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RESTORATION OF MOTOR AND NON-MOTOR FUNCTIONS BY NEUROTROPHIC FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE DEPLETION

Subramanian, Krishna (2013) RESTORATION OF MOTOR AND NON-MOTOR FUNCTIONS BY NEUROTROPHIC FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE DEPLETION. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Parkinson’s disease (PD) is a progressive debilitating neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia and postural instability. As the disease progresses there is a loss of dopamine (DA) neurons in the substantia nigra projecting to the various forebrain and sub-cortical regions. Current treatments for PD are unable to prevent or curtail the neurodegenerative process; so rescuing remaining dopamine in the mid-brain has been the recent focus of research examining the effectiveness of neurotrophic factors (NTFs) in the treatment of PD. In this dissertation, the ability of three novel, recently discovered NTFs to restore DA neurons and motor function in a nonhuman primate model of PD was examined. The NTFs were Cerebral Dopamine Neurotrophic Factor (CDNF) and two variants of Neurturin (NRTN), N2 and N4, that have mutations that prevent binding to heparin sulfate binding sites in the brain. These studies used the unilateral low dose (0.15 ± 0.001 mg/kg) monkey 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to cause loss of DA neurons. Six groups of monkeys were studied: vehicle-treated (negative control), Glial Cell-line Derived Neurotropic Factor (GDNF, positive control), two groups of CDNF-treated monkeys (450 μg and 150 μg), and N2 and N4-treated groups. After MPTP, monkeys developed moderate symptoms of PD (PD rating scale score=7.9±0.5 on a scale of 0-22, p<0.001), motor dysfunction and increased daytime sleepiness. After three months of infusions, all three NTFs (150 μg CDNF, N2 and N4) significantly increased the number of DA neurons in the substantia nigra, p=0.03, and improved parkinsonian symptoms measured by rating scale, p<0.001. Most motor functions were significantly correlated with the number of DA neurons in the substantia nigra. N4 significantly improved daytime sleep duration, bouts and wake-latency (p=0.02, p=0.06 and p=0.02, respectively). In summary, CDNF, N2 and N4 trophic factors are neurorestorative to DA neurons, motor function is tightly correlated with DA neuronal number, and N4 improved the non-motor symptom of increased daytime sleepiness in this monkey PD model. These factors hold promise for clinical therapy for PD patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Subramanian, Krishnamyemailiskrishna@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDavis, Brian M
Committee MemberSved, Alan F
Committee MemberZigmond, Michael J
Committee MemberSesack, Susan
Date: 16 December 2013
Date Type: Publication
Defense Date: 25 August 2013
Approval Date: 16 December 2013
Submission Date: 16 December 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 205
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: MPTP, NRTN, GDNF, CDNF, NEUOTROPHIC FACTORS
Date Deposited: 16 Dec 2013 20:17
Last Modified: 15 Nov 2016 14:16
URI: http://d-scholarship.pitt.edu/id/eprint/20301

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