Neurotoxins/neurotoxicity

Turning now to chemical attack, many predators immobilize their prey by injecting toxins, often neurotoxins, into them. Examples include venomous snakes, spiders, and scorpions. Some spider toxins (Quick and Usherwood 1990 Figure 1.3) are neurotoxic through antagonistic action upon glutamate receptors. The venom of some scorpions contains polypeptide neurotoxins that bind to the sodium channel. 

A striking feature of the toxic compounds considered so far is that many of them are neurotoxic to vertebrates or invertebrates or both. The nervous system of animals appears to be a particularly vulnerable target in chemical warfare. Not altogether surprisingly, all the major types of insecticides that have been commercially successful are also neurotoxins. Indeed, in 2003, neurotoxic insecticides accounted for over 70% of total insecticide sales globally (Nauen 2006). 

In order to understand the exact mechanism of the neurotoxic action, it is important to know the secondary structure of the neurotoxins as well. It is now known that postsynaptic neurotoxins attach to the a-subunits of acetylcholine receptor (AChR). 

The amino acid residues in neurotoxins which are important for neurotoxic action are still not entirely clarified. Some neurotoxins contain one free SH group, while others do not. From this fact, it would be logical to assume the sulfhydryl group is not essential. This was actually proven to be the case. 

While most investigations show that sea snake neurotoxins are postsynaptic type, Gawade and Gaitonde (23) stated that Enhydrina schistosa major toxin has dual actions or postsynaptic as well as presynaptic toxicity. E, schistosa venom phospholipase A is both neurotoxic and myotoxic. Neurotoxic action of the enzyme is weak so that there is sufficient time for myonecrotic action to take place (24), Sea snake, L. semifasciata toxin also inhibits transmission in autonomic ganglia, but has no effect on transmission in choroid neurons. 

The data deseribed above demonstrate that destruction of serotonin axons by MDMA involves the serotonin aetive uptake carrier and that administration of citalopram, a selective serotonin uptake blocker, prior to administration of MDMA, ean prevent the decreases in serotonin markers elicited by MDMA alone. These data are eonsistent with previous reports for other potent serotonin neurotoxins, demonstrating that pretreatment with serotonin uptake blockers can prevent the neurotoxic effects of parachloroamphetamine (Ross 1976 Sanders-Bush and Steranka 1978). Furthermore, it has been shown that MDMA-induced neurotoxicity can be prevented or reversed if a serotonin uptake blocker such as fluoxetine is administered no later than 12 hours after MDMA treatment (Schmidt 1986). 

In contrast, a similar injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) produced a zone of total 5-HT denervation at least 2 to 3 mm in diameter. These chronic intracerebral micro injection experiments lend further support to the view that the parent compound is not itself neurotoxic (Berger 1989 Berger et al., in preparation Molliver et al. 1986). 

One of the main human health concerns about organophosphate esters is the potential for neurotoxicity reactions, in particular a condition known as organophosphate-induced delayed neurotoxicity (OPIDN). Tri-ort/20-cresyl phosphate (TOCP) has been identified as one of the more potent OPIDN neurotoxins in humans, and was formerly a constituent in some organophosphate ester hydraulic fluid products (Marino 1992 Marino and Placek 1994). Production processes now routinely remove virtually all the TOCP. For instance, tricresyl phosphate (TCP) products now typically are manufactured to contain over 98% meta and para isomers and virtually no TOCP (Marino and Placek 1994). Products containing these compounds associated with OPIDN have now entirely disappeared from commercial use, and the vast majority of the industrial organophosphate esters are based on triaryl phosphates with no halogenated components (Marino 1992). At waste disposal sites, however, site contaminants from older product formulations containing the ortho form may be encountered. 

Neurotoxins such as mercaptopyrazide pyrimidine (MPP+) and 6-hydroxydopamine are also taken up by transporters, and this is required for their neurotoxic effects. Mice have been prepared with their transporter genes knocked out . Extensive studies with these mice confirm the important role of transporters (Table 12-1). Once an amine has been taken up across the neuronal membrane, it can be taken up by intracellular adrenergic storage vesicles as described above. 

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