To explore new therapeutic strategies for Parkinson's disease, we studied the possible protective effect of an immunosuppressant, cyclosporin A (CsA), treatment on changes in dopaminergic function in rats with intrastriatal injections of 6-hydroxydopamine (6-OHDA). Four weeks after injection of 6-OHDA, dopamine (DA) and dihydroxyphenylacetic acid in the striatum were depleted by 70-80%, and repeated high-dose CsA (20 mg/kg) treatment for 1 week significantly protected against these depletions. Tyrosine hydroxylase immunoreactivity (TH-IR) of the cell bodies in the substantia nigra pars compacta (SNc) ipsilateral to the injection were lower than on the contralateral side at 4 weeks but not at 1 week after 6-OHDA injection. The number of TH-positive cell bodies in the SNc decreased to 64% but CsA treatment increased this to 87%. The staining of microglia in the SN with OX42 and Griffonia simplicifolia B4 isolectin was intense at 3 days and gradually decreased by 28 days after injection. At 3 and 7 days after injection, the microglial staining in the SN was prominent and equal both in the 6-OHDA group and in ascorbic acid (SA)-injected controls. By 28 days postinjection, the staining had decreased to control levels in the SA group but was still above the control in the 6-OHDA group. CsA treatment did not affect this staining in either group. These results suggest that CsA protects against 6-OHDA-induced injury of nigrostriatal DA neurons by a mechanism not involving microglia.