Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model.

The protective role of exercise in the nervous system is extensive. Documented in both the central nervous system and peripheral nervous system, exercise preserves neuronal structure and promotes rehabilitation of motor and cognitive function in rodents and humans with neurodegeneration.1–3 Rodent models given an array of neurotoxins in both the hippocampus and brainstem while undergoing treadmill exercise retained spatial memory and motor coordination.4 In humans, both aging individuals and Alzheimer's patients exhibited improvements in cognitive function when prescribed regular exercise regimens.5,6 Additionally, exercise has been shown to improve motor skill acquisition after stroke.7 Retinal neurons are also responsive to neuroprotection through exercise. Mice subjected to treadmill exercise training before and after light-induced retinal degeneration (LIRD) had significantly preserved retinal function and structure compared to mice that were exposed to LIRD but were placed only on stationary treadmills.8 Similarly, with a swimming exercise regimen, rodents subjected to acute retinal injury via intraocular pressure elevation exhibited not only significant preservation of retinal physiology, but also suppression of astrocytic gliosis and macrophage activation.9 While the mechanism of such protection with regular exercise remains to be comprehensively understood, brain-derived neurotrophic factor (BDNF), a ligand of the tropomyosin-related kinase B (TrkB) receptor, may play a key role.10–12 Brain-derived neurotrophic factor signaling via the TrkB receptor promotes neuron growth and survival.13,14 TrkB agonists, like N-[2-(-indol-3-yl)ethyl]-2-oxopiperideine-3-carboximide, have been shown to mitigate retinal cell death as a result of LIRD.15 Additionally, 7,8-dihydroxyflavone, another TrkB agonist, is protective against retinal apoptotic events induced by kainic acid or stroke and is also protective against excitotoxic and oxidative stress in primary cultures of rat retinal ganglion cells.16,17 Local11 and systemic10 BDNF levels have been documented to increase post exercise, suggesting a relationship between neuroprotection and physical activity. In support of this hypothesis, Lawson et al.8 found that retinal, hippocampal, and serum BDNF levels were upregulated immediately after nonvoluntary treadmill exercise. When injected with a TrkB receptor antagonist, these mice that were exercised and exposed to toxic light exhibited significantly less protection of retinal structure and function than their vehicle-injected counterparts.8 Similarly, systemic injection of K252a, a tyrosine kinase inhibitor whose use can disrupt BDNF signaling, eliminates the protective effects of exercise in a rodent model of Parkinson's disease, further supporting the hypothesis that BDNF signaling may mediate exercise-induced neuroprotection.12 Previous studies showing protective effects of exercise on the retina have been limited to acute injury models such as LIRD and intraocular pressure elevation and “forced” exercise paradigms such as treadmill running or swimming.8,9 In this study, we examined the benefits of voluntary running wheel exercise to retinal structure and function in an inherited mouse model of RP, the Pde6brd10 (rd10) strain. The rd10 mice have an autosomal recessive mutation in 3′,5′-cyclic phosphodiesterase in rod photoreceptors, causing rods to degenerate significantly by postnatal day 18 (P18).18,19 A selective TrkB receptor antagonist, ANA-12, was then used to preclude the protective effects of exercise and to explore the subsequent consequences on outer nuclear layer (ONL) cell survival in the rd10 strain. C57BL/6J mice were used as a wild-type control. This voluntary exercise scheme enabled us to explore a more clinically applicable intervention for a model of an as yet incurable human neurodegenerative disease.