Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome.

Background: Previous studies suggest that specific genes may predispose some to increased risk of dysphagia in the geriatric population, but whether these genes may affect swallowing recovery after a stroke is unknown. This study investigated whether single-nucleotide polymorphisms (SNP) of the brain-derived neurotrophic factor (BDNF), catechol-O-methyl transferase, apolipoprotein E, interleukin-1 receptor antagonist, and dopamine, which have been linked to swallowing, could adversely affect the prognosis of post-stroke dysphagia. Methods: In this study, 218 subjects with confirmed post-stroke dysphagia were enrolled. The primary endpoint was failed recovery from nil per mouth (NPM) status with the first 3 months post-stroke. Key Results: The Val/Val group from the rs6265, BDNF, showed higher score changes on the Functional Oral Intake Scale at 1 month. The proportion of patients with recovery from NPM status within the first 1 month was 60.8% in the Val/Val group, which was statistically higher than those in the Met allele groups (38.1%, P = .017). At 3 months, the BDNF rs6265 showed significant group differences in Modified Barium Swallow Impairment Profile © score changes with the Val/Val allele leading to greater improvement. However, no single SNP was associated with increased risk of poor recovery with persistence of NPM at 3 months post-stroke. Conclusions and Inferences: Those with the dominant Val/Val phenotype of BDNF manifested with faster and greater improvement than the Met-phenotypes. Based on our results, the BDNF Val allele may play a positive role with faster score improvement and rapid recovery from NPM than the Met allele.

Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKβ and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKβ-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKβ-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.