Program Project on the Pathogenesis and Treatment of Parkinson's Disease
Abstract
We are investigating the role of inflammation in, dopaminergic (DA) neuron death in the substantia nigra pars compacta (SNpc) of MPTP-treated mice. Following MPTP administration to mice, there is a robust microglial response in the SNpc that peaks earlier than the peak 0f SNpc DA neuronal death. Several enzymes are up-regulated or induced during the microglial response. Inducible nitric oxide synthase (iNOS), a principle enzyme in the synthesis of nitric oxide, is up-regulated in microglia in the SNpc following MPTP intoxication. Decreasing the presence of iNOS with the antibiotic minocycline, lessened the impact of NPTP on SNpc DA neurons. NADPH oxidase is also up-regulated in microglia. This enzyme is a major source of superoxide radical and is up-regulated significantly after MPTP administration. M40401, a manganese superoxide dismutase mimetic which can penetrate the blood brain barrier and which can react with the superoxide radical at rates equal to or greater than native SOD, significantly attenuated MPTP-induced SNpc DA neuronal death. We also saw less apoptotic cells in the SNpc of COX-2 knockout compared to their non-engineered littermates. Interestingly, thus far, this project has given credence to the oxidative stress theory of SNpc dopaminergic neuron death.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2004
- Accession Number
- ADA430576
Entities
People
- Serge E. Przedborski
Organizations
- Columbia University