Unité INSERM U887 Motricité-Plasticité, Dijon, France.
PLoS One. 2009 Dec 1;4(12):e8101. doi: 10.1371/journal.pone.0008101.
The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration.
缺血性中风的发病机制是一个复杂的事件序列，包括炎症反应，其中小胶质细胞似乎是主要的细胞贡献者。然而，小胶质细胞在缺血后的激活是否具有有益或有害的影响仍有待阐明，特别是在长期的大脑可塑性事件中。我们的研究目的是通过调节中风后的炎症反应，确定小胶质细胞在神经元可塑性、神经突生长和突触发生的某些特定事件中参与的程度。由于小胶质细胞是神经营养因子的来源，因此还试图确定脑源性神经营养因子（BDNF）是否是参与这些事件的可能分子。作为一种下调缺血诱导的小胶质细胞反应的手段，3-氨基苯甲酰胺（3-AB，90mg/kg，腹腔注射）用于抑制聚（ADP-核糖）聚合酶-1（PARP-1）。事实上，PARP-1 有助于转录因子 NF-kB 的激活，NF-kB 对促炎基因的上调至关重要，特别是对小胶质细胞激活/增殖负责。实验在光血栓性缺血大鼠中进行，该模型导致强烈和早期的小胶质细胞激活/增殖，随后在皮质病变内浸润巨噬细胞，通过 OX-42 和 ED-1 的免疫染色在连续时间点评估这些事件，直至中风后 1 个月。我们最引人注目的发现是，3-AB 诱导的急性小胶质细胞激活减少与两种神经元可塑性蛋白表达的长期下调有关，突触素（突触发生标志物）和 GAP-43（神经突发生标志物），以及组织 BDNF 产生的显著减少。因此，我们的数据支持小胶质细胞在大脑神经可塑性刺激中的支持作用，可能是通过 BDNF 的产生，这表明靶向保护小胶质细胞可能是增强中风后神经再生的一种创新方法。
