Methylcobalamin (MeCbl), the activated form of vitamin B12, has been used to treat some nutritional diseases and other diseases in clinic, such as Alzheimer’s disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present. 1. Introduction Vitamin B12 had been usually treated as sport nutrition, and used to keep old people from getting anemic in past years. Vitamin B12 was regarded as painkilling vitamin in some countries from 1950. Recently studies have shown that vitamin B12 played a key role in the normal functioning of the brain and nervous system and the formation of blood. Vitamin B12 is normally involved in several metabolisms such as DNA synthesis and regulation, fatty acid synthesis, and energy production. Vitamin B12 has some analogs including cyanocobalamin (CNCbl), methylcobalamin (MeCbl), hydroxocobalamin (OHCbl), and adenosylcobalamin (AdoCbl). In mammalian cells, CNCbl and OHCbl are inactive forms and AdoCbl acts as a coenzyme of methylmalonyl Co-A mutase in mitochondria. However, vitamin B12 was not used directly in human body, and it should be translated into activating forms such as MeCbl or AdoCbl. MeCbl differs from vitamin B12 in that the cyanide is replaced by a methyl group (Figure 1) [1]. It is a coenzyme of methionine synthase, which is required for the formation of methionine from homocysteine in the methylation cycle which involves methylation of DNA or proteins [2–5]. Compared with other analogs, MeCbl is the most effective one in being uptaken by subcellular organelles of neurons. Therefore, MeCbl may provide better treatments for nervous disorders through effective systemic or local delivery. Figure 1: The chemical structure of MeCbl. As an auxiliary agent, MeCbl has been always used to treat many diseases, such as B12 deficiency and Alzheimer’s disease syndromes [6, 7]. L-methylfolate, MeCbl, and N-acetylcysteine improved memory, emotional functions, and communication with other people among Alzheimer’s patients [7, 8]. MeCbl also has
References
[1]
L. R. McDowell, Vitamins in Animal and Human Nutrition, John Wiley & Sons, 2008.
[2]
R. Banerjee and S. W. Ragsdale, “The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes,” Annual Review of Biochemistry, vol. 72, pp. 209–247, 2003.
[3]
S. K. Ghosh, N. Rawal, S. K. Syed, W. K. Paik, and S. D. Kim, “Enzymic methylation of myelin basic protein in myelin,” Biochemical Journal, vol. 275, part 2, pp. 381–387, 1991.
[4]
A. Pfohl-Leszkowicz, G. Keith, and G. Dirheimer, “Effect of cobalamin derivatives on in vitro enzymatic DNA methylation: methylcobalamin can act as a methyl donor,” Biochemistry, vol. 30, no. 32, pp. 8045–8051, 1991.
[5]
J. I. Toohey, “Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood?” BioFactors, vol. 26, no. 1, pp. 45–57, 2006.
[6]
Y. Takahashi, S. Usui, and Y. Honda, “Effect of vitamin B12 (mecobalamin) on the circadian rhythm of rat behavior,” Clinical Neuropharmacology, vol. 15, supplement 1, part A, pp. 46A–47A, 1992.
[7]
A. McCaddon and P. R. Hudson, “L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline,” CNS Spectrums, vol. 15, supplement 1, no. 1, pp. 2–6, 2010.
[8]
T. Ikeda, K. Yamamoto, K. Takahashi et al., “Treatment of Alzheimer-type dementia with intravenous mecobalamin,” Clinical Therapeutics, vol. 14, no. 3, pp. 426–437, 1992.
[9]
M. Kikuchi, S. Kashii, Y. Honda, Y. Tamura, K. Kaneda, and A. Akaike, “Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture,” Investigative Ophthalmology and Visual Science, vol. 38, no. 5, pp. 848–854, 1997.
[10]
X. Kong, X. Sun, and J. Zhang, “The protective role of Mecobalamin following optic nerve crush in adult rats,” Yan Ke Xue Bao, vol. 20, no. 3, pp. 171–177, 2004.
[11]
A. Akaike, Y. Tamura, Y. Sato, and T. Yokota, “Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons,” European Journal of Pharmacology, vol. 241, no. 1, pp. 1–6, 1993.
[12]
G. Devathasan, W. L. Teo, and A. Mylvaganam, “Methylcobalamin in chronic diabetic neuropathy. A double-blind clinical and electrophysiological study,” Clinical Trials Journal, vol. 23, no. 2, pp. 130–140, 1986.
[13]
S. Kuwabara, R. Nakazawa, N. Azuma et al., “Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients,” Internal Medicine, vol. 38, no. 6, pp. 472–475, 1999.
[14]
H. Ishihara, M. Yoneda, W. Yamamoto, et al., “Efficacy of intravenous administration of methycobalamin for diabetic peripheral neuropathy,” Med Consult N Remedies, vol. 29, no. 1, pp. 1720–1725, 1992.
[15]
M. Sonobe, H. Yasuda, I. Hatanaka et al., “Methylcobalamin improves nerve conduction in streptozotocin-diabetic rats without affecting sorbitol and myo-inositol contents of sciatic nerve,” Hormone and Metabolic Research, vol. 20, no. 11, pp. 717–718, 1988.
[16]
T. Watanabe, R. Kaji, N. Oka, W. Bara, and J. Kimura, “Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy,” Journal of the Neurological Sciences, vol. 122, no. 2, pp. 140–143, 1994.
[17]
T. Iwasaki and S. Kurimoto, “Effect of methylcobalamin in accommodative dysfunction of eye by visual load,” Journal of UOEH, vol. 9, no. 2, pp. 127–132, 1987.
[18]
M. Yamashiki, A. Nishimura, and Y. Kosaka, “Effects of methylcobalamin (vitamin B12) on in vitro cytokine production of peripheral blood mononuclear cells,” Journal of Clinical and Laboratory Immunology, vol. 37, no. 4, pp. 173–182, 1992.
[19]
M. Ikeda, M. Asai, T. Moriya, M. Sagara, S. Inoué, and S. Shibata, “Methylcobalamin amplifies melatonin-induced circadian phase shifts by facilitation of melatonin synthesis in the rat pineal gland,” Brain Research, vol. 795, no. 1-2, pp. 98–104, 1998.
[20]
K. Takahashi, M. Okawa, M. Matsumoto et al., “Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders,” Psychiatry and Clinical Neurosciences, vol. 53, no. 2, pp. 211–213, 1999.
[21]
H. Ide, S. Fujiya, Y. Asanuma, M. Tsuji, H. Sakai, and Y. Agishi, “Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy,” Clinical Therapeutics, vol. 9, no. 2, pp. 183–192, 1987.
[22]
G. Li, “Effect of mecobalamin on diabetic neuropathies. Beijing Methycobal Clinical Trial Collaborative Group,” Zhonghua Nei Ke Za Zhi, vol. 38, no. 1, pp. 14–17, 1999.
[23]
Y. U. Dongre and O. C. Swami, “Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience,” International Journal of General Medicine, vol. 6, pp. 413–417, 2013.
[24]
J. W. Frymoyer, “Back pain and sciatica,” The New England Journal of Medicine, vol. 318, no. 5, pp. 291–300, 1988.
[25]
W. Waikakul and S. Waikakul, “Methylcobalamin as an adjuvant medication in conservative treatment of lumbar spinal stenosis,” Journal of the Medical Association of Thailand, vol. 83, no. 8, pp. 825–831, 2000.
[26]
C. K. Chiu, T. H. Low, Y. S. Tey, V. A. Singh, and H. K. Shong, “The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial,” Singapore Medical Journal, vol. 52, no. 12, pp. 868–873, 2011.
[27]
L. Manchikanti, E. E. Dunbar, B. W. Wargo, R. V. Shah, R. Derby, and S. P. Cohen, “Systematic review of cervical discography as a diagnostic test for chronic spinal pain,” Pain Physician, vol. 12, no. 2, pp. 305–321, 2009.
[28]
L. Manchikanti, S. Abdi, S. Atluri, et al., “American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part I—evidence assessment,” Pain Physician, vol. 15, no. 3, pp. S1–S65, 2012.
[29]
I. Y. Hanai, M. K'Yatsume, et al., “Clinical study of methylcobalamin on cervicales,” Drug Therapy, vol. 13, no. 4, p. 29, 1980.
[30]
G. Xu, Z. W. Lv, Y. Feng, W. Z. Tang, and G. X. Xu, “A single-center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia,” Pain Medicine, vol. 14, no. 6, pp. 884–894, 2013.
[31]
P. M. Singh, M. Dehran, V. K. Mohan, A. Trikha, and M. Kaur, “Analgesic efficacy and safety of medical therapy alone vs combined medical therapy and extraoral glossopharyngeal nerve block in glossopharyngeal neuralgia,” Pain Medicine, vol. 14, pp. 93–102, 2013.
[32]
J. Teramoto, “Effects of Methylcobalamin on neuralgia,” Neurological Therapeutics, vol. 1, no. 2, p. 315, 1984.
[33]
A. S. Morani and S. L. Bodhankar, “Neuroprotecive effect of early treatment with pioglitasone and methylcobalamin in alloxan induced diabetes in rats,” Pharmacologyonline, vol. 3, pp. 282–293, 2007.
[34]
A. S. Morani and S. L. Bodhankar, “Early co-administration of vitamin E acetate and methylcobalamin improves thermal hyperalgesia and motor nerve conduction velocity following sciatic nerve crush injury in rats,” Pharmacological Reports, vol. 62, no. 2, pp. 405–409, 2010.
[35]
I. Jurna, “Analgesic and analgesia-potentiating action of B vitamins,” Schmerz, vol. 12, no. 2, pp. 136–141, 1998.
[36]
Y. Sun, M. S. Lai, and C. J. Lu, “Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials,” Acta Neurologica Taiwanica, vol. 14, no. 2, pp. 48–54, 2005.
[37]
K. Okada, H. Tanaka, K. Temporin et al., “Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model,” Experimental Neurology, vol. 222, no. 2, pp. 191–203, 2010.
[38]
K. Yamatsu, Y. Yamanishi, T. Kaneko, and I. Ohkawa, “Pharmacological studies on degeneration and regeneration of peripheral nerves. (II). Effects of methylcobalamin on mitosis of Schwann cells and incorporation of radio active leucine into protein fraction of crushed sciatic nerve in rats,” Folia Pharmacologica Japonica, vol. 72, no. 2, pp. 269–278, 1976 (Japanese).
[39]
K. Yamazaki, K. Oda, C. Endo, T. Kikuchi, and T. Wakabayashi, “Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse,” Neuroscience Letters, vol. 170, no. 1, pp. 195–197, 1994.
[40]
A. M. Jacobs and D. Cheng, “Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5′-phosphate,” Reviews in Neurological Diseases, vol. 8, no. 1-2, pp. 39–47, 2011.
[41]
W.-H. Xiao and G. J. Bennett, “Synthetic ω-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 274, no. 2, pp. 666–672, 1995.
[42]
Y. W. Yoon, H. S. Na, and J. M. Chung, “Contributions of injured and intact afferents to neuropathic pain in an experimental rat model,” Pain, vol. 64, no. 1, pp. 27–36, 1996.
[43]
Y. S. Lyu, S. K. Park, K. Chung, and J. M. Chung, “Low dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model,” Brain Research, vol. 871, no. 1, pp. 98–103, 2000.
[44]
J. Lai, M. S. Gold, C. S. Kim et al., “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8,” Pain, vol. 95, no. 1-2, pp. 143–152, 2002.
[45]
S. R. Chaplan, H.-Q. Guo, D. H. Lee et al., “Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain,” The Journal of Neuroscience, vol. 23, no. 4, pp. 1169–1178, 2003.
[46]
I. T. Atsuta Y, O. Sugawara, T. Muramoto, T. Watakabe, and Y. Takemitsu, “The study of generating and suppressive factors of ectopic firing in the lumbar dorsal root using an in vitro model,” Rinsho Seikei Geka, vol. 29, pp. 441–446, 1994.
