Objective: To characterize the distribution of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the substantia nigra of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated hemiparkinsonian monkeys, in order to validate PPAR-gamma as a target for neuroprotection.
Methods: Immunohistochemical analysis of PPAR-gamma expression was performed in the substantia nigra and other select brain regions of fifteen rhesus monkeys including controls (n = 3), hemiparkinsonian necropsied after 3 (n = 5) or 12 (n = 3) months after MPTP, and animals who received MPTP+5 mg/kg of the PPAR-gamma agonist pioglitazone (n = 4).
Results: PPAR-gamma expression was prominent in the subthalamic nucleus, oculomotor nucleus, ventral tegmental nucleus, and to a lesser extent, in the putamen; 3 or 12 months after MPTP, only the lesioned putamen had increased PPAR-gamma. Stereological cell quantification in normal subjects showed that approximately 50% of neurons in the substantia nigra pars compacta (SNpc) expressed PPAR-gamma. After MPTP, there was a significant loss of dopaminergic neurons in the ipsilateral SNpc and the actual numbers of tyrosine hydroxylase (TH) and PPAR-gamma cells were not significantly different at either time point. Pioglitazone dosing protected TH-positive neurons, closely matching the number of PPAR-gamma expressing cells in the ipsilateral SNpc. Nigral immunofluorescence verified colocalization of PPAR-gamma in neurons.
Discussion: These results demonstrate that PPAR-gamma is expressed in the SNpc and putamen of nonhuman primates and, that the dopaminergic nigral neurons expressing PPAR-gamma are more likely to survive neurotoxin challenge after ligand activation by pioglitazone, therefore providing neuroanatomical validation for the use of PPAR-gamma agonists in Parkinson's disease (PD).
Keywords: Basal ganglia,; Inflammation,; MPTP,; Nonhuman primates,; PPAR-gamma,; Parkinson’s disease,; Pioglitazone,; Substantia nigra,; TH.