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Role of Exercise and GDNF in an Animal Model of Parkinson's Disease: Implications for Neuroprotection

Cohen, Annie D (2006) Role of Exercise and GDNF in an Animal Model of Parkinson's Disease: Implications for Neuroprotection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Cohen, Annie Dcohenad@upmc.eduANC2597
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCard, J. Patrickcard@bns.pitt.eduCARD
Committee MemberSmith, Amanda Dsmithad@pitt.eduSMITHAD
Committee MemberDavis, Brian MDavisB@dom.pitt.eduBMD1
Committee MemberDeFranco, Donald Bdod1@pitt.eduDOD1
Committee MemberZigmond, Michael Jzigmond@pitt.eduZIGMOND
Committee MemberHastings, Teresa Ghastingst@upmc.eduTHASTING
Date: 11 December 2006
Date Type: Completion
Defense Date: 16 August 2006
Approval Date: 11 December 2006
Submission Date: 30 November 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: 6-hydroxydopamine; Dopamine; Exercise; GDNF; Nigrostriatal Pathway; Parkinson's Disease
Other ID:, etd-11302006-134350
Date Deposited: 10 Nov 2011 20:06
Last Modified: 19 Dec 2016 14:37


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