PROGLUMIDE, A CHOLECYSTOKININ RECEPTOR ANTAGONIST, EXACERBATES BETA, BETA'-IMINODIPROPIONITRILE-INDUCED DYSKINETIC SYNDROME IN RATS

The present investigation was undertaken to study the effect of proglu mide, a cholecystokinin (CCK) receptor antagonist, on iminodipropionit rile (IDPN)-induced excitation, chorea, and circling (ECC) syndrome in rats. The animals were exposed to IDPN in the dose of 100 mg/kg/day I P for 9 days. Proglumide (PG) was administered TP daily 1 h before IDP N in the doses of 250, 500, and 750 mg/kg body weight in three differe nt groups of rats. The animals were observed daily for neurobehavioral abnormalities including dyskinetic head movements, circling, tail han ging, air righting reflex, locomotor activity, and contact inhibition of the righting reflex. After behavioral studies, blood and brain samp les were collected for the analysis of malondialdehyde (MDA), conjugat ed dienes, vitamin E, and glutathione peroxidase (GSH-Px). The tempora l bones were also collected for inner ear histopathology. Our results showed that proglumide significantly and dose-dependently exacerbated the incidence and the severity of IDPN-induced ECC syndrome during the treatment period as well as up to 3 weeks of postdosing. Administrati on of IDPN produced a significant increase in MDA and conjugated diene s and a decrease in vitamin E and GSH-Px, suggesting the role of oxyge n-derived free radicals (ODFR) in IDPN-induced neurotoxicity. Concomit ant treatment with proglumide potentiated IDPN-induced oxidative stres s. The histopathology of the inner ear showed significantly high degen eration of sensory hair cells in the crista ampullaris of the rats tre ated with IDPN plus proglumide compared to IDPN-alone-treated animals. Further studies are warranted to determine the role of CCK in nitrile toxicity and drug-induced dyskinesia. (C) 1998 Elsevier Science Inc.