Numerical Simulation of Motility Patterns of the Small Bowel. II. Comparative Pharmacological Validation of a Mathematical Model

“…Results of our numerical experiments on the role of benzodiazepines displayed a series of intrinsic processes that are obscure in the usual biological preparations on the somas of neurons and in the muscle syncytium [22]. Only with the modeling approach it was possible to observe in parallel the changes in processes that contribute to the net effect -the cessation of contractions.…”

Section: Discussionmentioning

confidence: 95%

Mathematical modeling in drug discovery and development

Miftahof¹,

Akhmadeev²

2007

Modelling in Medicine and Biology VII

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Mathematical modeling and computer simulations are emerging technologies in drug discovery, development and drug assessment for short-and long-term biological effects. They promise to be cheap, practical, sensitive and specific, and capture real aspects of the disease phenotype that is accepted as clinically and biologically meaningful. However, existing computer-based platforms are not capable of integrating complex nonlinear interactions of molecular, cellular, tissue, organ and system activities that are required in drug discovery. Novel software, ABS Technologies©, is designed on a "reductionism-integration" principle. It offers solutions with regard to rational decision making at different stages of drug development. Examples of numerical investigations into the effects of Lotronex (GSK) and benzodiazepines provided valuable information related to the dynamics of visceral perception and motility of the gut. The results revealed the intricate role of nonlinear interplay between different signaling pathways in the pathogenesis of visceral hypersensitivity and functional gastrointestinal disorders. Advantages and limitations of the use of computer-based technologies in drug discovery are briefly reviewed.

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“…With proper experimental data, the model can be extended for parameter estimation in Dogiel type II myenteric sensory neurons from different species. Furthermore, the proposed framework can be developed to simulate the functional network, such as myenteric plexus ganglion behavior by a combination of the single neuron models with various neuronal properties and synaptic strengths [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Simulations of Myenteric Neuron Dynamics in Response to Mechanical Stretch

Liao

Zhao²,

Gregersen³

2020

Computational Intelligence and Neuroscience

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Background. Intestinal sensitivity to mechanical stimuli has been studied intensively in visceral pain studies. The ability to sense different stimuli in the gut and translate these to physiological outcomes relies on the mechanosensory and transductive capacity of intrinsic intestinal nerves. However, the nature of the mechanosensitive channels and principal mechanical stimulus for mechanosensitive receptors are unknown. To be able to characterize intestinal mechanoelectrical transduction, that is, the molecular basis of mechanosensation, comprehensive mathematical models to predict responses of the sensory neurons to controlled mechanical stimuli are needed. This study aims to develop a biophysically based mathematical model of the myenteric neuron with the parameters constrained by learning from existing experimental data. Findings. The conductance-based single-compartment model was selected. The parameters in the model were optimized by using a combination of hand tuning and automated estimation. Using the optimized parameters, the model successfully predicted the electrophysiological features of the myenteric neurons with and without mechanical stimulation. Conclusions. The model provides a method to predict features and levels of detail of the underlying physiological system in generating myenteric neuron responses. The model could be used as building blocks in future large-scale network simulations of intrinsic primary afferent neurons and their network.

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Numerical Simulation of Motility Patterns of the Small Bowel. II. Comparative Pharmacological Validation of a Mathematical Model

Cited by 11 publications

References 40 publications

T-type Ca2+ channels in non-vascular smooth muscles

T-type Ca2+ channels in non-vascular smooth muscles

Mathematical modeling in drug discovery and development

Simulations of Myenteric Neuron Dynamics in Response to Mechanical Stretch

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