RICHARD LOPACHIN

..These findings provide a foundation for identifying potential pharmacotherapeutic approaches and for discerning corresponding mechanisms of neuroprotection...

..This is a challenging but critical objective that will be facilitated by recent advances in proteomic methodologies...

..Together, these findings implicate loss of mobile NF proteins as the primary mechanism of axon atrophy...

..The resulting disruption of neurotransmitter storage might mediate defective presynaptic release...

..In this publication we provide an overview of recent advances in AA research. This includes a discussion of the cumulative nature of AA neurotoxicity and the putative sites and molecular mechanisms of action...

..The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes...

..This is consistent with our hypothesis that the mechanism of ACR neurotoxicity involves formation of Michael adducts with protein sulfhydryl groups...

..These findings suggest that the neurotoxicity of ACR and its conjugated alkene analogs is related to electrophilic softness and that the thiolate state of cysteine residues is the corresponding adduct target...

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..Based on a presumed common nerve terminal site of action, we propose that the onset and progression of this neuropathogenic process is accelerated by environmental exposure to other type-2 alkenes...

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..Understanding the molecular actions of acrolein and HNE could provide insight into many pathogenic conditions that involve initial cellular oxidative stress and could, thereby, offer new efficacious avenues of pharmacological defense...

..These results suggest that HD intoxication is primarily associated with depletion of soluble NF proteins, which could produce axon atrophy through disruption of cytoskeletal turnover and maintenance...

..Evidence presented in this review suggests that "distal axonopathy" is an inaccurate classification and future nosological schemes should be based on the apparent primacy of axon atrophy...

..In this commentary we will review the evidence for the dose-related dependency of distal axonopathies and discuss how this concept might influence our current understanding of chemical-induced neurotoxicities...

..Thus, we suggest that voltage-gated tetrodotoxin-sensitive Na+ channels and glutamate-gated ionotropic NMDA or AMPA receptors are important routes of ion flux during nerve cell injury induced by oxygen-glucose deprivation/reperfusion...

..Our proposal suggests a reevaluation of current classification schemes and mechanistic hypotheses that regard ACR axonopathy as a primary lesion...

..These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD...

..These findings have important implications for future mechanistic research, classification schemes, and assessment of neurotoxicity risk...

..Appl. Pharmacol. 135 (1995) 58; and Toxicol. Appl. Pharmacol. 165 (2000) 127) indicate that axon atrophy, and not axonal swelling, is a primary neuropathic phenomenon...

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..These data suggest that ACR-induced synaptic dysfunction involves adduction of presynaptic protein thiol groups and subsequent reduction in neurotransmitter release...

..Adduction of thiol groups also might be common to the reproductive and carcinogenic effects of ACR. A final goal of this review is to identify data gaps that retard a comprehensive understanding of ACR pathophysiological processes...

..The selective depletion of Triton-soluble protein suggested that HD adduction of NFs interfered with the dynamic interactions of the polymeric and mobile monomeric pools...

..These data suggest that, like other type 2 alkenes, HNE produces nerve terminal toxicity by forming adducts with sulfhydryl thiolates on proteins involved in neurotransmission...

..Given their critical role in cytoskeletal physiology, MAPs could represent a relevant target for the induction of gamma-diketone axonopathy...

..Determining how these chemicals work will provide a rational basis for establishing occupational exposure conditions and for development of efficacious pharmacotherapeutic approaches. ..

..Understanding the role and mechanism of axon atrophy in solvent neurotoxicity has broad-based implications for human occupational health and risk assessment. ..

..Understanding the role and mechanism of axon atrophy in solvent neurotoxicity has broad-based implications for human occupational health and risk assessment. ..

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..In addition, our studies might suggest novel pharmacotherapies based on neurotrophin intervention or replacement. ..

..Results could lead to a better understanding of acquired and inherited human neuropathies and the development of efficacious pharmacotherapies. ..

..In addition, this proposal might have broad-based implications for other toxic chemicals (acrylamide, carbon disulfide) and disease processes (diabetes) associated with axonal atrophy. ..

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