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.
Key words
SNARE - small molecule polyphenol - acetylcholine - muscle paralysis - myricetin
References
-
1
Sollner T, Whiteheart S W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman J E.
SNAP receptors implicated in vesicle targeting and fusion.
Nature.
1993;
362
318-324
-
2
Weber T, Zemelman B V, McNew J A, Westermann B, Gmachl M, Parlati F, Sollner T H, Rothman J E.
SNARE pins: minimal machinery for membrane fusion.
Cell.
1998;
92
759-772
-
3
Sutton R B, Fasshauer D, Jahn R, Brunger A T.
Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution.
Nature.
1998;
395
347-353
-
4
Poirier M A, Xiao W, Macosko J C, Chan C, Shin Y K, Bennett M K.
The synaptic SNARE complex is a parallel four-stranded helical bundle.
Nat Struct Biol.
1998;
5
765-769
-
5
Hanson P I, Roth R, Morisaki H, Jahn R, Heuser J E.
Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy.
Cell.
1997;
90
523-535
-
6
Lin R C, Scheller R H.
Structural organization of the synaptic exocytosis core complex.
Neuron.
1997;
19
1087-1094
-
7
Montecucco C, Schiavo G.
Mechanism of action of tetanus and botulinum neurotoxins.
Mol Microbiol.
1994;
13
1-8
-
8
Jung C H, Yang Y S, Kim J S, Shin J I, Jin Y S, Shin J Y, Lee J H, Chung K M, Hwang J S, Oh J M, Shin Y K, Kweon D H.
A search for synthetic peptides that inhibit soluble N-ethylmaleimide sensitive-factor attachment receptor-mediated membrane fusion.
FEBS J.
2008;
275
3051-3063
-
9
Jung C H, Yang Y S, Kim J S, Shin Y K, Hwang J S, Son E D, Lee H H, Chung K M, Oh J M, Lee J H, Kweon D H.
Inhibition of SNARE-driven neuroexocytosis by plant extracts.
Biotechnol Lett.
2009;
31
361-369
-
10
Yang Y, Shin J Y, Oh J M, Jung C H, Hwang Y, Kim S, Kim J S, Yoon K J, Ryu J Y, Shin J, Hwang J S, Yoon T Y, Shin Y K, Kweon D H.
Dissection of SNARE-driven membrane fusion and neuroexocytosis by wedging small hydrophobic molecules into the SNARE zipper.
Proc Natl Acad Sci USA.
2010;
107
22145-22150
-
11
Ray P, Berman J D, Middleton W, Brendle J.
Botulinum toxin inhibits arachidonic acid release associated with acetylcholine release from PC12 cells.
J Biol Chem.
1993;
268
11057-11064
-
12
Hay D W, Wadsworth R M.
The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug-induced rhythmic contractions in the rat vas deferens.
Br J Pharmacol.
1983;
79
347-362
-
13
Richardson C M, Dowdall M J, Bowman D.
Inhibition of acetylcholine release from presynaptic terminals of skate electric organ by calcium channel antagonists: a detailed pharmacological study.
Neuropharmacology.
1996;
35
1537-1546
-
14
Aoki K R.
A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice.
Toxicon.
2001;
39
1815-1820
-
15
Sugiyama H, Brenner S L, Dasgupta B R.
Detection of Clostridium botulinum toxin by local paralysis elicited with intramuscular challenge.
Appl Microbiol.
1975;
30
420-423
1 These authors made equal contributions to this work.
Dae-Hyuk Kweon
Department of Genetic Engineering
School of Biotechnology and Bioengineering
Sungkyunkwan University
Suwon
Gyeonggi-do 440-746
South Korea
Telefon: +82 3 12 90 78 69
Fax: +82 3 12 90 78 70
eMail: dhkweon@skku.edu
