Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease

Cardiotrophin-1 (CT-1) has potent survival-promoting effects on motor neuro ns in vitro and in vivo and may be effective in treating motor neuron disea ses (MND). We investigated the effects of CT-1 treatment in wobbler mouse M ND. Wobbler mice were randomly assigned to receive subcutaneously injected CT-1 (1 mg/kg, n = 18, in two experiments) or vehicle (n = 18, in two exper iments) daily, 6 times/week for 4 weeks after clinical diagnosis at age 3 t o 4 weeks. Cardiotrophin-1 treatment prevented deterioration in paw positio n and walking pattern abnormalities. Grip strength declined steadily in the vehicle group, whereas in the CT-1 group it declined at week 1 but increas ed thereafter to exceed baseline strength by 5% (P = 0.0002) at week 4. Run ning speed was faster with CT-1 (P = 0.007). Biceps muscle twitch tension, muscle weight, mean muscle fiber diameter, and intramuscular axonal sprouti ng were significantly greater with CT-1 treatment than with vehicle treatme nt. Histometry revealed a trend that indicated CT-1 modestly increased the number of immunoreactive motor neurons, as determined by both choline acety ltransferase and c-Ret antibodies, and reduced the number of phosphorylated neurofilament immunoreactive perikarya (P = 0.05). The number of large mye linated motor axons significantly increased with treatment (206 versus 113, P = 0.01). We conclude that CT-1 exerts myotrophic effects as well as neur otrophic effects in a mouse model of spontaneous MND, a finding that has po tential therapeutic implications for human MND. (C) 2001 John Wiley & Sons, Inc.