Neurotoxins/neurotoxicity targets

Neurotoxicity can include effects on behavior and physiology, including motor function, sensory function, and cognitive function. These aspects are mainly studied in safety pharmacology, where the emphases are on functional and behavioral tests (e.g., functional observational battery FOB) (OECD 2004), and neurotoxicity may or may not be associated with changes in neuropathology. Neurotoxins may target different parts of the neuron, and neuronopathies may involve injury to the neurones, followed by necrosis and loss the effects may be broad or selective for a subpopulation of neurons. 

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). 

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). 

Singh, B.R. 2006. Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting. Neurotox. Res. 9. 13-91. 

Many questions still remain, such as whether extracellular Ap modulates intracellular Ap, or the mechanism by which Ap accumulation leads to synaptic dysfunction. Other factors, such as oxidative stress, which is extensive in AD, may aid the early accumulation of Ap (Butterfield et al., 2(X)2b). AP peptides stimulate oxidative stress by direct and indirect mechanisms. AP-induced oxidative stress may result from an imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS), which could react with a number of cellular macromolecular targets including proteins, lipids, carbohydrates, DNA, and RNA. An early marker for oxidative stress is the formation of protein carbonyls, 4-hydroxy-2-tra 5-nonenal (4-HNE) and 3-nitrotyrosme (3-NT), a marker for the nitration of proteins (Butterfield, 2002). Ap peptide can bind to mitochondrial proteins to generate free radicals, or it can promote oxidative stress via neuroinflanunation. Ap peptides stimulate microglial cells to release a neurotoxin, quinoUnic acid, which may also play a role in neurotoxicity (Guillemin et al., 2003). 

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