Haloperidol - induced neurotoxicity - possible implications for tardive dyskinesia

Tardive dyskinesia (TD) is one of the major side effects of long term neuro leptic treatment. The pathophysiology of this disabling and commonly irreve rsible movement disorder is still obscure. The traditional concept of super sensitivity of striatal dopamine receptors as the mechanism involved in the development of TD is not satisfying, and current studies have focused on t he role of neuroleptic - induced neuronal toxicity in the development of TD . We performed a series of experiments to gain a better understanding on th e mechanisms involved in induction of TD. We have evaluated the direct neur otoxic effect of haloperidol (HP), a widely - used neuroleptic drug, and it s three metabolites, in mouse neuronal cultures and in PC-12 cells. We found that the features of HP-induced cell death were apoptotic rather t han necrotic, as indicated by different DNA-staining methods and specific c aspases inhibitors. Moreover, cotreatment with antioxidants such as vitamin E and N-acetylcysteine (NAC) significantly protected the cultures. Further studies on the mechanisms underlying HP-induced toxicity may lead to the d evelopment of new neuroprotective therapeutic strategies.