Role of brain-derived neurotrophic factor in wobbler mouse motor neuron disease.
Brain-derived neurotrophic factor (BDNF) is neuroprotective for motoneurons undergoing degeneration, including those in natural motor neuron disease (MND) in wobbler mice. To assess the role of BDNF in this model of MND, endogenous BDNF immunoreactivity was analyzed by semiquantitative video-image analysis. Affected cervical spinal cord motoneurons had significantly greater BDNF immunoreactivity compared to motoneurons of healthy littermates (P = 0.01) and affected lumbar spinal cord motoneurons (P = 0.008 at age 4 weeks; P = 0.005 at age 8 weeks). Neuronal nitric oxide synthase (n-NOS) immunocytochemistry revealed increased immunoreactivity in the affected cervical spinal cord motoneurons. Exogenous BDNF treatment partially inhibited the increased NOS activity, as quantitatively measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry. The mean number of NADPH-d(+) motoneurons in the cervical anterior horn decreased from 3.5 +/- 1.2 to 1.5 +/- 1.2 (P = 0.002). The increase in endogenous BDNF immunoreactivity in the affected spinal cord may be compensatory in diseased motoneurons, yet it appears to still be inadequate because exogenous BDNF treatment is required to suppress increased NOS activity in degenerating motoneurons. Our study indicates that BDNF is important in halting nitric oxide (NO)-mediated motor neuron degeneration, which has potential implications for the treatment of neurodegenerative disorders.
Department of Neurology and Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
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Tsuzaka
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Ishiyama
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Pioro
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Mitsumoto
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000378:metabolism*; D002452:Cell Count; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D051379:Mice; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D009252:NADPH Dehydrogenase