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.

Neurotrophic Factors and Amyotrophic Lateral Sclerosis

“…These data indicate that the application of CNTF, and most probably of other neurotrophic factors as well, could interfere with disease mechanisms which primarily have nothing to do with programmed cell death. Similar beneficial effects have also been observed in wobbler mice with CNTF, BDNF and IGF-I (MITSUMOTO et al 1994a,b;HANTAI et al 1995;IKEDA et al 1995), and the data obtained in this mouse mutant have been the basis of previous clinical studies using these factors in ALS patients.…”

BDNF Serum Levels with Respect to Multidimensional Assessment in Amyotrophic Lateral Sclerosis

“…BDNF, in particular, has been shown to impact survival of motor neurons by both in vitro and in vivo models of neuron injury or death [11,12,13,14,15,16]. However, therapeutic trials of BDNF infusion have failed to show significant clinical benefit [17,18].…”

Neurotrophic Factors and Amyotrophic Lateral Sclerosis

“…These favorable effects observed in animal models have relied on in vivo read-out parameters such as grip strength and weight change observations but also on in vitro parameters such as estimation of axonal degeneration and neuronal loss. Slowed disease onset and/or progression have been observed after administration of BDNF [137,143], CNTF [92], LIF [144] or GDNF [142,146] to these animals. Several neuropoietic cytokines (CNTF, LIF, IL-6) have proven to protect motor neurons from axotomy-induced death in a neonatal murine motor neuron degeneration model [38].…”

“…SOD1 mouse/rat, mice overexpressing neurofilament and vegf mouse). Several of these animal models have benefited from subcutaneous [38,90,90,[136][137][138][139][140], intramuscular [141][142][143] or intraperitoneal [144,145] injections of different neurotrophic factors. These favorable effects observed in animal models have relied on in vivo read-out parameters such as grip strength and weight change observations but also on in vitro parameters such as estimation of axonal degeneration and neuronal loss.…”