Dronne Marie-Aimée, Grenier Emmanuel, Chapuisat Guillemette, Hommel Marc, Boissel Jean-Pierre
Université de Lyon, Lyon, F-69003, France.
Prog Biophys Mol Biol. 2008 May;97(1):60-78. doi: 10.1016/j.pbiomolbio.2007.10.001. Epub 2007 Oct 30.
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.
缺血性中风是工业化国家的第三大死因，但目前尚无令人满意的治疗方法。为阻断缺血级联反应而研发的数百种神经保护药物在动物模型中取得了非常有前景的结果，但用这些药物进行的临床试验在中风患者中并未显示出有益效果。人们提出了许多假说来解释这种差异，其中包括人类和啮齿动物大脑在形态和功能上的差异。这种差异可能部分归因于人类和啮齿动物大脑在白质和胶质细胞比例上的差异。为了验证这一假说，我们构建了一个关于啮齿动物和人类大脑中风主要早期病理生理机制的数学模型。该模型是一个双尺度模型，依赖于一组常微分方程。我们构建了该模型的两个版本（针对人类和啮齿动物大脑），它们在白质和胶质细胞比例上有所不同。然后，我们用各种神经保护药物进行了计算机模拟实验。用钠通道阻滞剂获得的模拟结果表明，啮齿动物大脑中半暗带恢复的比例远高于人类大脑，并且与在III期试验中测试的其他一些神经保护药物的结果相似。这项计算机模拟研究表明，胶质细胞和白质的比例会影响神经保护药物的疗效。它强化了这样一种假说，即啮齿动物和人类大脑之间的组织学和形态学差异可以部分解释这些药物在临床试验中的失败。
