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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models
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A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

机译：基于羟吡喃酮的金属蛋白酶12抑制剂在癫痫持续状态和视神经挤压动物模型中均显示神经保护特性

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Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.
机译：最近，我们发现基质金属蛋白酶12（MMP-12）在小胶质细胞和髓样浸润液中高表达，推测它们参与了血脑屏障（BBB）渗漏和随后的癫痫持续状态（SE）之后的神经元细胞死亡。在这里，我们评估了对毛果芸香碱诱导的SE大鼠模型中MMP-12选择性基于羟基吡喃酮的抑制剂的作用，以确定海马细胞的存活率。在接受毛果芸香碱治疗的大鼠海马中，海马内注射MMP-12抑制剂可保护Cornu Ammonis 3（CA3）和齿状回神经元hilus免受细胞死亡，并限制了通常在大鼠脑中形成的缺血性病变的发展。海马的CA3腔隙层分子。此外，我们发现MMP-12抑制作用会限制SE后免疫球蛋白G和白蛋白的外渗，提示BBB渗漏减少。最后，为排除癫痫发作调节可能参与MMP-12抑制的神经保护作用，在视神经压伤后在治疗动物的视网膜中也观察到了神经保护作用。总体而言，这些结果支持以下假设：MMP-12抑制可直接抵消神经元细胞死亡，并且本研究中使用的基于特定羟基吡喃酮的抑制剂可能是针对以重要炎症反应和/或为特征的神经系统疾病/障碍的潜在治疗剂。神经细胞丢失。

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