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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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Conceptual rendering of the neuromuscular junction and NetLogo rendering of the junction as relates to the model.
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Fig1: Conceptual rendering of the neuromuscular junction and NetLogo rendering of the junction as relates to the model.

Mentions: The work presented here develops a PD model of the mammalian neuromuscular junction (NMJ) based on an agent-based model (ABM) describing acetylcholine signaling through nicotinic receptors (Figure 1). Agent-based modeling is a discrete, rules-based method of computational modeling that focuses on the individual components of an experimental system to perform in silico experiments [13]. ABMs are well suited for cases where the modeling goal is to test the validity of a mechanistic hypothesis [14], such as the case herein where allosteric activation of AChE is proposed to protect against OP intoxication. For example, the use of an ABM to model signaling events in the NF-κB pathway showed strong correlation between ABM, differential equation approaches (ODE), and in vitro measurements [15]. Lipniacki [16] showed that a purely ODE approach within the NF-κB system does not fully account for singular events, which required superposition of stochastic modeling onto the ODE. Furthermore, a recent modeling method has extended the ABM to include even finer resolution of physical space in chemical reactions, generating a spatial model of toll-like receptor 4 immune signaling that qualitatively reproduced the observed dynamics of tumor necrosis factor secretion [17].Figure 1


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)

Conceptual rendering of the neuromuscular junction and NetLogo rendering of the junction as relates to the model.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Conceptual rendering of the neuromuscular junction and NetLogo rendering of the junction as relates to the model.
Mentions: The work presented here develops a PD model of the mammalian neuromuscular junction (NMJ) based on an agent-based model (ABM) describing acetylcholine signaling through nicotinic receptors (Figure 1). Agent-based modeling is a discrete, rules-based method of computational modeling that focuses on the individual components of an experimental system to perform in silico experiments [13]. ABMs are well suited for cases where the modeling goal is to test the validity of a mechanistic hypothesis [14], such as the case herein where allosteric activation of AChE is proposed to protect against OP intoxication. For example, the use of an ABM to model signaling events in the NF-κB pathway showed strong correlation between ABM, differential equation approaches (ODE), and in vitro measurements [15]. Lipniacki [16] showed that a purely ODE approach within the NF-κB system does not fully account for singular events, which required superposition of stochastic modeling onto the ODE. Furthermore, a recent modeling method has extended the ABM to include even finer resolution of physical space in chemical reactions, generating a spatial model of toll-like receptor 4 immune signaling that qualitatively reproduced the observed dynamics of tumor necrosis factor secretion [17].Figure 1

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