NEUROPROTECTIVE PROPERTIES OF SELECTIVE PPAR GAMMA AGONIST LY554862

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To assess neuroprotective properties of the PPAR GAMMA AGONIST LY554862 in treating Parkinson's disease. Our laboratory has recently shown that chronic oral administration of pioglitazone induces modest neuroprotection against MPTP intoxication in a primate model. Based on this information we continued to investigate PPAR-¿ activation as a possible therapeutic target for PD. Progress: Peroxisome proliferator-activated receptors (PPARs) are part of the nuclear receptor super family and are ligand-dependent transcription factors with three isoforms: ¿, ¿/¿ and ¿. Current evidence suggests that activation of PPAR-¿ can modulate neuroprotection against Parkinson's disease (PD). PPAR-¿ agonists such as rosiglitazone and pioglitazone have been shown to protect against nigrostriatal damage in MPTP mouse models of PD. Our laboratory has recently shown that chronic oral administration of pioglitazone induces modest neuroprotection against MPTP intoxication in a primate model. Based on this information we continued to investigate PPAR-¿ activation as a possible therapeutic target for PD. Eli Lilly Ltd. has synthesized a novel PPAR-¿ agonist, LY554862, which has the potential to be more effective than pioglitazone as it has higher brain penetration. We therefore examined the effects of oral administration of LY554862 to MPTP-treated mice. C57BL/6 and antioxidant response element (ARE)-hPAP reporter mice were orally administered LY554862 (30 mg/kg) or vehicle three days prior to MPTP administration (30 mg/kg, i.p for five days). ARE-hPAP reporter mice were sacrificed seven days after the last MPTP injection and following the last dose of LY554862, while C57BL/6 mice were sacrificed 21 days after the last MPTP injection and following the last dose of LY554862. Preliminary results showed higher expression of tyrosine hydroxylase (TH) in the striatum in animals treated with LY554862 compared to placebo. Higher levels of striatal TH were detected in animals treated with 30 mg/kg of LY554862 alone (no MPTP) compared to placebo. Analysis of striatal catecholamines and ARE levels have not revealed differences between treatment groups at this time. Currently, we are continuing to assess if the PPAR-¿ agonist, LY554862, can be a candidate therapy in PD. This research used WNPRC Assay Services and is precursor work to nonhuman primate studies. A publication is in preparation.