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(-)-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.

SUBMITTER: Chen J

PROVIDER: S-EPMC4067273 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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(-)-Phenserine attenuates soman-induced neuropathology.

Chen Jun J Pan Hongna H Chen Cynthia C Wu Wei W Iskandar Kevin K He Jeffrey J Piermartiri Tetsade T Jacobowitz David M DM Yu Qian-Sheng QS McDonough John H JH Greig Nigel H NH Marini Ann M AM

PloS one 20140623 6

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, su ...[more]

PMID: 24955574

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Project description:ObjectiveExposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long-term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout (ES1-/-) mouse.MethodsElectroencephalography (EEG) electrode-implanted ES1-/- and wild-type (C57BL/6) mice were exposed to various seizure-inducing doses of GD, treated with atropine sulfate and the oxime HI-6 at 1 minute after exposure, and administered midazolam at 15-30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed.ResultsGD-exposed ES1-/- mice displayed a dose-dependent response in seizure severity. Only ES1-/- mice exposed to the highest tested dose of GD developed SE, subchronic alterations in EEG power spectra, and SRS. Degree of neuronal cell loss and neuroinflammation were dose-dependent; no significant neuropathology was observed in C57BL/6 mice or ES1-/- mice exposed to lower GD doses.SignificanceThe US Food and Drug Administration (FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNAs. We present evidence that argues for the use of the ES1-/- mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD-induced toxicity, as well as to identify mechanisms of GD-induced epileptogenesis.

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(-)-Phenserine attenuates soman-induced neuropathology.

Publications

(-)-Phenserine attenuates soman-induced neuropathology.

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