%0 Journal Article
%T Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-¦Ã Agonist against MPTP
%A Christine R. Swanson
%A Eric Du
%A Delinda A. Johnson
%A Jeffrey A. Johnson
%A Marina E. Emborg
%J PPAR Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/582809
%X Activation of the peroxisome proliferator activated receptor-gamma (PPAR)-¦Ã is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR-¦Ã 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. ¡Á£¿£¿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-¦Ã and PGC1¦Á 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-¦Ã and PGC1¦Á expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR-¦Ã agonist for neuroprotective treatment of PD. 1. Introduction Neuroinflammation plays a key role in nigral dopaminergic (DA) cell loss in Parkinson¡¯s disease (PD; [1]). Microglia serve as resident immune cells of the nervous system, and under normal conditions they monitor the environment of the brain in a resting state. However, in response to trauma or insult, microglia become activated, exhibiting phagocytic morphology and upregulation of CD1 and cell adhesion molecules such as MAC-1 (CD11b) and CD54 [1]. When activated for a prolonged period of time, microglia release a cascade of proinflammatory cytokines such as TNF-¦Á, IL-1¦Â, and IL-6, which may lead to mitochondrial dysfunction and cell death [1]. Activated microglia are present at a high density in the substantia nigra of patients with PD [2, 3]. Nigral DA neurons seem to be particularly susceptible to inflammation due to a number of factors including decreased glutathione levels (reducing antioxidant ability [4], diminished redox activity [5], high density of neuromelanin [6], and elevated
%U http://www.hindawi.com/journals/ppar/2013/582809/