A modelling approach to explore some hypotheses of the failure of neuroprotective trials in ischemic stroke patients
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A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia
Published on: August 18, 2015
Marie-Aimée Dronne1, Emmanuel Grenier, Guillemette Chapuisat
1Université de Lyon, Lyon, F-69003, France. md@upcl.univ-lyon1.fr
Abstract:
Ischemic stroke is the third cause of death in industrialised countries, but no satisfactory treatment is currently available. The hundreds of neuroprotective drugs developed to block the ischemic cascade gave very promising results in animal models but the clinical trials performed with these drugs showed no beneficial effects in stroke patients. Many hypotheses were advanced to explain this discrepancy, among which the morphological and functional differences between human and rodent brains. This discrepancy could be partly due to the differences in white matter and glial cell proportions between human and rodent brains. In order to test this hypothesis, we built a mathematical model of the main early pathophysiological mechanisms of stroke in rodent and in human brains. This model is a two-scale model and relies on a set of ordinary differential equations. We built two versions of this model (for human and rodent brains) differing in their white matter and glial cell proportions. Then, we carried out in silico experiments with various neuroprotective drugs. The simulation results obtained with a sodium channel blocker show that the proportion of penumbra recovery is much higher in rodent than in human brain and the results are similar with some other neuroprotective drugs tested during phase III trials. This in silico investigation suggests that the proportions of glial cells and white matter have an influence on neuroprotective drug efficacy. It reinforces the hypothesis that histological and morphological differences between rodent and human brains can partly explain the failure of these agents in clinical trials.
Insights
Differences in brain composition between rodents and humans may explain why neuroprotective drugs fail in clinical trials. Mathematical modeling suggests glial cell and white matter proportions impact drug efficacy for ischemic stroke treatment.
Area of Science:
- Neuroscience
- Computational Biology
- Pharmacology
Background:
- Ischemic stroke is a leading cause of death with limited treatment options.
- Numerous neuroprotective drugs show promise in animal models but fail in human clinical trials.
- Differences in brain structure between humans and rodents are hypothesized to cause this discrepancy.
Purpose of the Study:
- To investigate the impact of white matter and glial cell proportions on neuroprotective drug efficacy.
- To develop and utilize a mathematical model simulating early ischemic stroke pathophysiology in human and rodent brains.
Main Methods:
- Developed a two-scale mathematical model using ordinary differential equations.
- Created two model versions differing in white matter and glial cell proportions for human and rodent brains.
- Conducted in silico experiments with neuroprotective drugs, including a sodium channel blocker.
Main Results:
- Simulations showed significantly higher penumbra recovery in the rodent model compared to the human model using a sodium channel blocker.
- Similar discrepancies in recovery rates were observed with other tested neuroprotective agents.
- The proportion of glial cells and white matter influenced the simulated efficacy of neuroprotective drugs.
Conclusions:
- Glial cell and white matter proportions are critical factors influencing neuroprotective drug efficacy in ischemic stroke.
- These histological and morphological differences between rodent and human brains likely contribute to the failure of neuroprotective agents in clinical trials.
- Mathematical modeling provides valuable insights into the translational gap between preclinical and clinical stroke research.