Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease.
Cardiotrophin-1 (CT-1) has potent survival-promoting effects on motor neurons in vitro and in vivo and may be effective in treating motor neuron diseases (MND). We investigated the effects of CT-1 treatment in wobbler mouse MND. 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 experiments) daily, 6 times/week for 4 weeks after clinical diagnosis at age 3 to 4 weeks. Cardiotrophin-1 treatment prevented deterioration in paw position and walking pattern abnormalities. Grip strength declined steadily in the vehicle group, whereas in the CT-1 group it declined at week 1 but increased thereafter to exceed baseline strength by 5% (P = 0.0002) at week 4. Running speed was faster with CT-1 (P = 0.007). Biceps muscle twitch tension, muscle weight, mean muscle fiber diameter, and intramuscular axonal sprouting were significantly greater with CT-1 treatment than with vehicle treatment. Histometry revealed a trend that indicated CT-1 modestly increased the number of immunoreactive motor neurons, as determined by both choline acetyltransferase and c-Ret antibodies, and reduced the number of phosphorylated neurofilament immunoreactive perikarya (P = 0.05). The number of large myelinated motor axons significantly increased with treatment (206 versus 113, P = 0.01). We conclude that CT-1 exerts myotrophic effects as well as neurotrophic effects in a mouse model of spontaneous MND, a finding that has potential therapeutic implications for human MND.
Mitsumoto
H
H
Department of Neurology and Neurosciences, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. hm264@columbia.edu
Klinkosz
B
B
Pioro
E P
EP
Tsuzaka
K
K
Ishiyama
T
T
O'Leary
R M
RM
Pennica
D
D
D000818:Animals; D016207:Cytokines / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D005684:Gait / Q000187:drug effects; D007279:Injections, Subcutaneous; D051379:Mice; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000187:drug effects; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D012420:Running; D013997:Time Factors
D016207:Cytokines; C092073:cardiotrophin 1