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

ABSTRACT: Activation of the peroxisome proliferator activated receptor-gamma (PPAR)- ? is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR- ? 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- ? and PGC1 ? 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- ? and PGC1 ? expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR- ? agonist for neuroprotective treatment of PD.

SUBMITTER: Swanson CR

PROVIDER: S-EPMC3808726 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Swanson Christine R CR Du Eric E Johnson Delinda A DA Johnson Jeffrey A JA Emborg Marina E ME

PPAR research 20131002

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 ...[more]

PMID: 24223584

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Dataset Information

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

Publications

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

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