The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease

Abstract

Ciliary neurotrophic factor is the first neurotrophic factor to show survival-promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary neurotrophic factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary neurotrophic factor (n = 6) resulted in delayed weight gain (p < 0.001), grip strength normalized to body weight in the factor-treated mice was significantly greater (p < 0.02) and declined at a slower rate (p < 0.05) compared to that in vehicle-treated animals. Human ciliary neurotrophic factor (n = 27) produced no change in body weight and reduced paw position and walking pattern abnormalities (p < 0.001 and p < 0.02, respectively). After 4 weeks of treatment, the mean grip strength of human ciliary neurotrophic factor-treated animals was twice as great (p < 0.001) and declined at a much slower rate (p < 0.005) than that of control mice. The time required to run 2.5 ft was less (p < 0.005) and muscle twitch tension was greater (p < 0.002) in ciliary neurotrophic factor-treated animals. Thus, ciliary neurotrophic factor retarded the disease progression and improved muscle strength in this motor neuron disease model.

Dysmyelinated Lower Motor Neurons Retract and Regenerate Dysfunctional Synaptic Terminals

“…Running time is defined as the shortest time (the best of three trials) to run 75 cm and is calculated in centimeters per second. The test-retest reliability of these assessment techniques has been established previously (Mitsumoto et al, 1994).…”

“…Body weight, running speed, and grip strength were assessed in P 0 tg and wild-type (WT) littermates at postnatal day 30 (P30) (P 0 tg , n ϭ 6; WT, n ϭ 6), P60 (P 0 tg , n ϭ 4; WT, n ϭ 6), and P90 (P 0 tg , n ϭ 3; WT, n ϭ 5) using methods described in detail Mitsumoto et al (1994). Forelimb paw grip strength was measured using a digital force transducer (Chatillion DFIS-2; AMETEK, Paoli, PA).…”

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

“…Indeed, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF) protect motoneurons from acute death induced by peripheral nerve axotomy in neonate rodents (6)(7)(8)(9)(10). Furthermore, CNTF, NT-3, and BDNF show protective effects on motoneurons in murine models of inherited progressive motoneuron degeneration such as progressive motor neuronopathy (pmn) (11,12) and wobbler (13,14). None of these factors, however, has prevented the onset or halted the course of the disease, which has prompted us to test other factors in motoneuron disease models.…”

Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

“…Moreover, endogenous Cntf modulates onset and severity of disease in patients and mouse models for motoneuron disease and other neurological disorders (19)(20)(21). In progressive motor neuronopathy and wobbler mice, Cntf treatment protects motoneurons from cell death and improves motor performance (22,23), indicating that this factor is a major mediator of the protective effects of Schwann cells, both under physiological and pathological conditions.…”