Neuroprotective and Anti-inflammatory Effects of the Adenosine A2A Receptor Antagonist ST1535 in a MPTP Mouse Model of Parkinson's Disease

Adenosine A(2A) receptor antagonists are one of the most attractive classes of drug for the treatment of Parkinson's disease (PD) as they are effective in counteracting motor dysfunctions and display neuroprotective and anti-inflammatory effects in animal models of PD. In this study, we evaluated the neuroprotective and anti-inflammatory properties of the adenosine A(2A) receptor antagonist ST1535 in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6J mice were repeatedly administered with vehicle, MPTP (20 mg/kg), or MPTP + ST1535 (2 mg/kg). Mice were sacrificed three days after the last administration of MPTP. Immunohistochemistry for tyrosine hydroxylase (TH) and cresyl violet staining were employed to evaluate dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu). CD11b and glial fibrillary acidic protein (GFAP) immunoreactivity were, respectively, evaluated as markers of microglial and astroglial response in the SNc and CPu. Stereological analysis for TH revealed a 32% loss of dopaminergic neurons in the SNc after repeated MPTP administration, which was completely prevented by ST1535 coadministration. Similarly, CPu decrease in TH (25%) was prevented by ST1535. MPTP treatment induced an intense gliosis in both the SNc and CPu. ST1535 totally prevented CD11b immunoreactivity in both analyzed areas, but only partially blocked GFAP increase in the SNc and CPu. A(2A) receptor antagonism is a new opportunity for improving symptomatic PD treatment. With its neuroprotective effect on dopaminergic neuron toxicity induced by MPTP and its antagonism on glial activation, ST1535 represents a new prospect for a disease-modifying drug. Synapse 65:181-188, 2011. (C) 2010 Wiley-Liss, Inc.