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

Ikeda, Ken; Iwasaki, Yasuo; Kaji, Ryuji

doi:10.1016/j.jns.2015.04.052

Cited by 29 publications

(32 citation statements)

References 30 publications

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“…HCY induced exacerbation of ALS is supported by clinical evidence of the favorable effect of HCY-lowering folate and B12 supplements (Zhang et al, 2008 ; Song et al, 2013 ; Ikeda et al, 2015 ). One could suggest that the measurement of endogenous level of HCY in ALS patients should be monitored to determine the best type of treatments (and perhaps prophylaxis).…”

Section: Discussionmentioning

confidence: 97%

“…The role of HCY in ALS is supported by several studies showing the beneficial effects of folate or vitamin B12/B6 treatments (Zhang et al, 2008 ; Song et al, 2013 ), which are well known most efficient approaches to lower the level of endogenous HCY. In line, a large-scale human trial on the action of methylcobalamin in ALS patients is currently ongoing (Ikeda et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Bukharaeva

Shakirzyanova

Khuzakhmetova

et al. 2015

Front. Cell. Neurosci.

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Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Bukharaeva

Shakirzyanova

Khuzakhmetova

et al. 2015

Front. Cell. Neurosci.

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“…Wobbler mouse revealed neuromuscular deficits and neuropathological findings partially mimicking sporadic ALS [ 7 – 10 ]. We previously examined therapeutic responses of several agents in this mouse [ 11 – 18 ]. The present study was aimed to whether symptomatic and neuropathological changes can be ameliorated in wobbler mice treated with edaravone after onset of motor neuron disease.…”

Section: Introductionmentioning

confidence: 99%

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

Ikeda

Iwasaki

2015

PLoS ONE

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Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

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“…There is at least one methodological problem with this study in that it does not appear that raters were blinded. Secondly, in the wobbler mouse model of ALS, post symptomatic treatment with high dose MeCbl (30 mg/kg) was associated with better preserved grip strength compared to lower dose MeCbl (3 mg/kg) or vehicle (16). There are methodological problems with this study according to published guidelines (17), including small animal numbers, and failure to randomize.…”

Section: Pre-clinical Datamentioning

confidence: 97%

ALSUntangled No. 30: Methylcobalamin

2015

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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

Cited by 29 publications

References 30 publications

Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

ALSUntangled No. 30: Methylcobalamin

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