ABSTRACT
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 A. Nerve Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 B. Delayed Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 C. Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
II. Cholinergic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 A. Biochemical Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 B. Histopathological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 C. Cholinergic Toxicity under Stressful Conditions . . . . . . . . . . . . . . . . . . . 101
III. Non-Cholinergic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 A. Biochemical Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 B. Histopathological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 C. Non-Cholinergic Toxicity under Stressful Conditions . . . . . . . . . . . . . . . 108
IV. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Nerve agents were developed over six decades ago for military use and continue to be a significant threat on the battlefields of the world or as terrorist weapons. Organophosphate (OP) nerve agents (tabun, sarin, soman, and VX) are the most toxic compounds that cause biological effects by inhibiting the enzyme cholinesterase. The first OP nerve agent, tabun (O-ethyl N, N-dimethyl phosphoraminocyanidate) was synthesized by German chemist Dr. Gerhard Schrader in 1936.1 Later sarin (isopropyl methyl phosphonofluoridate) was synthesized in 1938 followed by soman (pinacolyl methyl phosphonofluoridate) in 1944. A few years after the end of World
FIGURE 3.1 Chemical structures of organophosphorous nerve agents. (Adapted from Somani et al.212)
War II, Dr. Ranajit Ghosh of England synthesized a nerve agent called VX (O-ethyl-S2-N,N-diisopropyl amino ethyl methylphosphonothiolate) that was much more potent than sarin. The chemical structures of OP nerve agents are depicted in Figure 3.1.
