Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate
Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate
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DOI：
10.1046/j.1460-9568.2003.02876.x
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发表时间：
2003-09-01
影响因子：
3.4
通讯作者：
Rivera, S
中科院分区：
文献类型：
--
作者：
Jourquin, J;Tremblay, EN;Rivera, S
基质金属蛋白酶（MMPs）和基质金属蛋白酶的组织抑制剂（TIMPs）正在成为脑生理病理的重要调节剂。在兴奋性毒性/神经炎症过程中，MMPs和TIMPs的表达发生显著变化。然而，只有净蛋白酶活性的测量在生理学上是相关的，MMP/TIMP比例改变在大脑中的功能后果仍然难以捉摸。为了评估MMP在脑组织中的活性和作用，我们结合海碱盐（KA）诱导的兴奋毒性的体内和器官型培养模型，在海马中引起选择性神经元死亡和神经炎症。利用原位酶谱法，我们发现ka诱导的大鼠兴奋性毒性癫痫发作在癫痫发作后8小时，即大鼠死亡前，会增加海马神经元的净MMP活性，并且这种增加是神经元活动依赖的。KA后3天，易损区血管和反应性胶质细胞的蛋白水解活性增加，与神经炎症有关。在第7天和第15天，血管中的蛋白水解率仍然很高，而胶质细胞中的蛋白水解率降低。在缺乏血细胞介导的炎症和外在连接的器官型海马培养中，一种广谱MMPs抑制剂（MMPI）和一种选择性MMP-9抑制剂可以保护海马神经元免受ka诱导的兴奋性毒性。此外，重组MMP-9，而不是MMP-2，在这些培养中诱导选择性锥体细胞死亡，ka诱导的神经元活性加剧了MMP-9促进神经元死亡的作用。这些数据强烈暗示MMPs，特别是MMP-9，在兴奋性毒性神经元损伤和随后的神经炎症过程中，并表明选择性MMPIs可能与相关神经系统疾病的治疗相关。
Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) are emerging as important modulators of brain physiopathology. Dramatic changes in the expression of MMPs and TIMPs occur during excitotoxic/neuroinflammatory processes. However, only the measurement of net protease activity is relevant physiologically, and the functional consequences of MMP/TIMP ratio modifications in the brain remain elusive. In order to assess MMP activity and effects in brain tissue, we combined in vivo and organotypic culture models of kainate (KA)-induced excitotoxicity to provoke selective neuronal death and neuroinflammation in the hippocampus. Using in situ zymography, we show that KA-induced excitotoxic seizures in rats increase net MMP activity in hippocampal neurons 8 h after seizures, before their death, and that this increase is neuronal activity-dependent. Three days after KA, proteolytic activity increases in blood vessels and reactive glial cells of vulnerable areas, in relation with neuroinflammation. At 7 and 15 days, proteolysis remains high in blood vessels whereas it is reduced in glia. In organotypic hippocampal cultures, which lack blood cell-mediated inflammation and extrinsic connections, a broad-spectrum inhibitor of MMPs (MMPI), but also a selective MMP-9 inhibitor, protect hippocampal neurons against KA-induced excitotoxicity. Moreover, recombinant MMP-9, but not MMP-2, induces selective pyramidal cell death in these cultures and KA-induced neuronal activity exacerbates the neuronal death promoting effects of MMP-9. These data strongly implicate MMPs, and MMP-9 in particular, in both excitotoxic neuronal damage and subsequent neuroinflammatory processes, and suggest that selective MMPIs could be therapeutically relevant in related neurological disorders.