Neurotoxins/neurotoxicity effects

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). 

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. 

EDC. It is a recognized neurotoxin, resembling other solvents and halohydrocarbons in this respect. Its neurotoxic effects at lower exposures are sufficiently subtle to have been missed clinically at first. The following is a summary of conclusions drawn from an extensive literature review by Tuttle et al. (refs. 49a,b). 

A plant neurotoxin that is receiving much current publicity because of its effectiveness in the chemotherapeutic treatment of at least one form of cancer is taxol, a complex molecule that belongs to the class of taxine alkaloids. Taxol occurs in most tissues of Taxus breviofolia, the western yew tree, and is isolated from the bark of that tree (once considered a nuisance tree in forestry, but in short supply following discovery of the therapeutic value of taxol until alternate sources were developed). Ingestion of taxol causes a number of neurotoxic effects, including sensory neuropathy, nausea and gastrointestinal disturbances, and impaired respiration and cardiac function. It also causes blood disorders (leukopenia and thrombocytopenia). The mechanism of taxol neurotoxicity involves binding to tubulin, a protein involved in the assembly of microtubules, which assemble... 

The tetrahydropyridine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) 288 is a well-known neurotoxin that induces symptoms like those for Parkinson s disease. The toxic effects of this compound have been attributed to its oxidation by monoamine oxidase (MAO) to form the pyridine MPP+ 289. MPP+ migrates into the mitochondria of neural cells inhibiting the production of ATP and results in cell death <2000MI1, 2001MI1>. Numerous compounds, such as 4-phenoxy- 290<1997BMC1519> and 4-pyrrole-tetrahydropyridines 291 <2002BMC3031>, have been modelled on MPTP in an attempt to inhibit MAO without exhibiting neurotoxic effects. 

Compound 79 is structurally related to TIQ 80, obtained on condensation of norepinephrine with formaldehyde (164), and to TIQ 81, detected in animal tissues after exposure to acetaldehyde (165). Acid-catalyzed dehydration of TIQ 82, the N-methyl analog of TIQ 79, should lead to the iminium species 83 (166), which on two-electron oxidation or by disproportionation should give the isoquinolinium salt 84. Such reactions, if occurring in vivo, would parallel similar reactions seen with the neurotoxin MPTP in its conversions to MPDP and MPP (167) and could possibly explain the neurotoxic effects seen with 117 (168). 

Numerous neurotoxic chemicals have been identified. These include pesticides (particularly, but not limited to, organophosphates and carbamates), aliphatic and aromatic hydrocarbons, alcohols, ethers, ketones, heavy metals (including lead, mercury, manganese, and others), and mixtures of these. Hundreds of individual chemicals are established or suspected neurotoxins. The EPA Guidelines for Neurotoxicity Risk Assessment and the Scorecard list of neurotoxicantsl5 contain partial lists of neurotoxic chemicals. The actual number of chemicals with neurotoxic potential has been estimated to range between 3% and 28% of all the approximately 80,000 chemicals in use (2400-22,400) Clearly, the number of mixtures possible is infinite, though little attention has been devoted to the neurotoxic effects of mixtures. 

It is estimated that 28% of all chemicals used in commerce could be neurotoxicJ42l Common household products including air fresheners, fragrance products, marking pens, and mattress covers contain known neurotoxins. I43 461 The neurotoxic effects of marking pens are attributed to chemical mixtures. I46l Aspertaine, saccharin, artificial food colors, benzyl alcohol, and other excipients used in pharmaceutical preparations and foods are neurotoxins. I47 48 ... 

DNLM 1. Environmental Illness—etiology. 2. Neurotoxicity Syndromes. 3. Mental Disorders—etiology. 4. Neurotoxins— adverse effects. WL 140 B878e 2002]... 

The clearest refutation of the idea advanced by hereditarian behavior geneticists that the prenatal environment is of only small consequence for childhood and adult IQ is the research on known IQ effects of prenatal exposure to certain neurotoxins. Any argument that this neurotoxic impact is extreme, rare, and therefore irrelevant is unsound. In addition, every known neurotoxic effect confirms the possible prenatal impact of other environmental agents not yet studied, and we do know there are literally hundreds of such neurotoxins already dispersed in the environment.15... 

Despite the connection with weapons of mass destruction, the most common neurotoxin in society is ethanol, found in alcoholic beverages. Neurons convey signals by manipulating ion concentrations, and neurotoxins reduce their ability to do so. Alcohol does this by essentially overloading the entire cell and hindering its abihty to function. Many of the characteristics of alcohol intoxication, such as slurred speech and erratic motion, are the result of improper function of neurons in the brain. As the body metabolizes the alcohol and removes it from the blood, the neurotoxic effects wear off. With large overdoses of alcohol, however, the effects do not wear off, and death due to alcohol poisoning is a dramatic and tmfortunately too common manifestation of neurotoxins. 

Many of the substituted (hydroxy, dihydroxy) tryptamines are neurotoxic. These molecules have not been tested in human subjects for obvious reasons. In the study of brain biochemistry, neurotoxins are discovered and then molecules are developed to block the actions of the toxins. Drugs which block these neurotoxic effects might be useful in the treatment of mental illness. In many cases drugs which have been effective in the treatment of mental illness have been found to block the neurotoxic effects of various molecules. This allows scientists to gain a better understanding of disease mechanisms and future development of more effective drugs for the mentally ill. 

Neurotoxic chemicals can induce an adverse effect on the structure or function of the central and/or peripheral nervous system, which can be permanent or reversible. In some cases the detection of neurotoxic effects may require specialized laboratory techniques, but often they can be inferred from behavior such as slurred speech and staggered gait. Many neurotoxins... 

Toxicity The acute toxicity of methyl iodide is moderate by ingestion, inhalation, and skin contact. This substance is readily absorbed through the skin and may cause systemic toxicity as a result. Methyl iodide is moderately irritating upon contact with the skin and eyes. Methyl iodide is an acute neurotoxin. Symptoms of exposure (which may be delayed for several hours) can include nausea, vomiting, diarrhea, drowsiness, slurred speech, visual disturbances, and tremor. Massive overexposure may cause pulmonary edema, convulsions, coma, and death. Chronic exposure to methyl iodide vapor may cause neurotoxic effects such as dizziness, drowsiness, and blurred vision. There is limited evidence for the carcinogenicity of methyl iodide to experimental animals it is not classified as an OSHA "select carcinogen."... 

In comparative studies of the neurotoxic effects of NMDA and kainic acid in the hippocampal formation, we have found that NMDA is approximately 100-fold less potent as a neurotoxin than kainic acid on a molar basis (Zaczek et aL, 1981). The lesion associated with local injection of NMDA is limited to the injection site in the hippocampal formation and appears to uniformly affect all neuronal perikarya within its circumference. However, doses of NMDA effective in causing significant lesions in the dentate gyrus precipitated a severe electroencephalographic and behavioral seizure disturbance punctuated by frequent tonic-clonic convulsions occasionally resulting in death. Thus, the superiority of NMDA over kainic acid and ibotenic acid for intracerebral injection remains to be established. 

Virtually aU human environmental exposures to toxic chemicals are to mixtures. This is particularly the case for exposures to pesticides, heavy metals, and organic solvents, known as neurotoxins. Despite this, relatively few studies have been carried out on the neurotoxic effects of chemical mixtures. This section addresses the results of these mixture studies. 

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. 

---