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 endplate 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.
Fighting Neurotoxicity
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.
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