Respiratory Motor Neuron Survival and Plasticity in a Rodent Model of Familial Amyotrophic Lateral Sclerosis.

摘要

Amyotrophic Lateral Sclerosis is an upper and lower motor neuron degenerative disease that is progressive and fatal often within 2 – 5 years of diagnosis. There is conflicting data on some factors related to survival in ALS patients such as gender and enteral nutrition; however, respiratory function is related to ALS prognosis. The ultimate cause of death is most often due to respiratory insufficiency. Despite the vital function of respiration and its prognostic role in ALS, there has been scant translational research of the respiratory system in this disease process. We chose to focus attention on respiratory motor function and motor neuron loss in the SOD1G93A rat model of familial ALS (fALS). We hypothesized that spontaneous compensatory respiratory neuroplasficity preserves ventilatory function until late in disease progression despite severe motor neuron degeneration. We investigated mechanisms of induced compensatory spinal plasticity from chronic treatments known to elicit respiratory plasticity, including intermittent hypoxia, hypercapnia, somatic exercise, and TrkB activation, to determine if further plasticity could be induced beyond the endogenous neuroplasticity of the respiratory system. We investigated the role of treatments shown to increase trophic/growth factors such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) to determine their effectiveness at sparing respiratory motor neurons from degeneration and quantified ventilatory function throughout disease progression. ALS patients often develop sleep-disordered breathing that reduces quality of life for these individuals. We are also presenting novel data that has never been studied before on sighs and post-sigh apneas in the rodent model of fALS. None of the treatments we studied were effective in improving ventilatory function or in ameliorating motor neuron loss in respiratory-associated motor neuron pools, and in the case of oral pharmacological dosing of the TrkB ligand 7,8-dihydroxyflavone (7,8-DHF), there was a decrease in survival time after the onset of symptoms. However, we have shown the remarkable innate compensatory respiratory plasticity that already exists in these animals. Perhaps neurotrophic factors are already at their most effective endogenous levels and there may be a deleterious effect of raising some of these levels above potential therapeutic levels.