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Behavioral and electroencephalographic effects of delta sleep inducing peptide and its analogue on metaphit-induced audiogenic seizures in rats

Stanojlović Olivera P. (Institut za fiziologiju, Medicinski fakultet, Beograd)
Živanović Dragana P. (Institut za fiziologiju, Medicinski fakultet, Beograd)
Mirković Slobodan (Institut za fiziologiju, Medicinski fakultet, Beograd; Institut za patološku fiziologiju, Medicinski fakultet, Beograd)
Vučević Danijela (Institut za patološku fiziologiju, Medicinski fakultet, Beograd)

INTRODUCTION Delta sleep inducing peptide (DSIP) is well known natural somnogenic peptide that has many other physiological functions. DSIP analogues representing hepta-and octapeptides (also known as long) as well as tetrapeptide (termed short, used in our experiments) were synthesized with a view to evaluate the peptide specificity in sleep. The effects of DSIP and its analogue DSIP1-4 on metaphit 1-[1(3-isothiocyanatophenyl-ciclohexyl)-piperidine] induced audiogenic seizures were evaluated in rats. METHODS Male Wistar albino rats were divided into 4 groups: 1. Saline; 2. Metaphit; 3. Metaphit + DSIP, and 4. Metaphit + DSIP1-4. To examine the blocking effects of DSIP and its analogue on fully developed metaphit seizures, the last two groups were injected after the 8th audiogenic testing. Animals were injected with metaphit (10 mg/kg) intraperitoneally (i.p.) and exposed to sound stimulation (100±3 dB, 60 s) at hourly intervals. The incidence and severity (running, clonus and tonus) of seizures were analyzed. For electroencephalographic (EEG) recordings, three gold-plated electrodes were used. Convulsive behavior was assessed by incidence of motor seizure and by seizure severity grade, determined by descriptive rating scale ranging from 0 to 3:0- no response, 1 -wild running only; 2-wild running followed by clonic seizures of all four limbs with body rollover; 3 - wild running progressing to generalized clonic convulsions followed by tonic extension of fore-and hind legs and tail. Sound onset, seizure events, and sound offset, along with the animal's behavior (convulsive or other) were characterized with EEG changes. RESULTS In most animals, the administration of metaphit resulted in electroencephalographic abnormalities, elicited epileptic-form activity in the form of spikes, polyspikes and spike-wave complexes. Maximum incidence and severity of metaphit convulsions occurred 8 h after the injection (9/12, 75%), then abated gradually and disappeared 30 h later. Both DSIP and DSIP1-4 significantly increased the power spectra of d waves and decreased the incidence of seizures, mean seizure grade and tonic component of metaphit-induced convulsions. DISCUSSION Metaphit has been shown to induce audiogenic seizures after systemic and intracerebroventricular administration and to be truly epileptic in small rodents [8-11], although about 8 h after metaphit administration, the power spectra increased and was more intense in the period of sound onset and seizure events. Taken together, DSIP makes an optimal ratio between inhibitory and excitatory amino acid neurotransmitters and may represent one of the endogenous control systems of the brain, thus exerting the protective effect against the seizures [14,15,19]. The results obtained throughout the present study corroborate and broaden the data on prolonged antiepileptic DSIP effect. CONCLUSION The results of the present study strongly suggest that treatment of adult rats with DSIP and its analogue DSIPM should be considered as potential natural antiepileptics.

Keywords: metaphit, audiogenic seizures, DSIP, DSIP1-4, EEG