SNARE-wedging polyphenols as small molecular botox.

ABSTRACT

Most cosmetic and therapeutic applications of Clostridium botulinum neurotoxin (BoNT) are related to muscle paralysis caused by the blocking of neurotransmitter release at the neuromuscular junction. BoNT specifically cleaves SNARE proteins at the nerve terminal and impairs neuroexocytosis. Recently, we have shown that several polyphenols inhibit neurotransmitter release from neuronal PC12 cells by interfering with SNARE complex formation. Based on our previous result, we report here that myricetin, delphinidin, and cyanidin indeed paralyze muscle by inhibiting acetylcholine release at the neuromuscular junction. While the effect of myricetin on muscle paralysis was modest compared to BoNT/A, myricetin exhibited a shorter response time than BoNT/A. Intraperitoneally-injected myricetin at an extreme dose of 1000 mg/kg did not induce death of mice, alleviating the safety issue. Thus, these polyphenols might be useful in treating various human hypersecretion diseases for which BoNT/A has been the only option of choice.