Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity

The neuroprotective properties of cyclosporin A (CsA) are mediated by its a bility to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxi n 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20 -30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD- ir) neurons, A single treatment with CsA protected GAD-ir neurons from 3NP toxicity at lower (0.2 or 1.0 mu M), but not at higher (5.0 mu M) doses. Si milar findings were seen when the cultures were treated twice with cyclospo rin. In vivo experiments used the Lewis rat model of Huntington's disease ( HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injec tions to disrupt the blood-brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP-lesioned rats displayed significantly more dopamine-and adenosine-3',5'-monophosphate-reg ulated phosphoprotein (DARPP32-ir) neurons ipsilateral to BBB disruption co mpared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second ex periment, stereological counts of DARPP32-ir neurons revealed that CsA prot ected striatal neurons in a dose-dependent manner following bilateral disru ption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) bu t not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32-ir striatal neurons relative to vehicle-treated 3NP-lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant p rotection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by prot ecting vulnerable neurons from the primary pathological event observed in H D. (C) 2000 Wiley-Liss, Inc.