Neuroprotection against Cerebral Ischemic Damage : A role for caspase

本研究的目的是阐明脑缺血诱导神经元死亡的分子机制，并制定脑缺血的神经保护策略。特别关注由caspase激活和炎症反应诱导的细胞凋亡。本研究采用大鼠脑缺血模型，研究结果如下。(1)检测脑缺血后caspase3、caspase8、Fas配体和肿瘤坏死因子α的表达。Caspase3在半影区的神经元中表达上调，但在其他方面我们并没有得到恒定的结果。我们正在进行进一步的实验。(2)免疫亲和素FK506结合蛋白-12(FKBP12)也调节细胞内钙通道受体，主要定位于神经元，在脑缺血后迅速下降，但在半影区存活神经元和侵袭梗死区的炎性细胞中表达上调。(3)小胶质反应因子-1(MRF-1)是一个新分离的基因，在小胶质细胞激活后表达上调。MRF-1在脑缺血后表达上调，存在于所有类型的吞噬细胞/巨噬细胞系(小胶质细胞、单核/巨噬细胞和血管周围细胞)中。(4)细胞因子巨噬细胞移动抑制因子(MIF)存在于正常神经元和星形胶质细胞中，在脑缺血后迅速下降，但在半影区存活神经元和炎性细胞侵袭梗死区时表达上调。(5)正常脑组织不表达增殖细胞核抗原，少数活化的小胶质细胞、侵袭的巨噬细胞和少量反应性星形胶质细胞表达增殖细胞核抗原。

The purpose of this study was to clarify the molecular mechanisms of cerebral ischemia-induced neuronal death, and to develop the strategy for neuroprotection from cerebral ischemia. Special attention was focused on apoptosis induced by caspase activation and inflammatory response. The findings obtained in this study using rat models of cerebral ischemia were as follows. (1) Postischemic expressions of caspase 3, caspase 8, Fas ligand, and TNFα were examined. Caspase 3 was upregulated in neurons in penumbra, but otherwise we have not obtained constant results. We are conducting further experiments. (2) An immunophilin FK506 binding protein-12 (FKBP12), which also modulates intracellular calcium channel receptors, was localized predominantly in neurons, and decreased rapidly after cerebral ischemia, but was upregulated in surviving neurons in the penumbra and inflammatory cells invading the area of infarction. (3) Microglial response factor-1 (MRF-1) is a newly isolated gene upregulated in response to microglial activation. MRF-1 was upregulated following cerebral ischemia and was present in all the cell types of phagocyte/macrophage lineage (microglia, monocytes/macrophages, and perivascular cells). (4) A cytokine macrophage migration inhibitory factor (MIF), which was present in normal neurons and astrocytes, decreased rapidly after cerebral ischemia, but was upregulated in surviving neurons in the penumbra and inflammatory cells invading the area of imfarction. (5) Proliferating cell nuclear antigen (PCNA) was not present in normal brains and was detected in a number of activated microglia and invading macrophages, and in a small number of reactive astrocytes.