(-)-Phenserine attenuates soman-induced neuropathology.
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4067273?pdf=render |
| _version_ | 1819010403177332736 |
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| author | Jun Chen Hongna Pan Cynthia Chen Wei Wu Kevin Iskandar Jeffrey He Tetsade Piermartiri David M Jacobowitz Qian-Sheng Yu John H McDonough Nigel H Greig Ann M Marini |
| author_facet | Jun Chen Hongna Pan Cynthia Chen Wei Wu Kevin Iskandar Jeffrey He Tetsade Piermartiri David M Jacobowitz Qian-Sheng Yu John H McDonough Nigel H Greig Ann M Marini |
| author_sort | Jun Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T01:11:42Z |
| format | Article |
| id | doaj.art-f1f566335cc54844a09602afaeb064ba |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T01:11:42Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f1f566335cc54844a09602afaeb064ba2022-12-21T19:20:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e9981810.1371/journal.pone.0099818(-)-Phenserine attenuates soman-induced neuropathology.Jun ChenHongna PanCynthia ChenWei WuKevin IskandarJeffrey HeTetsade PiermartiriDavid M JacobowitzQian-Sheng YuJohn H McDonoughNigel H GreigAnn M MariniOrganophosphorus (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.http://europepmc.org/articles/PMC4067273?pdf=render |
| spellingShingle | Jun Chen Hongna Pan Cynthia Chen Wei Wu Kevin Iskandar Jeffrey He Tetsade Piermartiri David M Jacobowitz Qian-Sheng Yu John H McDonough Nigel H Greig Ann M Marini (-)-Phenserine attenuates soman-induced neuropathology. PLoS ONE |
| title | (-)-Phenserine attenuates soman-induced neuropathology. |
| title_full | (-)-Phenserine attenuates soman-induced neuropathology. |
| title_fullStr | (-)-Phenserine attenuates soman-induced neuropathology. |
| title_full_unstemmed | (-)-Phenserine attenuates soman-induced neuropathology. |
| title_short | (-)-Phenserine attenuates soman-induced neuropathology. |
| title_sort | phenserine attenuates soman induced neuropathology |
| url | http://europepmc.org/articles/PMC4067273?pdf=render |
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