Neurotoxic species

Tellurium-induced demyelination seems to be a result of squalene monooxygenase inhibition, and dimethyl tellurium dichloride may be the neurotoxic species presented to Schwann cells in vivo. 

This compound is a protoxicant that readily crosses the blood-brain barrier, where it is acted on by the monoamine oxidase enzyme system to produce a positively charged neurotoxic species that cannot readily cross the blood-brain barrier to leave the brain. The result has been described as selective neuronal death of the dopaminergic neurons in the zona compacta of the substantia nigra. 3 The symptoms of this disorder are very similar to Parkinson s disease, one of several common and devastating neurodegenerative diseases. 

In vitro studies of synthetic Af) show monomeric Af) aggregates in a time-dependent manner that may be accelerated by Zn leading to oligomeric species, which may eventually form fibrils (Chromy et al., 2003 Hke et al., 1991 Walsh et al., 1997). Increasing evidence suggests that these soluble oligomeric species are the predominant neurotoxic species for neurons (Demuro et al., 2005 Klein,... 

De Eehce EG, Vieira MN, Saraiva LM, Figueroa-Villar JD, Garcia-Abreu J, Liu R, Chang L, Klein WL, Ferreira ST (2004) Targeting the neurotoxic species in Alzheimer s disease Inhibitors of Abeta oligomerization. FASEB J 18 1366-1372. 

The cyanobacteria produce a plethora of natural products with a wide variety of bioactivities. Many of these compounds are potent toxins and pose a significant hazard to human health and the environment. In freshwater systems, blooms of hepatotoxic cyanobacteria are of greatest concern, while in marine environments neurotoxic species are more problematic. More than 65 neurotoxins have been isolated from cyanobacteria to date. Most notably, these include the highly potent alkaloids anatoxins and saxitoxins (also known as paralytic shellfish toxins, PSTs) however, a variety of other neurotoxic substances have also been isolated from cyanobacteria including the lipopeptides, jamaicamide, antillatoxin, and kalkitoxin, as well as the nonproteinogenic amino acid, p-W-methylamino-L-alanine (BMAA). 

HTPP, Figure 1) and its many 5-hydroxylated indolic metabolites might also be potential candidates for anomalous oxidation reactions leading to neurotoxic species. 

Alzheimer s, Parkinson s and prion diseases are characterized by neuronal loss and protein aggregates that may or may not be fibrillar. However, the exact identity of the neurotoxic species and the mechanism by which it kills neurons are unknown. Biophysical studies support the emerging notion that a prefibrillar oligomer (protofibril) may be responsible for cell death and that the fibrillar form that is typically observed post mortem may actually be neuroprotective. The laboratory of Peter Lansbury suggests that a subpopulation of the soluble protofibrils may function as pathogenic pores that might have the ability to permeabilize cell or mitochondrial membranes 35). Annular, pore-like structures are observed in familial mutants of a-synuclein (Parkinson s disease) and Alzheimer s precursor protein (Alzheimer s disease) as shown in Plate 3A 56). 

Reliable lifetime TDI values cannot be derived, since long-term studies at the appropriate doses and in the appropriate species are not available. Medium-term exposure TDIs for the estimation of risk were estimated (as the chlorides) as 0.0012 mg/kg body weight for monomethyltin and dimethyltin based on neurotoxicity, 0.003 mg/kg body weight for dibutyltin based on immunotoxicity, and 0.002 mg/kg body weight for dioctyltin, also based on immunotoxicity. No reliable TDI could be derived for monobutyltin or monooctyltin. 

Mechanism of action can be an important factor determining selectivity. In the extreme case, one group of organisms has a site of action that is not present in another group. Thus, most of the insecticides that are neurotoxic have very little phytotoxicity indeed, some of them (e.g., the OPs dimethoate, disyston, and demeton-5 -methyl) are good systemic insecticides. Most herbicides that act upon photosynthesis (e.g., triaz-ines and substituted ureas) have very low toxicity to animals (Table 2.7). The resistance of certain strains of insects to insecticides is due to their possessing a mutant form of the site of action, which is insensitive to the pesticide. Examples include certain strains of housefly with knockdown resistance (mutant form of Na+ channel that is insensitive to DDT and pyrethroids) and strains of several species of insects that are resistant to OPs because they have mutant forms of acetylcholinesterase. These... 

Broadly speaking, the direct behavioral effects of neurotoxic pollutants on wild animals may be on feeding, breeding, or avoidance of predation (Beitinger 1990), or any combination of these. Any of these changes may have adverse effects on populations. Additionally, in the natural world, populations may be affected indirectly because of neurotoxic and behavioral effects on other species. Thus, a population decline of one species due to a behavioral effect of a pollutant may lead to a consequent decline of its parasites or predators, even though they are not themselves directly affected by the chemical. Direct effects will now be discussed before considering indirect ones. 

Turning now to indirect effects of neurotoxic pollutants, the status of predators and parasites can be affected by reductions in numbers of the species that they feed upon. Thus, the reduction in numbers of a prey species due to a behavioral effect can, if severe enough, cause a reduction in numbers of a predator. Also, as mentioned earlier, behavioral effects upon a prey species may lead to selective bioaccumulation of persistent neurotoxic pollutants such as DDT and dieldrin by predators thus, a behavioral effect may be hazardous for predator and prey alike ... 

Apart from the use of this approach to study the ecotoxicology of neurotoxic pollutants in the field, it also has potential for use during the course of environmental risk assessment. An understanding of the relationship between biomarker responses to neurotoxic compounds and effects at the population level can be gained from both field studies and the use of mesocosms and other model systems. From these it may be possible to define critical thresholds in biomarker responses of indicator species above which population effects begin to appear. In the longer term, this approach... 

Ongoing experiments with methylenedioxymethamphetamine (MDMA) show a systematic dose-dependent decrease in attack and threat behavior in mice confronting an intruder into their homecage (Miczek et al., unpublished observations). The decrement in aggressive behavior appears to be behaviorally specific it is obtained at MDMA doses (0.3, 1, 3 mg/kg) that are lower than those necessary to decrease measures of conditioned performance under the control of schedules of positive reinforcement. Because of species-dependent neurotoxicity, MDMA s effects on aggressive behavior need to be explored in other species, including primates. 

Studies were performed in the squirrel monkey (Saimiri sciureus). This primate species was selected because of its size, availability, and prior use in neurotoxicity studies (Langston et al. 1984). Initial dose-response determinations were carried out using the following doses of MDMA ... 

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