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

• Published in: Muscle & nerve Vol. 24; no. 6; pp. 769 - 777
• Main Authors: Mitsumoto, Hiroshi, Klinkosz, Bogdan, Pioro, Erik P., Tsuzaka, Kazufumi, Ishiyama, Takeo, O'Leary, Rhona M., Pennica, Diane
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.06.2001; Wiley
• Subjects: amyotrophic lateral sclerosis; animal model; Animals; Biological and medical sciences; cardiotrophin-1; Cytokines - administration & dosage; Cytokines - therapeutic use; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Gait - drug effects; Injections, Subcutaneous; Medical sciences; Mice; Mice, Neurologic Mutants; Motor Activity - drug effects; motor neuron disease; Motor Neuron Disease - drug therapy; Motor Neuron Disease - pathology; Motor Neuron Disease - physiopathology; Muscle Contraction - drug effects; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Neurology; neurotrophic cytokines; neurotrophic factor; Organ Size - drug effects; Running; Time Factors; wobbler mice; Nervous system diseases; Rodentia; Cytokine; Motor neuron disease; Myelinated nerve fiber; Motor neuron; In vitro; Survival; Neurotrophic factor; Locomotion; Vertebrata; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Degenerative disease; Motor nerve; Cardiotrophin; Spinal cord disease; Myotrophic factor
• ISSN: 0148-639X; 1097-4598
• DOI: 10.1002/mus.1068

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. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 769–777, 2001