepam, carbamazepine, sodium valproate and their combinations with vitamin preparations on epileptic activity

The anticonvulsive action of diazepam, carbamazepine, sodium valproate and their combinations with pyridoxal-5-phosphate, nicotinamide, and alpha-tocopherol were investigated in acute experiments on mice with corazole-induced seizures. Diazepam (0.5 mg/kg), carbamazepine (50 mg/kg) and sodium valproate (200 mg/kg) were shown to reduce convulsive intensity and lethality. Vitamins nicotinamide (250 mg/kg), pyridoxal-5-phosphate (10 mg/kg) and alpha-tocopherol (100 mg/kg) potentiated anticonvulsive action of the above antiepileptic drugs. The results of the investigation suggest the efficacy of pathogenetic therapy and give new evidence of the advisability of using vitamins in combination with synthetic anticonvulsive drugs.     

Modulation of the state of the antiepileptic cerebral system by the influence of a ketogenic diet under conditions of the resistant epileptic syndrome

In experiments on rats subjected to a procedure of corazole kindling with the development of antiepileptic drug-resistant seizures, we found that manifestations of resistance were suppressed under conditions of feeding the rats with a ketogenic diet (KD) including 80% lipids and 16.6% proteins. Against the background of using this diet, such means as electrical stimulations of the paleocerebellum, irradiation with extremely high-frequency electromagnetic waves (length 7.1 mm), and administration of L-histidine (300 mg/kg) were more effective from the aspect of inhibition of the above seizure activity. At the same time, keeping rats on the KD modified the action of L-arginine on the epileptic activity to a significantly weaker extent.     

The effect of delta sleep-inducing peptide on the convulsive activity in corasol kindling

The influence of intraperitoneal delta-sleep inducing peptide (DSIP) injection (100 micrograms/kg) on the epileptic activity was investigated in the experiments on Wistar rats and (CBA X C57B1/6)F1 mice. The model of chronically developing epileptic activity--the model of pharmacological kindling--was created by daily repeated corasole injections in subconvulsive doses (30 mg/kg). It has been shown that DSIP injection delayed the manifestation of generalized seizures during kindling, led to the suppression of seizure activity and reduced the mortality rate of animals that developed kindled seizures. The antiepileptic effect of DSIP was observed throughout the period of 5 minutes to 24 hours after the injection. Naloxone (2.5 mg/kg) did not change the antiepileptic effect of DSIP.     

Pentylenetetrazol (PTZ)-kindling development in intact and subcortical structure lesioned rats

Kindling was induced in male wistar rats (280-320 g) by daily ip injections of PTZ in subthreshold doses (30 mg/kg). Repeated administration of PTZ to animals resulted in developing of enhanced seizures and also enhanced seizure susceptibility which could be sustained for a long time (6 months) after last seizure paroxysm. The lesioned hippocampus retarded the manifestation of PTZ kindling, where as lesioned caudate nuclei increased the seizure kindling development. Results also revealed hippocampus as a determinant structure in PTZ kindling formation, which stabilize the epileptic manifestations and make them chronic, at the same time caudate nuclei retarded the epileptic seizures stabilization. This role may be only antiepileptic, and not anti-kindling as is known for caudate nuclei.     

Effect of nicotinamide on epileptic activity in the cerebral cortex

The experiments on cats showed that intravenous administration of nicotinamide suppresses the epileptic activity in a solitary epileptic focus as well as in the complex of epileptic foci produced by strychnine application to various cortical zones under the influence of the most powerful focus that plays the role of a determinant. After the intravenous injection of nicotinamide (50-70 mg/kg) the complex was destabilized and broken down. The epileptic activity in the dependent foci of the complex disappeared first in the more remote from the determinant focus and then in the nearer one. The determinant focus was the last to disappear. The inhibitory effect of nicotinamide is associated with antiepileptic activity. Nicotinamide is suggested to be one of the endogenous drugs which may suppress brain hyperactivity and activate the antiepileptogenic system.     

Effects of activation and lesions of the superior colliculi of the lamina quadrigemina on epileptic activity in rats]

In acute experiments on rats it was shown that activation of SC by bilateral microinjection of penicillin (5-15 IU) or bicuculline (25-50 ng) resulted in the increased latency and decreased severity of i.p. picrotoxin-induced seizures (2 mg/kg). The suppression of behavioral convulsions and the decreased epileptic activity in the hippocampus and cerebral cortex were followed by occurrence of spike discharges in SC with an amplitude of 200-500 mcV and frequency of 5-12/sec which testifies to the formation of penicillin- or bicuculline-induced generator excitation in SC. The lesions of SC by kainic acid administration resulted in the decreased seizure threshold and, also, facilitated the development of seizure under conditions of picrotoxin kindling. The conclusion is made that SC activation plays an important role in the realization of functional integrative activity of the antiepileptic system.     

State of the antioxidant system during corazole kindling in rats

Antioxidation system was investigated in rats during kindling formation caused by daily administration of corazole in under-threshold doses. No changes have been observed in the activity of superoxide dismutase, glutathione peroxidase, glutathione reductase and alpha-tocopherol content in the rat brain and blood. It is suggested that corazole-induced predisposition to epileptic activity is formed by mechanisms which are not associated with lipid metabolism in nervous tissue.     

Effect of nicotinamide on focal and generalized epileptic activity in the cerebral cortex

Intraperitoneal injection of nicotinamide to rats inhibits epileptic activity induced by penicillin application in the animals' brain cortex. It has been found in experimental primary-generalized epileptic activity induced by bemegride that preliminary injection of nicotinamide increased the latency of the emergence of the first epileptic seizures. Addition of nicotinamide to synaptosomal suspension inhibited accumulation in it of the products of lipid peroxidation. Relationship between antioxidant properties of nicotinamide and its antiepileptic activity is discussed.     

Antiepileptic effects of nifedipine]

In experiments on freely moving male Wistar rats it was shown that nifedipine in a dose 10 mg/kg (i.p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. A similar suppressing effect of nifedipine was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg, i.p.). Nifedipine in the same dose was not effective on chronic PTZ administration (PTZ-kindling, 30 mg/kg i.p. during 28 days): when injected 30 min before each PTZ administration it didn't delay the development of kindling induced seizure susceptibility and had no effect on the severity of seizures. The administration of nifedipine in a dose of 10 or 30 mg/kg to control kindled animals which had not been treated with nifedipine had no influence on the severity of seizures provoked by a testing dose of PTZ (30 mg/kg i.p.): its intensity was similar to that of caused by PTZ injection along.     

Altered ATP Hydrolysis Induced by Pentylenetetrazol Kindling in Rat Brain Synaptosomes

The ectonucleotidase pathway is an important metabolic source of extracellular adenosine. Adenosine has potent anticonvulsant effects on various models of epilepsy. One of these models is pentylenetetrazol (PTZ) kindling, in which repeated administration of subconvulsive doses of this drug induces progressive intensification of seizure activity. In this study, we examine the effect of a single convulsive injection (60 mg/kg, i.p.) or 10 successive (35 mg/kg, i.p.) injections of PTZ on synaptosomal ectonucleotidases. Our results have shown that no changes in ectonucleotidase activities were seen at 0, 1, and 24 h or at 5 days after a single convulsive PTZ injection. However, after PTZ-kindling, rats which were more resistant to seizure development presented an increase in ATP hydrolysis in synaptosomes from hippocampus and cerebral cortex (44% and 28%, respectively). These results suggest that changes in nucleotide hydrolysis may represent an important mechanism in the modulation of chronic epileptic activity in this model.     

Effect of destruction of the hippocampus and caudate nucleus on the development of epileptic activity during corazole kindling

Experiments were carried out on random-bred white rats (250-350 g). Kindling was induced by daily intraperitoneal corazol injections in subthreshold (subconvulsive) doses (30 mg/kg). It has been demonstrated that bilateral hippocampal destruction did not change the seizure threshold, while bilateral caudate nucleus destruction lowered it. Hippocampal destruction delayed corazol kindling development and also accelerated the lowering of seizure susceptibility after corazol injections were discontinued, as compared to control animals. Caudate nucleus destruction induced more marked seizure reactions in the first 14 days after corazol injections were started. There were no significant differences in seizure manifestation severity in kindled and control groups. These data point to an essential role of caudate nucleus as an element of antiepileptic system and support the concept that hippocampus plays a role of pathologic determinant which is associated with the formation of an epileptic system underlying corazol kindling.     

Effect of Acute Stress on the Development of Seizures in a Kindling Model in Rats

We studied the effect of acute stress induced by nociceptive stimulation of the limbs on the duration of ECoG epileptiform activity and manifestation of generalized motor convulsive reactions under conditions of a kindling model of epilepsy in rats. Two and four weeks after termination of the kindling procedure, test stimulations of the hippocampus evoked intense attacks of epileptic activity. Short-lasting pain-inducing stimulation (intense electrical stimulation of the limbs) resulted in noticeable limitation of both ECoG and motor behavioral manifestations of epileptic activity determined by the formation of an epileptogenic nidus. The antiepileptic effect of acute stress was limited in time; manifestations of this effect reached their maximum about 3 h after painful stimulation, while about 6 h after such stimulation they became smoothed to a considerable extent.     

The role of transaminases in realizing the protective effect of L-aspartate in hypoxia]

Activation of aspartate aminotransferase and alanine aminotransferase of mitochondria introduced to the incubation medium of pyridoxal-5'-phosphate (40 microM) is approximately 2 times higher than that of the corresponding cytoplasmic forms. At hypoxia aspartate aminotransferase activity in mitochondria and postmitochondrial supernatant tends to an increase while that of alanine aminotransferase decreases (above 2 times). The protection from hypoxic damage when using L-aspartate (100 mg/kg subcutaneously 3-5 min before hypoxia) intensifies an adaptive increase of aspartate aminotransferase activity and removes a decrease of alanine aminotransferase activity. Under these conditions stimulating effect of pyridoxal-5'-phosphate on transaminases activity in vitro weakens. A simultaneous administration of vitamin-coenzyme complex (thiamine pyrophosphate, lipoate, sodium 4-phospho-pantothenate, flavin-mononucleotide, nicotinate) intensifies these metabolic shifts and protective action of L-aspartate.     

Effect of PGF2 alpha and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy.

The effect of PGF2alpha and 15(S)-15-methyl PGE2 methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE2 analogue given in single non-toxic doses (1.6-3 mug/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PG2alpha given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF2alpha for one hour (10 mug/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E2 analogue (greater than 16 mug/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or anatagonism of the depressant action of norepinephrine on Purkinje cells.     

Effect of Anacyclus pyrethrum on Pentylenetetrazole-Induced Kindling, Spatial Memory, Oxidative Stress and Rho-Kinase II Expression in Mice

Anacyclus pyrethrum (A. pyrethrum) has been reported to exhibit anticonvulsant activity. In the present study, the effect of hydro-alcoholic extract of A. pyrethrum root (HEAP) on pentylenetetrazole (PTZ) induced kindling, spatial memory, oxidative stress and rho kinase (ROCK II) was assessed. Male albino mice (25–30 g) were used in the study. PTZ (35 mg/kg, i.p. on alternate days) was injected to induce kindling and PTZ (70 mg/kg, i.p) challenge was given 7 days post-kindling. HEAP was administered orally daily in the doses of 100, 250 and 500 mg/kg along with PTZ injections during the kindling process and continued till PTZ challenge post kindling. Spatial memory was assessed using Morris water maze test. Oxidative stress parameters [malondialdehyde (MDA) and reduced glutathione (GSH)] and ROCK II expression were estimated in whole brain at the end of the study. Pre-treatment with HEAP (250 and 500 mg/kg) showed significant increase in the myoclonic jerk latency and delay in the development of kindling. A significant decrease in mortality was observed at higher doses of HEAP (250 and 500 mg/kg). Pre-treatment with HEAP significantly increased the number of platform crossings and decreased the escape latency, as opposed to the PTZ group, thus showing protection against memory deficit. HEAP pre-treatment also attenuated the oxidative stress induced by PTZ kindling. PTZ induced kindling increased the ROCK II expression whereas, HEAP pre-treatment attenuated the increase in ROCK II expression. To conclude, HEAP pre-treatment showed antiepileptic effect and also showed protection against cognitive impairment by decreasing oxidative stress and ROCK II expression in PTZ kindled mice.     

Role of globus pallidus in mechanisms of antiepileptic caudate- cortical effects]

The experiments on rats have shown that striatal electrostimulation influences inhibiting cortex epileptic activity decrease under conditions of globus pallidus destruction. Besides, it is noted that globus pallidus lesion exerts a pronounced antiepileptic effect on development of the neocortical epileptic activity complexes. Globus pallidus stimulation enhanced the neocortex interictal seizure activity and transformed it to ictal discharges. The results are discussed in terms of the role of pale globe in mechanisms of caudate inhibitory action on neocortex epileptic activity.     

Anti-epileptic effect of the new calcium channel blocker IOS-1.1212]

In experiments on freely moving male Wistar rats it was shown that IOS-1.1212 (1,4-dihydropyridine) in a dose 2 and 10 mg/kg (i. p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. Similar suppressing effect of IOS-1.1212 was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg i. p.) and on chronic PTZ administration (PTZ-kindling, 30 mg/kg i. p. during 30 days): when injected 30 min before each PTZ administration it delayed the development of kindling-induced seizures susceptibility in randomized animals (series 1) and attenuated the severity of seizures in PTZ-sensitive animals (series 2). However, IOS-1.1212 had no effect on the strychnine-induced focal epileptic activity. In male Icr:Icl mice IOS-1.1212 in a dose 1.5 and 5 mg/kg also influenced the PTZ convulsions (i. v. titration of 1% solution at a rate of 0.01 ml/s) and had no effect on the strychnine convulsions (i. v. titration of 0.01% solution at a rate of 0.01 ml/s) and on maximal electroshock. In addition, IOS-1.1212 significantly increased antiepileptic effect of phenobarbital on maximal electroshock.     

St. John's wort (Hypericum perforatum L.) and kindling epilepsy in rabbit.

Effects of different extracts of Hypericum perforatum L. on the kindling epileptic discharges were analyzed. The experiment was carried out on Chinchilla rabbits with chronically implanted electrodes in cortical structures and hippocampus. In our study we used water, n-butanol and ether fractions (mass concentrations 0.1 g/ml) of crude ethanol extract of Hypericum perforatum. The particular extracts were given intramuscularly in single dose of 1 ml/kg BW. The bioelectric activity was registered before and after applications of each extracts. The obtained results show that the effect depends on the constituents present in particular fractions. The repression of epileptic activity was in correlation with the polarity of plant constituents. Most polar constituents that remained in water fraction exerted highest antiepileptic activity in all (100%) animals tested. Substances present in butanol fraction repressed the epileptic manifestations in 40% of animals with kindling epilepsy, whereas lipid-soluble constituents in ether fraction potentated the epileptic activity.     

The effect of nicotinamide on the activity of the glutathione- glutathione reductase system in subcellular fractions of regenerating rat liver

Experiments on white rats have shown that growth rates of the glutathione reductase activity and reduced glutathione concentration in the cytoplasmic fraction of the generating liver tissue and especially in the mitochondrial one are more pronounced with an increase of the nicotinamide dose from 50 mg/kg to 150 mg/kg, than after administration of nicotinamide in a dose of 300 mg/kg. Higher doses of nicotinamide (500 mg/kg) produce less pronounced changes in these parameters.     

Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats

It is well known that neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) exert antiepileptic effects in animal models. It has recently been shown that ghrelin neurons increase the activities of GABA and NPY in the brain. Therefore it can be said that ghrelin is an antiepileptic agent. In this study we aimed to investigate the antiepileptic effect of ghrelin in an acute experimental epilepsy model in pentylenetetrazole (PTZ) injected rats. Adult male Wistar albino rats were divided into a control group and four experimental groups with seven rats in each group. In order to generate epileptic seizures, PTZ (50mg/kg) was injected intraperitoneally. The experimental groups received intraperitoneal injections of ghrelin at doses of 20, 40, 60 and 80microg/kg 30min before PTZ injection. After PTZ injection, the latencies were separated into three components: first myoclonic jerk, generalized clonic seizures and tonic generalized extension. The injection of 50mg/kg PTZ-induced epileptic seizures in the control group. The onset times of the three characteristic behavioral changes were significantly delayed and the duration of tonic generalized extension was diminished by dose-dependent ghrelin administration. Our results demonstrated that ghrelin suppresses the onset time of PTZ-induced seizures. In the light of our current knowledge, it seems that ghrelin may be considered as an antiepileptic drug.