Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Abstract

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:

• Parkinson’s disease
• Substantia nigra
• Inflammation
• Basal ganglia
• MPTP
• Nonhuman primates
• Pioglitazone
• PPAR-gamma
• TH

Acknowledgements

The authors would like to thank Valerie Joers for her expert confocal microscopy assistance and helpful discussions of this manuscript, Dr Viktoriya Bondarenko for excellent technical assistance during immunohistochemical procedures, and Dr Sylvia Perez for her advice on cerebral mapping. Support for this study was provided in part by the Michael J. Fox Foundation for Parkinson’s Research (ME) (Grant T32 AG000213 (CS) NIH-NIA), and Grant P51RR000167/P51OD011106 from NIH-NCRR to the Wisconsin National Primate Research Center, University of Wisconsin–Madison. The funding sources had no involvement in the study design, collection, analysis, or interpretation of this data.