MICE LACKING THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA GENE PRESENT REDUCED NUMBER OF DOPAMINE NEURONS IN THE SUBSTANTIA NIGRA WITHOUT ALTERING MOTOR BEHAVIOR OR DOPAMINE NEURON DECLINE OVER LIFE

Peroxisome proliferator-activated receptor alpha (PPAR-alpha), which is expressed by neurons of the nigrostriatal circuit, plays a prominent role in oxidative stress and neuroinflammation. The objectives were: (i) to discern if levels of antioxidant molecules and pro-inflammatory cytokines, along with PPAR-gamma expression are modified in the nigrostriatal region of null PPAR-alpha mice, (ii) to discern whether dopaminergic neuronal features of the substantia nigra pars compacta (SNpc) and dorsal striatum are affected in null mice, and (iii) to establish if aging-induced decline of nigral neurons is different in null PPAR-alpha mice relative to wild-type littermates. A substantial decrease in antioxidant molecules was found in SNpc of null mice, by using ELISA. The pro-inflammatory factors TNF-alpha and IL-3 were found to be reduced in the substantia nigra, suggesting dual and opposite effects of PPAR-alpha deficiency on oxidative and pro-inflammatory molecules. Immunohistological and stereological studies revealed that young null mice present a smaller SNpc (-19.8%; TH downregulation was discarded). Normal locomotion in an open-field was not affected in null mice. Dopamine cell death could be caused by reduced protection against oxidative stress. Old null mice showed a percentage reduction of nigral dopamine neurons similar to that of young null animals, with a rate of decline over life of around 44%, the same value than that of wild-type littermates. These findings suggest that nuclear PPAR-alpha is necessary for the normal development of the substantia nigra along with normal levels of antioxidant molecules. Lack of PPAR-alpha does not modify the normal motor behavior of mice or decline of nigral dopamine neurons throughout life. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.