Ciguatoxin Sodium Channel Antagonist
by Alan Cocchetto, NCF Medical Director ©2005
Ciguatoxins are potent, lipophilic sodium channel activator toxins which bind to the voltage sensitive sodium channel (site 5) on the cell membranes of all excitable tissues. Site 5 sodium channel activator toxins include ciguatoxins as well as brevetoxins. The presenting signs of ciguatera poisoning are primarily neurotoxic and include such pathogenomic features such as parasthesias, dysthesias and hightened nociperception. Other sensory abnormalities include pruritis, arthralgia, myalgia and pain. Cerebella dysfunction and weakness due to both neuropathy and polymyositis may be encountered. Autonomic dysfunction can lead to hypotension and bradycardia. Treatment has primarily been considered to be aimed at symptom reduction.
Dr. Daniel Baden, a professor in the chemistry and biological sciences departments, is director of the University of North Carolina at Wilmington (UNCW) Center for Marine Science. Dr. Baden and his team of scientists have been studying the toxins that are produced by red tides. They have found that when these toxins are released, they kill fish and irritate the respiratory system in mammals. Their research team discovered an antitoxin, known as brevenal, that acts to antagonize the action of ciguatoxin and brevetoxin on the voltage sensitive sodium channel site 5. This is exceptional news since such a sensitive antagonist had not been previously available to counteract the effects of ciguatoxin/brevetoxin. Earlier this year, Dr. Baden's team announced that the compound may aid in clearing the mucus build-up associated with cystic fibrosis and other lung diseases.
Because of the significant therapeutic potential of this new class of compounds and the
applications they may provide to the medical community, UNCW has entered into an exclusive license agreement with the pharmaceutical company aaiPharma Inc. Brevenal was discovered during research funded by a $6.6 million dollar grant from the National Institute of Environmental Health Sciences division of the National Institutes of Health.
The NCF examined the medical literature and found that voltage sensitive sodium channel site 5 toxins not only cause bronchoconstriction and alter mucus velocity to adversely affect airways but they are neurotoxic and lymphotoxic as well, suggesting that the immune systems of individuals exposed to these types of toxins (ciguatoxin/brevetoxin) may be at risk. Fortunately, in-vitro testing and animal tests thus far have shown that brevenal antagonizes these adverse effects of these toxins.
As for the NCF and the ciguatera epitope, scientific analysis would have to be conducted to see whether this epitope directly interacts with the voltage sensitive sodium channel site 5 subunit. If this proved to be the case, then brevenal would potentially be of significant therapeutic value to PWC/ME patients to negate the epitope's effect. Thus, should the science play out, this discovery would provide targeted drug therapy that could substantially help patients. As such, the NCF plans to pursue this avenue of research activity in an effort to seek answers to these important medical and scientific questions.
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1. Neurology of ciguatera; Pearn J; J Neurol Neurosurg Psychiatry, 2001 Jan;70(1):4-8
2. Isolation and characterisation of Caribbean ciguatoxins from the horse-eye jack (Caranx latus); Vernoux JP, Lewis RJ; Toxicon, 1997 Jun;35(6):889-900
3. The effect of brevenal on brevetoxin-induced DNA damage in human
lymphocytes; Sayer A, Hu Q, Bourdelais AJ, Baden DG, Gibson JE; Arch Toxicol, 2005 Jun 29
4. Concentration and particle size of airborne toxic algae (brevetoxin)
derived from ocean red tide events; Cheng YS, McDonald JD, Kracko D, Irvin CM, Zhou Y,
Pierce RH, Henry MS, Bourdelaisa A, Naar J, Baden DG; Environ Sci Technol, 2005
5. Natural and derivative brevetoxins: historical background, multiplicity, and effects;
Baden DG, Bourdelais AJ, Jacocks H, Michelliza S, Naar J; Environ Health Perspect,
6. A new polyether ladder compound produced by the dinoflagellate Karenia brevis;
Bourdelais AJ, Jacocks HM, Wright JL, Bigwarfe PM Jr, Baden DG; J Nat Prod, 2005
7. Airway responses to aerosolized brevetoxins in an animal model of asthma; Abraham
WM, Bourdelais AJ, Sabater JR, Ahmed A, Lee TA, Serebriakov I, Baden DG; Am J
Respir Crit Care Med, 2005 Jan 1;171(1):26-34
8. Brevenal is a natural inhibitor of brevetoxin action in sodium channel receptor binding
assays; Bourdelais AJ, Campbell S, Jacocks H, Naar J, Wright JL, Carsi J, Baden DG;
Cell Mol Neurobiol, 2004 Aug;24(4):553-63
10. US Patent Application #20050148539; Application date - July 7,
2005; Titled " Fused pentacyclic polyethers" by Inventors: Baden DG, Abraham WM, and
Bourdelais AJ; Assignee: University of North Carolina at Wilmington
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