The goal of effective neuroprotective treatments in Parkinson's disease (PD) is to slow or halt the progressive degeneration of nigrostriatal dopamine (DA) neurons associated with deteriorating motor function. Emerging evidence suggests that microglial activation and inflammation-mediated oxidative stress are important mechanisms in the pathogenesis and propagation of the nigrostriatal DA neuronal damage seen in PD [4, 5]. As such, anti-inflammatory agents and, more specifically, inhibitors of inflammation-mediated oxidative stress are rational candidates for neuroprotective drugs in patients with PD. Apocynin, a selective inhibitor of NADPH-oxidase, can block the production of superoxide and oxygen free radicals that typically accompany inflammation [6, 7]. Apocynin has been used to prevent oxidative stress-mediated cell damage in several disease models [8-18], but has not been investigated in animal models of PD. The goal of this project is to provide predinical efficacy and safety data for the use of apocynin as a neuroprotective therapy in PD. To this end, we propose to determine the ability of apocynin to inhibit damage to nigrostriatal DA neurons in mice following chronic l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) exposure. We hypothesize that apocynin will protect nigrostriatal DA neurons from MPTP-induced neuronal damage by inhibiting NADPH-oxidase mediated production of oxygen free radicals in the substantia nigra. The following specific aims are proposed: 1. To provide preclinical pharmacokinetc and safety data for the chronic use ofapocynin as a neuroprotective compound in PD. 2. To provide preclinical efficacy data for apocynin as a neuroprotective compound in the chronic MPTP mouse model of PD. The completion of the proposed studies will provide the critical preclincal data that would facilitate direct translation ofapocynin into phase I clinical testing as a potential neuroprotective compound in PD. If successful, the novel neuroprotective strategy of NADPH-oxidase inhibition could be developed to slow secondary disease progression in patients with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS051406-01
Application #
6905969
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Murphy, Diane
Project Start
2005-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$167,820
Indirect Cost
Name
Michigan State University
Department
Neurology
Type
Schools of Osteopathy
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824