Protective effect of rutin, a polyphenolic flavonoid against haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes

Abstract:

The occurrence and irreversibility of tardive dyskinesia (TD), a motor disorder of the orofacial region, resulting from chronic neuroleptic treatment has been considered a major clinical issue in the treatment of schizophrenia.

The molecular mechanism underlying the pathophysiology of TD is not completely known. Several animal studies have demonstrated an enhancement of oxidative damage and increased glutamatergic transmission after chronic administration of neuroleptics.

The present study investigated the effect of rutin, an antioxidant in haloperidol-induced orofacial dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypic rearing, locomotor activity, percent retention), biochemical [lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase)] and neurochemical (neurotransmitter levels) parameters.

Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements, tongue protrusions and facial jerking in rats, which were significantly inhibited by rutin. Chronic administration of haloperidol also resulted in dopamine receptor sensitivity as evident by a well-shaped response (initial decrease followed by increase) in locomotor activity and stereotypic rearing and also decreased percent retention time on elevated plus maze paradigm. Pretreatment with rutin reversed these behavioural changes.

Besides, haloperidol also induced oxidative damage in all regions of brain which was prevented by rutin, especially in the subcortical region containing striatum. Although turnover of dopamine and noradrenaline decreased in both cortical and subcortical regions after chronic administration of haloperidol, it was significantly reversed by high-dose rutin treatment.

The findings of the present study suggested the involvement of free radicals in the development of neuroleptic-induced orofacial dyskinesia, a putative model of TD, and rutin as a possible therapeutic option to treat this hyperkinetic movement disorder.