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

Abstract

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.

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

“…Its receptor consists of a heterodimer made of glycoprotein 130 (GP130) receptor and leukaemia inhibitory factor receptor (LIFR), together with a yet to be described third component [5]. It is also known that CT-1 has beneficial effects in several tissues, such as motoneurons, by protecting them from apoptosis or by participating in regeneration mechanisms [6]. Recent studies have reported the protective role of CT-1 in the liver; CT-1 is upregulated during liver regeneration and exerts anti-apoptotic effects on hepatocytes [7].…”

Cardiotrophin-1: A multifaceted cytokine

“…CT-1 also provided therapeutic benefit in both functional and morphological parameters in a mouse model of spinal muscular atrophy (SMA) [79,80]. Furthermore, adenovirus-mediated gene transfer of CT-1 or the administration of rCT-1 delayed neurogenic muscular atrophy and progressive neuromuscular deficiency in an experimental model of amyotrophic lateral sclerosis (ALS) [79,81]. Finally, adenoviral CT-1 gene transfer into the injured cord promoted survival and regeneration of rubrospinalneurons in adult rats [82] and promyelinating effects of CT-1 have been demonstrated in vitro by Stankoff et al [83].…”

Cardiotrophin-1 Review

“…CT-1 is the fi rst bona fi de muscle-derived neurotrophic factor to be identifi ed that is required for the survival of subgroups of developing motoneurons 46 . It was concluded that CT-1 exerts myotrophic eff ects as well as neurotrophic eff ects in a mouse model of spontaneous moto neuron disease (MND), a fi nding that has potential therapeutic implications for human MND 51 . Summary of consequences between CT-1 and some additive organ systems and diseases are displayed below (Table 3).…”