Type of Document	Dissertation
Author	Cohen, Annie D
Author's Email Address	cohenad@upmc.edu
URN	etd-11302006-134350
Title	Role of Exercise and GDNF in an Animal Model of Parkinson's Disease: Implications for Neuroprotection
Degree	Doctor of Philosophy
Program	Neurobiology
School	School of Medicine
Advisory Committee	Advisor Name Title J. Patrick Card Committee Chair Amanda D. Smith Committee Member Brian M. Davis Committee Member Donald B. DeFranco Committee Member Michael J. Zigmond Committee Member Teresa G. Hastings Committee Member
Keywords	Nigrostriatal Pathway Parkinson's Disease 6-hydroxydopamine GDNF Exercise Dopamine
Date of Defense	2006-08-16
Availability	unrestricted
Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting in part from loss of nigrostriatal dopamine (DA) neurons. Treatments act only to relieve symptoms. It is therefore essential to develop treatments that slow or reverse the neurodegenerative process. Here, I explored exercise as a potential treatment against a 6-hydroxydopamine (6-OHDA) rat model. 6-OHDA causes selective loss of DA neurons, a PD model. Forced limb use after 6-OHDA ameliorates behavioral and striatal DA effects. Further, exercise increases trophic factors, such as GDNF, that have neuroprotective qualities in this model. I explored the effects of forced limb use prior to 6-OHDA on the effects of the toxin and GDNF levels in the striatum. I demonstrated that prior forced limb use attenuated the behavioral deficits and loss of DA typical of 6-OHDA and increased GDNF in the striatum of animals exposed to forced use. The protective effect of exercise could reflect a decrease in the vulnerability of DA neurons, a regeneration of axons, or sprouting of axon terminals from undamaged neurons. Thus, I investigated the hypothesis that casting induced neuroprotection was due to the preservation of DA cells and terminals. Here, I demonstrated that forced limb use protected from 6-OHDA induced loss of DA neurons and terminals. These findings suggest that exercise exerts its effects by decreasing the vulnerability of DA neurons and terminals to 6-OHDA. Because casting increased GDNF, I next examined the effects of GDNF on 6-OHDA neurotoxicity during the 8 wk period after 6-OHDA. Using phenotypic markers of the nigrostriatal system, a non-DA cellular marker, and striatal DA content, I demonstrated these markers in the striatum and SN were not protected at 2 wks after 6-OHDA but recovered by 8 wks. No loss of DA cells in the SN or DA content in the striatum was observed in animals pretreated with GDNF. These data suggest that GDNF prevents 6-OHDA-induced DA cell death, but that weeks are required before these cells begin to normally express phenotypic markers. In conclusion, exercise may function to enhance the brain’s ability to produce trophic factors, which may slow or halt the degenerative process in PD.
Files	Filename       Size       Approximate Download Time (Hours:Minutes:Seconds)     28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access    ann_d_cohen_doctoral_dissertation_2006.pdf 3.94 Mb 00:18:13 00:09:22 00:08:11 00:04:05 00:00:20

If you have questions or comments please send mail to ETD-Feedback or view
the University of Pittsburgh Electronic Theses and Dissertations (ETD) Project page.