Excitotoxicity, oxidative stress, and neuronal injury

Dejan Milatovic, Ramesh C. Gupta, Snjezana Zaja-Milatovic, Michael Aschner

Research output: Chapter in Book/Report/Conference proceedingChapter

5 Scopus citations

Abstract

This chapter explores mechanisms associated with organophosphates (OP) induced neurotoxicity by probing their effects on oxidative stress and associated dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. It also investigates different pathways to attenuate biomarkers of oxidative damage associated with anticholinesterase exposure and the extent to which such attenuation is accompanied by rescue from neurodegeneration. Exposure to OP nerve agents induces seizures, rapidly progressing to status epilepticus and profound structural brain damage. The progression of events includes initial high cholinergic activity followed by activation of glutamatergic neurons as a result of release of glutamate. Moreover, glutamate stimulates the continuous release of ACh, contributing to further excitatory stimulation, prolongation of the seizures, and excitotoxic neurodegeneration in vulnerable brain areas. The ensuing neuronal damage is thought to result from intense transient influx of calcium leading to mitochondrial functional impairment, cytochrome c inactivation, depletion of ATP, simultaneous formation of free radical species, and oxidative stress. Among promising candidates as antidotes against CNS intoxication by OP nerve agents, memantine (MEM) has been shown to pose both antiexcitotoxic and antiepileptic properties. Memantine is an uncompetitive NMDA receptor antagonist, clinically used for the treatment of Alzheimer's disease, Parkinson's disease, and spasticity, in the absence of serious side effects.

Original languageEnglish (US)
Title of host publicationHandbook of Toxicology of Chemical Warfare Agents
PublisherElsevier Inc.
Pages633-651
Number of pages19
ISBN (Print)9780123744845
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

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  • Cite this

    Milatovic, D., Gupta, R. C., Zaja-Milatovic, S., & Aschner, M. (2009). Excitotoxicity, oxidative stress, and neuronal injury. In Handbook of Toxicology of Chemical Warfare Agents (pp. 633-651). Elsevier Inc.. https://doi.org/10.1016/B978-012374484-5.00042-0