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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 4 hr prior to soman protects against soman-induced neuronal cell death.Rats were pre-treated with (−)-phenserine, posiphen or saline 4 hr prior to soman. Photographs were acquired from three representative fields in each brain region/animal. The bar represents the average percent neuronal cell death ± SD in the pirform cortex (A), hippocampus (B), basolateral amygdala (C), cingulate cortex (D). The number of fluorescein-positive neurons was counted by an investigator that was blinded to the treatment. n = 6/group. *p<0.001 vs saline/soman by ANOVA+Tukey post hoc analysis.
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pone-0099818-g003: Administration of (−)-phenserine 4 hr prior to soman protects against soman-induced neuronal cell death.Rats were pre-treated with (−)-phenserine, posiphen or saline 4 hr prior to soman. Photographs were acquired from three representative fields in each brain region/animal. The bar represents the average percent neuronal cell death ± SD in the pirform cortex (A), hippocampus (B), basolateral amygdala (C), cingulate cortex (D). The number of fluorescein-positive neurons was counted by an investigator that was blinded to the treatment. n = 6/group. *p<0.001 vs saline/soman by ANOVA+Tukey post hoc analysis.

Mentions: Neuronal cell death is a major consequence of nerve agent exposure that leads to long-term cognitive and behavioral deficits in individuals surviving initial exposure [12], [40], [41]–[45]. In the present study, fluorojade C staining was employed to evaluate phenserine-induced neuroprotection against soman-induced neuropathology, in accordance with its prior use to quantify soman-induced brain damage [33], [46]. Four regions were assessed in rat brain known to be vulnerable to soman: basolateral amygdala, piriform cortex, hippocampus, and cingulate cortex, as these brain regions display the most damage upon soman exposure [9]. The percent neuronal cell death from groups of animals treated with either (-)-phenserine or posiphen+soman was compared to saline+soman groups. The number of fluoroJadeC-positive neurons was quantified in each of the four brain regions and the percent neuronal cell death was calculated as described in Materials and Methods. Across treatment times, (-)-phenserine administration significantly protected neurons in the four vulnerable brain regions whereas posiphen treatment was not statistically different from controls (saline+soman). Representative images of the effect of phenserine on soman-induced damage in the piriform cortex are shown in Figure 2. There is a marked increase in the number of fluorescein-positive neurons (degenerating neurons) following soman (Figure 2B). In sharp contrast, administration of a single dose of (-)-phenserine 30 min prior to soman exposure strikingly reduces the number of fluorescein-positive neurons (Figure 2D) compared to saline (Figure 2A) Administration of posiphen 30 min prior to soman exposure did not significantly reduce the number of fluorescein-positive neurons in the piriform cortex (Figure 2C). Administration of (-)-phenserine 4 hr prior to soman challenge significantly reduced neuronal cell death in the piriform cortex (30.4%), hippocampus (12.5%), basolateral amygdala (33.8%), and cingulate cortex (31.2%) vs saline+soman [Figure 3]. Administration of (-)-phenserine 30 min prior to soman exposure significantly reduced neuronal cell death in the piriform cortex (24.7%), hippocampus (12.2%), basolateral amygdala (30.6%), and cingulate cortex (30.4%) [Figure 4]. When rats were treated 5 min after soman exposure, (-)-phenserine continued to provide neuroprotection; significantly reducing neuronal cell death to 27.3% in piriform cortex, 31.2% in hippocampus, 42.9% in basolateral amygdala, and 41.6% in cingulate cortex (Figure 5). This effect was diminished but, nevertheless, still statistically significant when (-)-phenserine was administered 30 min post soman; reducing neuronal cell death to 68.8% in piriform cortex, 46.2% in hippocampus, 61% in basolateral amygdala, and 61.6% in cingulate cortex (Figure 6).


(-)-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 4 hr prior to soman protects against soman-induced neuronal cell death.Rats were pre-treated with (−)-phenserine, posiphen or saline 4 hr prior to soman. Photographs were acquired from three representative fields in each brain region/animal. The bar represents the average percent neuronal cell death ± SD in the pirform cortex (A), hippocampus (B), basolateral amygdala (C), cingulate cortex (D). The number of fluorescein-positive neurons was counted by an investigator that was blinded to the treatment. n = 6/group. *p<0.001 vs saline/soman by ANOVA+Tukey post hoc analysis.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4067273&req=5

pone-0099818-g003: Administration of (−)-phenserine 4 hr prior to soman protects against soman-induced neuronal cell death.Rats were pre-treated with (−)-phenserine, posiphen or saline 4 hr prior to soman. Photographs were acquired from three representative fields in each brain region/animal. The bar represents the average percent neuronal cell death ± SD in the pirform cortex (A), hippocampus (B), basolateral amygdala (C), cingulate cortex (D). The number of fluorescein-positive neurons was counted by an investigator that was blinded to the treatment. n = 6/group. *p<0.001 vs saline/soman by ANOVA+Tukey post hoc analysis.
Mentions: Neuronal cell death is a major consequence of nerve agent exposure that leads to long-term cognitive and behavioral deficits in individuals surviving initial exposure [12], [40], [41]–[45]. In the present study, fluorojade C staining was employed to evaluate phenserine-induced neuroprotection against soman-induced neuropathology, in accordance with its prior use to quantify soman-induced brain damage [33], [46]. Four regions were assessed in rat brain known to be vulnerable to soman: basolateral amygdala, piriform cortex, hippocampus, and cingulate cortex, as these brain regions display the most damage upon soman exposure [9]. The percent neuronal cell death from groups of animals treated with either (-)-phenserine or posiphen+soman was compared to saline+soman groups. The number of fluoroJadeC-positive neurons was quantified in each of the four brain regions and the percent neuronal cell death was calculated as described in Materials and Methods. Across treatment times, (-)-phenserine administration significantly protected neurons in the four vulnerable brain regions whereas posiphen treatment was not statistically different from controls (saline+soman). Representative images of the effect of phenserine on soman-induced damage in the piriform cortex are shown in Figure 2. There is a marked increase in the number of fluorescein-positive neurons (degenerating neurons) following soman (Figure 2B). In sharp contrast, administration of a single dose of (-)-phenserine 30 min prior to soman exposure strikingly reduces the number of fluorescein-positive neurons (Figure 2D) compared to saline (Figure 2A) Administration of posiphen 30 min prior to soman exposure did not significantly reduce the number of fluorescein-positive neurons in the piriform cortex (Figure 2C). Administration of (-)-phenserine 4 hr prior to soman challenge significantly reduced neuronal cell death in the piriform cortex (30.4%), hippocampus (12.5%), basolateral amygdala (33.8%), and cingulate cortex (31.2%) vs saline+soman [Figure 3]. Administration of (-)-phenserine 30 min prior to soman exposure significantly reduced neuronal cell death in the piriform cortex (24.7%), hippocampus (12.2%), basolateral amygdala (30.6%), and cingulate cortex (30.4%) [Figure 4]. When rats were treated 5 min after soman exposure, (-)-phenserine continued to provide neuroprotection; significantly reducing neuronal cell death to 27.3% in piriform cortex, 31.2% in hippocampus, 42.9% in basolateral amygdala, and 41.6% in cingulate cortex (Figure 5). This effect was diminished but, nevertheless, still statistically significant when (-)-phenserine was administered 30 min post soman; reducing neuronal cell death to 68.8% in piriform cortex, 46.2% in hippocampus, 61% in basolateral amygdala, and 61.6% in cingulate cortex (Figure 6).

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