Anticonvulsant, but not antiepileptic, action of valproate on audiogenic seizures in metaphit-treated rats.

1. The blocking effects of valproate (2-propylpentanoic acid), a standard anti-epileptic drug, on metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl]-piperidine)-induced audiogenic seizures as a model of generalized, reflex audiogenic epilepsy in adult Wistar male rats were studied. 2. Rats were stimulated using an electric bell (100 +/- 3 dB, 5-8 kHz, 60 s) 60 min after i.p. metaphit (10 mg/kg) injection and afterwards at hourly intervals. For power spectra and electroencephalograph (EEG) recordings, three gold-plated screws were implanted into the skull. Different doses of valproate (50, 75 and 100 mg/kg) were injected i.p. into rats with fully developed metaphit seizures after the eighth audiogenic testing. 3. In metaphit-treated animals, the EEG appeared as polyspikes, spike-wave complexes and sleep-like patterns, whereas the power spectra were increased compared with the corresponding controls. 4. Valproate reduced the incidence and intensity of convulsions and prolonged the duration of the latency period in a dose-dependent manner 4 h after administration. 5. The ED(50) of valproate in the first hour after injection was 63.19 mg/kg (95% confidence interval 51.37-77.71 mg/kg). 6. None of the doses of valproate applied eliminated the EEG signs of metaphit-provoked epileptiform activity. 7. Taken together, these results suggest that all doses of valproate examined acted to suppresse behavioural but not epileptic EEG spiking activity in metaphit-induced seizures.

Antiepileptic activity of delta sleep-inducing peptide and its analogue in metaphit-provoked seizures in rats.

PROBLEM: Previous studies have shown that humoral, endogenous and somnogenic, delta sleep-inducing peptide (DSIP) has influence on insomnia, pain, adaptation to stress, epilepsy, etc. We investigated the potential of DSIP and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DSIP molecule substituted by beta-alanine) to antagonize metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine) induced generalized, reflex audiogenic seizures in adult male Wistar albino rats. METHODS: The rats divided in four groups received (i.p.): saline; metaphit; metaphit+DSIP; and metaphit+DSIP-12, respectively. Metaphit-treated animals displaying seizure in eight previous tests received DSIP or DSIP-12 and afterwards audiogenic stimuli were applied at hourly intervals for the next 30 h. The animals were exposed to sound stimulation 60 min after metaphit administration and further on at hourly intervals. Incidence and severity of seizures were behaviorally analyzed. Selected EEGs and power spectra were recorded and analyzed. RESULTS AND CONCLUSIONS: Metaphit led to hypersynchronous epileptiform activity (polyspikes and spike-wave complexes) and increased power spectra 0.5-30 h after the treatment. Severity of metaphit seizures increased with time to reach the peak 7-12 h after injection. DSIP and DSIP-12 significantly (*P<0.05 and **P<0.01) increased in delta and theta frequency bands and decreased the incidence, mean seizure grade and duration of metaphit convulsions. The results suggest that DSIP and DSIP-12 may be considered as potential antiepileptics in the animal model, DSIP-12 being more efficient than DSIP.

[Experimental models of epilepsy]. / Eksperimentalni modeli epilepsije.

INTRODUCTION: An epileptic seizure is a clinical event and epilepsy is rather a group of symptoms than a disease. The main features all epilepsies have in common include, spontaneous occurrence, repetitiveness, and ictal correlation within the EEG. Epilepsies are manifested with distinct EEG changes, requiring exact clinical definition and consequential treatment. Current data show that 1% of the world's population (approximately 50 million people) suffers from epilepsy, with 25% of patients bpeing refractory to therapy and requiring search for new substances in order to decrease EEG and behavioral manifestations of epilepsies. MATERIAL AND METHODS: In regard to discovery and testing of anticonvulsant substances the best results were achieved by implementation of experimental models. Animal models of epilepsy are useful in acquiring basic knowledge regarding pathogenesis, neurotransmitters (glutamate), receptors (NMDA/AIPA/kainate), propagation of epileptic seizures and preclinical assessment of antiepileptics (competitive and non-competitive NMDA antagonists). RESULTS AND CONCLUSIONS: In our lab, we have developed a pharmacologic model of a (metaphit, NMDA and remacemide-cilastatin) generalized, reflex, and audiogenic epilepsy. The model is suitable for testing various anticonvulsant substances (e.g. APH, A4P, CPP, Mk-801) and potential antiepileptics (e.g. DSIP, its tetra- and octaanalogues).

The effects of delta sleep-inducing peptide on incidence and severity in metaphit-induced epilepsy in rats.

The effects of delta sleep-inducing peptide (DSIP) on metaphit- (1-(1(3-isothiocyanatophenyl)-cyclohexyl) (piperidine)-) induced audiogenic seizures in adult male Wistar rats were studied. The animals were divided into four experimental groups: 1. saline injected; 2. metaphit administered (10 mg x kg (-1)); 3. metaphit administered plus DSIP injected (dose range 0.1-1 mg x kg (-1)) and 4. DSIP injected (1 mg x kg (-1)). Upon treatment, the rats were exposed to sound stimulation ( 100 +/- 3 dB, 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analyzed. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike-wave complex and increased power spectra. Time-course studies revealed the peak of convulsive activity 7-12 h after the injection in metaphit-treated rats. DSIP acted as an anticonvulsant and the most potent anticonvulsive dose of 1 mg x kg (-1)significantly increased power spectra of deltawaves (2-11 h) in comparison with the saline-control group and decreased the incidence and duration of convulsive response, as well as mean seizure grade of metaphit-induced convulsions. These results suggest that DSIP should be considered as having potential anticonvulsant activity in this animal model.