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Complex Gene Expression Changes Associated with the Neuroprotective Effect of Forced Limb Use After 6-OHDA Lesion in the Rat Striatum

Karoly Mirnics, M.D.
Departments of Psychiatry and Neurobiology
University of Pittsburgh School of Medicine

Parkinson’s Disease (PD) is a progressive disorder affecting one percent of individuals above age 55, which results largely from the loss of dopamine-containing neurons projecting from the substantia nigra to the dorsal striatum. Little is known about the cause of this deficit, although a leading hypothesis is that PD results from the selective loss by apoptosis of dopamine (DA) neurons due to oxidative stress. That stress might be a result of exposure to an environmental toxin, often exacerbated by age, and/or an inherited abnormality in the production or handling of reactive oxygen species (ROS).

Used in research, 6-hydroxydopamine (6-OHDA), a neurotoxin, can be used to selectively destroy DA neurons. It has been found that motor intervention appears to be neuroprotective against 6-OHDA. The forced use of the impaired forelimb after unilateral 6-OHDA lesion produces, in addition to behavioral sparing, a remarkable sparing of striatal DA, its metabolites, and vesicular monoamine transporter.

Dr. Mirnics believes that neuroprotection by forced limb use is associated with specific, reproducible, and complex gene expression changes in striatum. The molecular bases of the recovery process (or lack of it) are currently unknown, but likely represent a complex cascade of cellular events involving multiple pathways that are differentially changing over the time course of the recovery phase.

Preliminary results of Dr. Mirnic’s research produced novel, exciting, and reproducible gene expression data. The data will be analyzed and verified using standard procedures that are routinely used in their laboratories. The obtained data will constitute a foundation for a funding application to a major granting agency.

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