EXPRESS: Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats: Effect on loss of peripheral nerve fibers and imbalance of cytokines in the spinal dorsal horn.
BACKGROUND
Vincristine, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and there are currently no effective drugs to prevent or treat this side effect. Previous studies have shown that methylcobalamin has potential analgesic effect in diabetic and chronic compression of dorsal root ganglion model; however, whether methylcobalamin has effect on vincristine-induced painful peripheral neuropathy is still unknown.


RESULTS
We found that vincristine-induced mechanical allodynia and thermal hyperalgesia, accompanied by a significant loss of intraepidermal nerve fibers in the plantar hind paw skin and an increase in the incidence of atypical mitochondria in the sciatic nerve. Moreover, in the spinal dorsal horn, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the protein expression of p-p65 as well as tumor necrosis factor a was increased, whereas the protein expression of IL-10 was decreased following vincristine treatment. Furthermore, intraperitoneal injection of methylcobalamin could dose dependently attenuate vincristine-induced mechanical allodynia and thermal hyperalgesia, which was associated with intraepidermal nerve fibers rescue, and atypical mitochondria prevalence decrease in the sciatic nerve. Moreover, methylcobalamin inhibited the activation of NADPH oxidase and the downstream NF-kB pathway. Production of tumor necrosis factor a was also decreased and production of IL-10 was increased in the spinal dorsal horn following methylcobalamin treatment. Intrathecal injection of Phorbol-12-Myristate-13-Acetate, a NADPH oxidase activator, could completely block the analgesic effect of methylcobalamin.


CONCLUSIONS
Methylcobalamin attenuated vincrinstine-induced neuropathic pain, which was accompanied by inhibition of intraepidermal nerve fibers loss and mitochondria impairment. Inhibiting the activation of NADPH oxidase and the downstream NF-kB pathway, resulting in the rebalancing of proinflammatory and anti-inflammatory cytokines in the spinal dorsal horn might also be involved. These findings might provide potential target for preventing vincristine-induced neuropathic pain.
Jing
J
Xu
Wei
W
Wang
Xiong-Xiong
XX
Zhong
Yiwei
Y
Feng
Xuhong
X
Wei
Xian-Guo
XG
Liu
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009437:Neuralgia / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy*; D010703:Phorbol Esters / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology*; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014750:Vincristine / Q000009:adverse effects*; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D016207:Cytokines; D016328:NF-kappa B; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C119222:phorbol-12-myristate; D014750:Vincristine; C019476:mecobalamin; D019255:NADPH Oxidases; D014805:Vitamin B 12