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Brain-Derived Neurotrophic Factor and Exercise-Induced Neuroprotection in the spastic Han-Wistar rat, a model of ataxia
Moderate aerobic exercise has been shown to enhance motor skills and protect the nervous system from injury and neurodegenerative diseases, like ataxia. Our lab uses the spastic Han-Wistar rat as a model of ataxia. Mutant rats develop fore limb tremor, hind limb rigidity and have a significantly decreased life span. Our lab has previously shown that moderate treadmill exercise reduced Purkinje cell degeneration in the cerebellum, delayed the onset of visible motor dysfunction, and significantly increased life span. This suggested that aerobic exercise ameliorates the observed cerebellar dysfunction in the sHW rat. The focus of this thesis is to understand the mechanism of how exercise may mediate neuroprotection by studying Brain-Derived Neurotrophic Factor (BDNF). BDNF is known to increase after exercise and has been reported to be crucial in Purkinje cell survival through activation of various signaling cascades. The actions of BDNF are mediated by the TrkB receptor. To link BDNF to exercise-induced neuroprotection, 28-day-old mutant and normal rats received surgically implanted Alzet osmotic pumps that chronically infused the TrkB antagonist K252a or the control vehicle (1% DMSO) into the third ventricle. During the 28 day infusion rats were subjected to five-day-per-week exercise regimens on a motorized treadmill. Mutant rats receiving K252a exhibited a 21.4% loss in Purkinje cell survival compared to control mutants. Cerebellar TrkB expression was evaluated using non-drug treated 30-day-old rats that were subjected to various regimens: 7 days of running, 30 days of running, or non-running controls for each age. Running animals expressed up to 3× more TrkB than sedentary animals. BDNF was quantified via Sandwich ELISA, and cerebellar expression was found to be 26.6% greater in mutant rats on 7-day treadmill exercise regimen compared with those subjected to 30 days of treadmill exercise. In normal animals, BDNF expression in acute runners was 10% greater than in chronic runners. Rats did not express significantly more BDNF than sedentary controls in either exercise duration group. In summary, these results suggest the neuroprotective benefits of aerobic exercise can be blocked using the K252a TrkB antagonist, and that BDNF activation of the TrkB receptor signaling pathway is involved in mediating exercise-induced neuroprotection.