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Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition.

Chapleau RR, Robinson PJ, Schlager JJ, Gearhart JM - Theor Biol Med Model (2014)

Bottom Line: Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors.It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors.We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

View Article: PubMed Central - PubMed

Affiliation: Henry M Jackson Foundation for the Advancement of Military Medicine, 2729 R Street, Wright Patterson AFB, OH 45433, USA. richard.chapleau.ctr@us.af.mil.

ABSTRACT

Background: One of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures.

Methods: Our model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models.

Results: Our model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors.

Conclusion: We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

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Related in: MedlinePlus

Prediction of effects of activating AChE on e.p.p. duration in the presence of a 1:1 GB:AChE ratio. Varying activation parameters has a greater effect than varying activator concentration.
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Fig3: Prediction of effects of activating AChE on e.p.p. duration in the presence of a 1:1 GB:AChE ratio. Varying activation parameters has a greater effect than varying activator concentration.

Mentions: To test the effects of general activation as a therapy for AChE inhibition by OPs, the impacts of small changes in activation parameters and activator concentrations on the e.p.p. were evaluated (Figure 3). By altering these parameters by 10, the inhibitor binding coefficient (ε-inh), was identified as the most critical parameter in affecting e.p.p. duration. Following the demonstration that modulating inhibitor binding could alleviate OP inhibition, the model was used to predict optimal activation coefficients to rescue severely inhibited NMJs. Considering this worst-case situation in which the majority of AChE would be inhibited, the inhibitor to activator ratio (IAR) at which the e.p.p. duration was 25% that of the uninhibited duration (Table 1) for several OP inhibitors was found, and used with a fully inhibited enzyme (inhibitor to enzyme ratio of 2:1) to calculate the lowest ε-inh for again returning the e.p.p. duration to within 25% of the uninhibited value. We hypothesize that the activator used here is allosterically activating, in that we observe changes in OP binding as being more critical than altering active site chemistry. Allosteric binding sites can be associated with long-range structural rearrangements [22] which could modulate the AChE active site cleft and “neck” without significantly altering the arrangement of the catalytic triad.Figure 3


Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition.

Chapleau RR, Robinson PJ, Schlager JJ, Gearhart JM - Theor Biol Med Model (2014)

Prediction of effects of activating AChE on e.p.p. duration in the presence of a 1:1 GB:AChE ratio. Varying activation parameters has a greater effect than varying activator concentration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4209019&req=5

Fig3: Prediction of effects of activating AChE on e.p.p. duration in the presence of a 1:1 GB:AChE ratio. Varying activation parameters has a greater effect than varying activator concentration.
Mentions: To test the effects of general activation as a therapy for AChE inhibition by OPs, the impacts of small changes in activation parameters and activator concentrations on the e.p.p. were evaluated (Figure 3). By altering these parameters by 10, the inhibitor binding coefficient (ε-inh), was identified as the most critical parameter in affecting e.p.p. duration. Following the demonstration that modulating inhibitor binding could alleviate OP inhibition, the model was used to predict optimal activation coefficients to rescue severely inhibited NMJs. Considering this worst-case situation in which the majority of AChE would be inhibited, the inhibitor to activator ratio (IAR) at which the e.p.p. duration was 25% that of the uninhibited duration (Table 1) for several OP inhibitors was found, and used with a fully inhibited enzyme (inhibitor to enzyme ratio of 2:1) to calculate the lowest ε-inh for again returning the e.p.p. duration to within 25% of the uninhibited value. We hypothesize that the activator used here is allosterically activating, in that we observe changes in OP binding as being more critical than altering active site chemistry. Allosteric binding sites can be associated with long-range structural rearrangements [22] which could modulate the AChE active site cleft and “neck” without significantly altering the arrangement of the catalytic triad.Figure 3

Bottom Line: Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors.It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors.We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

View Article: PubMed Central - PubMed

Affiliation: Henry M Jackson Foundation for the Advancement of Military Medicine, 2729 R Street, Wright Patterson AFB, OH 45433, USA. richard.chapleau.ctr@us.af.mil.

ABSTRACT

Background: One of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures.

Methods: Our model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models.

Results: Our model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors.

Conclusion: We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

Show MeSH
Related in: MedlinePlus