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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000167-50
Application #
8358230
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$39,092
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ellis, Amy; Balgeman, Alexis; Rodgers, Mark et al. (2017) Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques. Infect Immun 85:
Mattison, Julie A; Colman, Ricki J; Beasley, T Mark et al. (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063
Buechler, Connor R; Bailey, Adam L; Lauck, Michael et al. (2017) Genome Sequence of a Novel Kunsagivirus (Picornaviridae: Kunsagivirus) from a Wild Baboon (Papio cynocephalus). Genome Announc 5:
Rodrigues, Michelle A (2017) Female Spider Monkeys (Ateles geoffroyi) Cope with Anthropogenic Disturbance Through Fission-Fusion Dynamics. Int J Primatol 38:838-855
Wu, Hong; Whritenour, Jessica; Sanford, Jonathan C et al. (2017) Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys. Toxicol Pathol 45:127-133
Shackman, A J; Fox, A S; Oler, J A et al. (2017) Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry 22:724-732
Kalin, Ned H (2017) Mechanisms underlying the early risk to develop anxiety and depression: A translational approach. Eur Neuropsychopharmacol 27:543-553
Singaravelu, Janani; Zhao, Lian; Fariss, Robert N et al. (2017) Microglia in the primate macula: specializations in microglial distribution and morphology with retinal position and with aging. Brain Struct Funct 222:2759-2771
Feltovich, Helen (2017) Cervical Evaluation: From Ancient Medicine to Precision Medicine. Obstet Gynecol 130:51-63
Sutton, Matthew S; Burns, Charles M; Weiler, Andrea M et al. (2016) Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV. J Virol 90:5541-8

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