Protection via Methylcobalamin
Protective effects of a vitamin B12 analogue, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons
Akaike A Tamura Y Sato Y Yokota T, Eur J Pharmacol (1993 Sep 7) 241(1):1-6
The effects of methylcobalamin, a vitamin B12 analogue, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h. Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium. Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of
methylcobalamin. Chronic exposure to methylcobalamin and S- adenosylmethionine also inhibited the cytotoxicity induced by methyl-D-aspartate or sodium nitroprusside that releases nitric oxide. In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity. These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.
Methylcobalamin and Diabetic Neuropathy
Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy
Ide H Fujiya S Asanuma Y Tsuji M Sakai H Agishi Y, Clin Ther (1987) 9(2):183-92
Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamin (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved. The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n=5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n=11). Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.
Nerve Regeneration with Methylcobalamin
Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy.
Watanabe T Kaji R Oka N Bara W Kimura J, J Neurol Sci (1994 Apr) 122(2):140-3
Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis. We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl- B12, and saline-treated control rats. Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies.
Methylcobalamin, Bell's Palsy
Methylcobalamin treatment of Bell's Palsy
Jalaludin MA, Methods Find Exp Clin Pharmacol (1995 Oct) 17(8):539-44
Bell's palsy patients were assigned into three treatment groups: steroid (group 1), methylcobalamin (group 2) and methylcobalamin + steroid (group 3). Comparison between the three groups was based on the number of days needed to attain full recovery, facial nerve scores, and improvement of concomitant symptoms. The time required for complete recovery of facial nerve function was significantly shorter in the methylcobalamin and methylcobalamin plus steroid groups than in the steroid group. The facial nerve score after 1-3 weeks of treatment was significantly more severe (p < 0.001) in the steroid group compared to the methylcobalamin and methylcobalamin plus steroid groups. The improvement of concomitant symptoms was better in the methylcobalamin treated groups than the group treated with steroid alone.
Nerve Terminal Regeneration
Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse.
Yamazaki K Oda K Endo C Kikuchi T Wakabayashi T, Neurosci Lett (1994 Mar 28) 170(1):195-7
We examined the effects of methylcobalamin (methyl-B12, mecobalamin) on degeneration of motor nerve terminals in the anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mice. GAD mice received orally methyl-B12 (1 mg/kg body wt/day) from the 40th day after birth for 25 days. In the distal end plate zone of the muscle, although most terminals were degenerated in both the untreated and methyl-B12-treated GAD mice, sprouts were more frequently observed in the latter. In the proximal endplate zone, where few degenerated terminals were seen in both groups of the mice, the perimeter of the terminals was increased and the area of the terminals was decreased significantly in the methyl-B12-treated GAD mice. These findings indicate that methyl-B12 promotes regeneration of degenerating nerve terminals in GAD mice.
Protective effects of methylcobalamin, a vitamin B12 analogue, against glutamate-induced neurotoxicity in retinal cell culture.
Kikuchi M Kashii S Honda Y Tamura Y Kaneda K Akaike, Invest Ophthalmol Vis Sci (1997 Apr) 38(5):848-54
Purpose: To examine the effects of methylcobalamin on glutamate- induced neurotoxicity in the cultured retinal neurons. Methods: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity
was assessed quantitatively using the trypan blue exclusion method. Results: Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAMe), which is formed in the metabolic pathway of methylcobalamin. Chronic
exposure to methylcobalamin and SAMe also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity. Conclusions: Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D- aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAMe-mediated methylation.
Methyl Donor Effects
Effect of cobalamin derivatives on in vitro enzymatic DNA methylation: methylcobalamin can act as a methyl donor.
Leszkowicz A Keith G Dirheimer G, Biochemistry (1991 Aug 13) 30(32):8045-51
Methylcytosine synthesis in DNA involves the transfer of methyl groups from S-adenosylmethionine to the 5'-position of cytosine through the action of DNA (cytosine-5)-methyltransferase. The rate of this reaction has been found to be enhanced by cobalt ions. We therefore analyzed the influence of vitamin B12 and related compounds containing cobalt on DNA methylation. Vitamin B12, methylcobalamin, and coenzyme B12 (methylcobalamin) were found to enhance significantly the de novo DNA methylation in the presence of S-adenosylmethionine for concentrations up to 1 microM, but at higher concentrations these compounds were found to inhibit DNA methylation. Methylcobalamin behaves as a competitive inhibitor of the enzymatic methylation reaction (Ki=15 microM), the Km for S-adenosylmethionine being 8 microM. In addition, the use of radioactive methylcobalamin shows that it can be used as a methyl donor in the de novo and maintenance DNA methylation reactions. Thus, two DNA methylation pathways could exist: one involving methylation from S-adenosylmethionine and a second one involving methylation from methylcobalamin.