U-74500A (lazaroid), a 21-aminosteroid attenuates neuroleptic-induced orofacial dyskinesia.

21-Aminosteroid, or lazaroid, is one of a novel class of antioxidant drugs designed to inhibit iron-dependent lipid peroxidation in biological lipid environments. They have shown promising results in several animal models of traumatic, ischemic and hemorrhagic injury of the central nervous system. Neuroleptic-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to oxidative stress in the basal ganglia. In this study, we have examined the protective role of U-74500A [pregna-1,4,9(11)-triene-3,20-dione, 21-(4-(5,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl)-16-ethyl-HCl (16-alpha)], a 21-aminosteroid having antioxidant property in attenuating the behavioral and biochemical effects of chronic haloperidol and chlorpromazine administration. Haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day i.p.) administered for 21 days caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the number of facial twitchings (FT) observed on day 22. U-74500A (1, 2 and 5 mg/kg i.p.), administered every day, along with haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day), attenuated the increase of VCMs and related behaviors on day 22. Haloperidol and chlorpromazine significantly increased lipid peroxidation in various brain areas such as the cortex, striatum and subcortical parts characterized by an increase in MDA levels. The coadministration of U-74500A limited the effect of haloperidol and chlorpromazine on MDA levels in the cortex and striatum but not in the subcortical parts. U-74500A, an aminosteroid, may have therapeutic use in typical neuroleptic-induced tardive dyskinesia-like effects.