论文标题
在缺血性中风期间建模小胶质细胞激活和基于炎症的神经保护剂策略
Modeling Microglia Activation and Inflammation-Based Neuroprotectant Strategies During Ischemic Stroke
论文作者
论文摘要
神经炎症立即遵循缺血性中风的发作。在此过程中，小胶质细胞可以被激活为两种不同的表型：M1表型，可以通过产生促炎性细胞因子来恶化脑损伤。或M2表型，可以通过产生抗炎细胞因子来帮助长期恢复。在这项研究中，我们制定了一个非线性方程式的非线性系统，以模拟小胶质细胞后中风后的激活，其中包括小胶质细胞表型之间的双向切换，以及这些细胞与它们产生的细胞因子之间的相互作用。此外，我们探索了基于神经保护剂的建模策略，以抑制有害M1表型的激活，同时促进有益M2表型的激活。通过使用全局灵敏度技术，我们分析了模型参数对M1与M2小胶质细胞比率的影响以及随着时间的推移在系统中激活的小胶质细胞的总数。结果表明，在不存在和存在神经保护剂项的情况下，双向小胶质细胞表型转换对M1与M2小胶质细胞的比率的重要性。模拟进一步表明，早期抑制M1激活和对M2激活的支持导致M1与M2小胶质细胞的最小比率降低，并且在更长的时间内允许比M1细胞更大的M2。
Neural inflammation immediately follows the onset of ischemic stroke. During this process, microglial cells can be activated into two different phenotypes: the M1 phenotype, which can worsen brain injury by producing pro-inflammatory cytokines; or the M2 phenotype, which can aid in long term recovery by producing anti-inflammatory cytokines. In this study, we formulate a nonlinear system of differential equations to model the activation of microglia post-ischemic stroke, which includes bidirectional switching between the microglia phenotypes, as well as the interactions between these cells and the cytokines that they produce. Further, we explore neuroprotectant-based modeling strategies to suppress the activation of the detrimental M1 phenotype, while promoting activation of the beneficial M2 phenotype. Through use of global sensitivity techniques, we analyze the effects of the model parameters on the ratio of M1 to M2 microglia and the total number of activated microglial cells in the system over time. Results demonstrate the significance of bidirectional microglia phenotype switching on the ratio of M1 to M2 microglia, in both the absence and presence of neuroprotectant terms. Simulations further suggest that early inhibition of M1 activation and support of M2 activation leads to a decreased minimum ratio of M1 to M2 microglia and allows for a larger number of M2 than M1 cells for a longer time period.
