title: (-)-Phenserine attenuates soman-induced neuropathology.
abstract: Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Jun
authors: J
authors: Chen
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Hongna
authors: H
authors: Pan
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Cynthia
authors: C
authors: Chen
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Wei
authors: W
authors: Wu
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Kevin
authors: K
authors: Iskandar
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Jeffrey
authors: J
authors: He
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Tetsade
authors: T
authors: Piermartiri
authors: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors: David M
authors: DM
authors: Jacobowitz
authors: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors: Qian-Sheng
authors: QS
authors: Yu
authors: Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
authors: John H
authors: JH
authors: McDonough
authors: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors: Nigel H
authors: NH
authors: Greig
authors: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.
authors: Ann M
authors: AM
authors: Marini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D008297:Male; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D012999:Soman; D010830:Physostigmine; C092280:phenserine