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PPAR Research
Volume 2013, Article ID 582809, 16 pages
Research Article

Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γ Agonist against MPTP

1Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI 53715, USA
2Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53715, USA
3Department of Neurology, University of Pennsylvania Perelman School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104, USA
4Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA 30322, USA
5School of Pharmacy, 777 Highland Avenue, University of Wisconsin-Madison, Madison, WI 53705, USA
6Department of Medical Physics, 1111 Highland Avenue, University of Wisconsin-Madison, Madison, WI 53705, USA

Received 20 April 2013; Revised 24 July 2013; Accepted 25 July 2013

Academic Editor: Paul Drew

Copyright © 2013 Christine R. Swanson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Activation of the peroxisome proliferator activated receptor-gamma (PPAR)-γ is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR-γ agonist, was neuroprotective in a mouse model of Parkinson’s disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p. ×  5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR-γ and PGC1α expression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR-γ and PGC1α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR-γ agonist for neuroprotective treatment of PD.