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Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.

ABSTRACT: A large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmacological treatment is provided directly at muscles to prevent contraction. Motor cortex is another potential target for therapy that exhibits pathological dynamics in dystonia, including heightened activity and altered beta oscillations. We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. These models demonstrated degeneracy, meaning that there were many ways of obtaining the pathological syndrome. There was no single parameter alteration which would consistently distinguish pathological from physiological dynamics. At higher dimensions in parameter space, we were able to use support vector machines to distinguish the two patterns in different regions of space and thereby trace multitarget routes from dystonic to physiological dynamics. These results suggest the use of in silico models for discovery of multitarget drug cocktails.

SUBMITTER: Neymotin SA

PROVIDER: S-EPMC4906029 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.

Neymotin Samuel A SA Dura-Bernal Salvador S Lakatos Peter P Sanger Terence D TD Lytton William W WW

Frontiers in pharmacology 20160614

A large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmac ...[more]

PMID: 27378922

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Project description:Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.

Dataset Information

Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.

Publications

Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.

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