[The delta-sleep inducing peptide and its effect on the electroencephalogram and power spectrum density in rats with metaphit-induced epilepsy].
BACKGROUND
Sleep has many common features with epilepsy (spontaneously, recurring event and EEG hypersynchrony including EEG potentials that look very similar to epileptiform sharp waves) [1]. Monnier et al. [4] reported the presence of a sleep-inducing factor inducing sleep with predominant EEG activity in the 8 band (1-4 Hz), and it was the reason for the term delta sleep-inducing peptide (DSIP). Metaphit was synthesized by Rafferty et al. (1985) [7] and was shown to increase general brain excitability and induce audiogenic seizures in small rodents. The effects of a natural somnogenic nonapeptide DSIP on metaphit-induced audiogenic epilepsy in rats were studied with the aim of shedding more light on answering the question whether DSIP could be included in the list of antiepileptic agents.


METHODS
Adult, 2-month-old male Wistar rats (170-200 g) were used. None of the animals screened for audiogenic susceptibility showed seizure activity. Audiogenic stimulation was used for 60 s using an electric bell (100 +/- 3 dB 5-8 kHz). Rats were divided into four groups: 1. Control, saline-injected (n = 6); 2. metaphit administered (10 mg/kg; n = 12); 3. metaphit + DSIP (1 mg/kg), (n = 14) group, DSIP administered after 8th to investigate blocking effect on fully developed metaphit seizure. 4.DSIP alone (1 mg/kg, n = 6).


RESULTS
In control saline-injected animals AGS provoked no convulsive response. Metaphit injection produced after 30 min initial EEG changes in the form of synchronized spikes and fast high-voltage activity that are typical seizure manifestations, power spectra increased and became more intense in the period of sound onset and seizure events. Our results demonstrate that DSIP acted increasing the EEG output in the 8 range and significantly elevated the mean power spectra in all checked experimental points. Besides, DSIP decreased the incidence and duration of convulsive component, as well as mean seizure grade in metaphit-induced seizures.


CONCLUSIONS
Metaphit induces a generalized, reflex epilepsy thus providing an experimental model of choice for the studies of the mechanism of epilepsy development and blockade of NMDA/PCP receptors. In our previous studies a competitive NMDA antagonist CPP [9] and a noncompetitive antagonist MK-801 [8] were used. Non-competitive, selective NMDA antagonists MK-801, PCP and ketamin expressed a partial agonist motor action (myoclonic jerks, ataxia and tremor of the whole body) in audiogenic epilepsy prone mice. DSIP produced no harmful effects even when overdosed or any effect over "normality" [4, 5]. DSIP has a capacity of suppressing various forms of convulsive activity in different animal species. It was suggested that it exerts an anticonvulsant action by influencing neurotransmitter (dopaminergic, adrenergic, GABA-ergic) and neuromodulator (peptidergic) brain systems [12, 13].


CONCLUSIONS
Our results, together with the fact that DSIP penetrates through the blood brain barrier after systemic administration and that overdoses of this natural peptide produce no harmful effects, strongly suggest that it could be an important therapeutic agent for the treatment of sleep disturbances. Also, our data demonstrating reduction in incidence, severity and duration of seizure components, suggest that this agent might be a suitable candidate as an antiepileptic drug.
Stanojlovic
O
O
Department of Physiology, University School of Medicine, Belgrade. maxol@eunet.yu
Zivanovic
D
D
Susic
V
V
D000818:Animals; D003701:Delta Sleep-Inducing Peptide / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects*; D020195:Epilepsy, Reflex / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives*; D051381:Rats; D017208:Rats, Wistar
D003701:Delta Sleep-Inducing Peptide; C044705:metaphit; D010622:Phencyclidine