Extracellular Superoxide dismutase in Parkinsonā€˜s disease

Tim D. Oury, MD, Ph.D.
University of Pittsburg

Although reactive oxygen species have been implicated in Parkinson’s disease (PD), the neuroprotective roles of specific antioxidant enzyme systems are unkown. Studying the effects of specific antioxidant enzymes may offer important clues not only towards potential therapies for preventing or slowing the progressive disease process, but also towards understanding the mechanisms of cell damage involved. Recent studies using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP) model of PD indicate that nitric oxide produced by reactive glial cells plays an important role in parkinsonian neurodegeneration, potentially due to peroxynitrite that is formed from reaction of nitric oxide with superoxide. Notably, nitric oxide produced by glial cells must traverse the extracellular space to affect neurons.We have previously shown that the enzyme extracellular superoxide dismutase (EC-SOD) modulates nitric oxide responses in the brain by inhibiting superoxide-nitric oxide reactions. Because EC-DOD is normally found in extracellular spaces and on cell membranes in regions where intercellular signaling by nitric oxide takes place place, we hypothesize that EC-SOD may play an important protective role in preventing parkinsonian neurodegeneration by inhibiting peroxynitrite formation. Our immunochemical studies indicate that EC-SOD, which is also seen inside specific populations of neurons, potentially within secretory vesicles. Furthermore, our in situ hybridization studies suggest that the same population of neurons that produce nitric oxide express EC-SOD has an important role in modulating nitric oxide responses in regional of the brain important to PD. Our preliminary data using EC-SOD transgenic mice indicate that EC-SOD does indeed confer protection in MPTP model, suggesting that of PD by preventing the reaction between superoxide and nitric oxide in extracellular spaces.