Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis

• We examine effects of methylcobalamin in wobbler mice motor neuron disease (MND).
• Ultra-high dose methylcobalamin (methy-B12) attenuates motor symptoms.
• Ultra-high dose methyl-B12 inhibits denervation muscle atrophy and motor axonal loss.
• Methyl-B12 treatment elevates vitamin B12 levels in sera, muscles and spinal cord.
• The data suggest therapeutic potentials of ultrahigh dose methy-B12 in MND patients.

BackgroundHigh-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS.MethodsAfter initial diagnosis of the disease at the postnatal age of 3–4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n = 5/group).ResultsIn comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle.ConclusionOur results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.