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

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