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.