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(-)-Phenserine attenuates soman-induced neuropathology.

Chen J, Pan H, Chen C, Wu W, Iskandar K, He J, Piermartiri T, Jacobowitz DM, Yu QS, McDonough JH, Greig NH, Marini AM - PLoS ONE (2014)

Bottom Line: Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage.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.

View Article: PubMed Central - PubMed

Affiliation: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.

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.

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Administration of (−)-phenserine prior to but not after soman protects against soman-induced mortality.Rats were administered (−)-phenserine, posiphen or saline 4 hr (A), or 30 min (B) prior to or 5 min (C) or 30 min (D) after soman. In the 4 hr pretreatment groups of animals, 12 rats died in the posiphen group and 11 rats died in the control group. There were no deaths in the (−)-phenserine group. In the 30 min pretreatment groups of animals, 2 animals died in the (−)-phenserine group. The bar represents the percent of surviving rats 24 hr after soman exposure calculated as: number of surviving rats 24 hr after soman/total number of rats ×100. n = 17–20. *p<0.026 vs saline/soman by Fisher exact test.
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pone-0099818-g001: Administration of (−)-phenserine prior to but not after soman protects against soman-induced mortality.Rats were administered (−)-phenserine, posiphen or saline 4 hr (A), or 30 min (B) prior to or 5 min (C) or 30 min (D) after soman. In the 4 hr pretreatment groups of animals, 12 rats died in the posiphen group and 11 rats died in the control group. There were no deaths in the (−)-phenserine group. In the 30 min pretreatment groups of animals, 2 animals died in the (−)-phenserine group. The bar represents the percent of surviving rats 24 hr after soman exposure calculated as: number of surviving rats 24 hr after soman/total number of rats ×100. n = 17–20. *p<0.026 vs saline/soman by Fisher exact test.

Mentions: Sprague-Dawley rats have been used as an animal model for soman toxicity studies for decades. We challenged rats with soman (180 ug/kg, sc), a dose that reliably produces status epilepticus within 10 min, and where the majority will survive for 24 hr or longer with proper care [15]. To evaluate the protective function of (-)-phenserine against nerve agent induced death, rats were administered (-)-phenserine 4 hr or 30 min before or 5 min or 30 min after soman exposure. (-)-Phenserine was administrated by intravenous bolus at a dose of 1 mg/kg, which translates to approximately 10 mg to a human (following normalization between species based on body surface area [38]. The rate of survival was calculated as the number of surviving rats one day following soman challenge (24 hr), divided by the total number of rats exposed. When (-)-phenserine was administered 4 hr prior to soman, about 90% of rats survived the soman challenge versus a survival rate of 60% and 70% for posiphen and saline, respectively. These were not statistically different from one another (Figure 1A). In contrast, administration of (-)-phenserine 30 min prior to soman provided a 100% survival rate (statistically significant vs saline treatment (60%) [Figure 1B]. Administration of posiphen 30 min prior to soman afforded an 80% survival rate that was not statistically different from control animals (Figure 1B). With regard to post soman treatment, a trend to improved survival was evident that did not reach statistical significance. Specifically, (-)-phenserine and posiphen provided an 88% survival, versus 63% for saline treatment when administered 5 min after soman (Figure 1C). When treatment was delayed to 30 min post-exposure, (-)-phenserine survival rate declined to 70% vs posiphen of 66% and saline treatment of 69% (Figure 1D).


(-)-Phenserine attenuates soman-induced neuropathology.

Chen J, Pan H, Chen C, Wu W, Iskandar K, He J, Piermartiri T, Jacobowitz DM, Yu QS, McDonough JH, Greig NH, Marini AM - PLoS ONE (2014)

Administration of (−)-phenserine prior to but not after soman protects against soman-induced mortality.Rats were administered (−)-phenserine, posiphen or saline 4 hr (A), or 30 min (B) prior to or 5 min (C) or 30 min (D) after soman. In the 4 hr pretreatment groups of animals, 12 rats died in the posiphen group and 11 rats died in the control group. There were no deaths in the (−)-phenserine group. In the 30 min pretreatment groups of animals, 2 animals died in the (−)-phenserine group. The bar represents the percent of surviving rats 24 hr after soman exposure calculated as: number of surviving rats 24 hr after soman/total number of rats ×100. n = 17–20. *p<0.026 vs saline/soman by Fisher exact test.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4067273&req=5

pone-0099818-g001: Administration of (−)-phenserine prior to but not after soman protects against soman-induced mortality.Rats were administered (−)-phenserine, posiphen or saline 4 hr (A), or 30 min (B) prior to or 5 min (C) or 30 min (D) after soman. In the 4 hr pretreatment groups of animals, 12 rats died in the posiphen group and 11 rats died in the control group. There were no deaths in the (−)-phenserine group. In the 30 min pretreatment groups of animals, 2 animals died in the (−)-phenserine group. The bar represents the percent of surviving rats 24 hr after soman exposure calculated as: number of surviving rats 24 hr after soman/total number of rats ×100. n = 17–20. *p<0.026 vs saline/soman by Fisher exact test.
Mentions: Sprague-Dawley rats have been used as an animal model for soman toxicity studies for decades. We challenged rats with soman (180 ug/kg, sc), a dose that reliably produces status epilepticus within 10 min, and where the majority will survive for 24 hr or longer with proper care [15]. To evaluate the protective function of (-)-phenserine against nerve agent induced death, rats were administered (-)-phenserine 4 hr or 30 min before or 5 min or 30 min after soman exposure. (-)-Phenserine was administrated by intravenous bolus at a dose of 1 mg/kg, which translates to approximately 10 mg to a human (following normalization between species based on body surface area [38]. The rate of survival was calculated as the number of surviving rats one day following soman challenge (24 hr), divided by the total number of rats exposed. When (-)-phenserine was administered 4 hr prior to soman, about 90% of rats survived the soman challenge versus a survival rate of 60% and 70% for posiphen and saline, respectively. These were not statistically different from one another (Figure 1A). In contrast, administration of (-)-phenserine 30 min prior to soman provided a 100% survival rate (statistically significant vs saline treatment (60%) [Figure 1B]. Administration of posiphen 30 min prior to soman afforded an 80% survival rate that was not statistically different from control animals (Figure 1B). With regard to post soman treatment, a trend to improved survival was evident that did not reach statistical significance. Specifically, (-)-phenserine and posiphen provided an 88% survival, versus 63% for saline treatment when administered 5 min after soman (Figure 1C). When treatment was delayed to 30 min post-exposure, (-)-phenserine survival rate declined to 70% vs posiphen of 66% and saline treatment of 69% (Figure 1D).

Bottom Line: Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage.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.

View Article: PubMed Central - PubMed

Affiliation: Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus