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首页> 外文期刊>The European Journal of Neuroscience >Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate.
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Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate.

机译：神经氨酸活性依赖的净基质金属蛋白酶活性的增加与红藻氨酸后的MMP-9神经毒性有关。

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摘要

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 excitotoxiceuroinflammatory 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.
机译：基质金属蛋白酶（MMPs）和MMPs组织抑制剂（TIMPs）正在成为脑生理病理学的重要调节剂。在兴奋性毒性/神经炎症过程中，MMP和TIMP的表达发生了巨大变化。然而，仅净蛋白酶活性的测量在生理上是相关的，并且大脑中MMP / TIMP比值修饰的功能后果仍然难以捉摸。为了评估MMP活性及其在脑组织中的作用，我们结合了由海藻酸盐（KA）引起的兴奋性毒性的体内和器官典型培养模型，以引起海马体选择性神经元死亡和神经炎症。使用原位酶谱法，我们表明，KA诱发的大鼠兴奋性癫痫发作会增加癫痫发作后8小时（死亡前）海马神经元的净MMP活性，并且这种增加是神经元活性依赖性的。 KA后三天，与神经发炎相关的脆弱区域的血管和反应性胶质细胞的蛋白水解活性增加。在第7天和第15天，蛋白水解在血管中保持较高水平，而在胶质细胞中则下降。在缺乏血细胞介导的炎症和外在联系的器官型海马培养物中，广谱的MMPs抑制剂（MMPI）以及选择性的MMP-9抑制剂可保护海马神经元免受KA诱导的兴奋性毒性。而且，重组MMP-9而不是MMP-2在这些培养物中诱导选择性锥体细胞死亡，并且KA诱导的神经元活性加剧了MMP-9的促进神经元死亡的作用。这些数据强烈暗示MMP，特别是MMP-9参与兴奋性毒性神经元损伤和随后的神经炎症过程，并表明选择性MMPI在相关神经系统疾病中可能与治疗相关。

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