Neurotoxins, naturally occurring

Brevetoxin B, the complex neurotoxin that opened Chapter 9, is a naturally occurring polyether that interferes with Na ion transport across cell membranes. 

Biogenic polyamines are long linear chains composed of 3 or more amino groups interconnected by methylene bridges (CH2)n where n typically is 3-5. Spermine is a quintessential example, isolated as its crystalline phosphate salt from human sperm by Anton van Leeuwenhoek in 1678. Spermine, and its bio-genetic precursor spermidine, occur in almost all tissues and they play a major role in the modulation of calcium-dependent immune processes and in cell differentiation and proliferation. The discovery that polyamines are structural components of potent spider neurotoxins has lent a certain frisson to their synthesis and it has elevated one of the dullest groups of natural compounds an aura of interest. 

Chemicals with the potential to disrupt the mammalian nervous system may occur naturally (neurotoxins) or arise by synthesis (neurotoxicants). While chemicals with neurotoxic potential are conveniently termed neurotoxins or neurotoxicants , this is not an intrinsic property but rather the description of an effect that may occur if the tissue concentration exceeds a certain threshold. Biological chemicals with neurotoxic properties often have high target specificity and toxic potency, discrete biological actions, and are among the best understood mechanistically. Examples of chemicals with direct or indirect neurotoxic potential are found in bacteria, algae, fungi, plants, coelenterates, insects, arachnids, moll-usks, amphibians, reptiles, fish, and certain mammals (Table 1). 

C,oH,jO, Mr 152.24, oil with a menthol-like odor. Bi-cyclic monoterpene ketones with the thujane structure occurring in two C-4-epimeric forms in nature i SAR,5R) -)-a-T, bp. 83.8-84.1 °C (17 hPa), [a]o -19.2° (neat), (15, 4S,5/ )(+)-)S-T., bp. 85.7 -86.2°C (17 hPa), [a]o +72.5° (neat). Not only the names a-and jS-thuJone but also thujone and isothujone are sometimes used incorrectly in the literature. T. are potent neurotoxins, cause epileptic seizures, and can lead to severe psychic damage. It is not yet known if both epimers exhibit the same biological effects. Occurrence Very widely distributed in the essential oils of Asteraceae, Cupressaceae, Lamiaceae, Pina-ceae species. Thuja oil (Thuja occidentalis, Cupressaceae) contains 40% (-)-a-T. and tansy oil (Tanace-tum vulgare, Asteraceae) 58% (+)-/S-T. 

In addition to the main neurotoxin ibotenic acid, the fly agaric (A. muscaria) contains the toxic amine muscarine (10-216) in small quantities. Much higher amounts of this amine (about 500 times) occur in mycorrhizal fungi of the genus Inocybe that cause the muscarinic poisoning. The muscarine molecule has three asymmetric centres, thus can exist in eight stereoisomers, but only three muscarine isomers, epimuscarine (10-217), allomuscarine (10-218) and epiallomuscarine (10-219), have been found in nature. 

Chapter 8 focused on natural poisons and dealt with chemicals that were directly involved in the day-to-day arms race between species. A ratdesnake s venom, for example, has to neutralize a rodent so that the snake can have dinner. Toxins such as these have to be administered via a spine or a fang or a stinger. In other cases, the poison is not delivered, but rather lies within the animal s body, and exposure only occurs when a predator eats, or attempts to eat, the poisonous prey. The tissues of the blowfish, for example, are edible but contain tetrodotoxin, and extreme care in preparation is necessary lest the diner receive a potentially lethal dose of the neurotoxin. 

Botulinum neurotoxins (BoNTs) are produced by the anaerobic Clostridium botulinum species of bacteria and are the cause of botulism, a life-threatening neuroparalytic disease. They are extremely potent food poisons, with a mouse LD50 of 0.1 ng/kg for type A [1,2]. Aerosol exposure of BoNTs does not occur naturally, but could be attempted by bioterrorists to achieve a widespread effect. It has been estimated that a single gram of crystalline toxin, evenly dispersed and inhaled, could kill more than one million people [2]. 

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