Effects of brain‐derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease

Abstract

Brain‐derived neurotrophic factor (BDNF) has been shown to promote the survival of developing motor neurons in vitro and to rescue motor neurons from axotomy‐induced cell death in vivo. In this study, we examined the effects of exogenous BDNF on the progression of wobbler mouse motor neuron disease (MND). After clinical diagnosis at age 3 to 4 weeks, 20 affected mice received subcutaneous injections of recombinant human BDNF (5 mg/kg, n = 10) or vehicle (n = 10), three times a week for 4 weeks. In a separate experiment done to conduct a histometric analysis of the C‐5 and C‐6 ventral roots and to determine the number of myelinated nerve fibers, 7 wobbler mice received identical BDNF treatment. In the 10 BDNF‐treated wobbler mice, grip strength declined at a slower rate (p < 0.03) and was twice as great as that of vehicle‐treated animals at the end of treatment (p < 0.01). In vivo biceps (p < 0.01‐) and in vitro muscle twitch tensions (p < 0.02) were also greater than those of vehicle‐treated mice. The biceps muscle weight was 20% greater (p < 0.05) and the mean muscle fiber diameter was significantly larger in BDNF‐treated mice (p < 0.001) because the number of small (denervated) muscle fibers was markedly reduced. The number of myelinated motor axons at the cervical ventral roots studied in the additional 7 affected mice was 25% greater with BDNF treatment (p < 0.0001). This study establishes that exogenous BDNF administration can retard motor dysfunction in a natural MND and diminish denervation muscle atrophy and motor axon loss.