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首页> 外文期刊>Infection and immunity >Matrix Metalloproteinase Inhibition Lowers Mortality and Brain Injury in Experimental Pneumococcal Meningitis
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Matrix Metalloproteinase Inhibition Lowers Mortality and Brain Injury in Experimental Pneumococcal Meningitis

机译：基质金属蛋白酶抑制降低实验性肺炎球菌性脑膜炎的死亡率和脑损伤

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Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.
机译：肺炎球菌性脑膜炎（PM）导致高死亡率和长期的神经功能缺损。海马细胞凋亡和皮质坏死是啮齿动物模型中神经功能后遗症的组织病理学相关因素，在死于PM的患者的尸检研究中经常观察到。在实验性PM中，抑制基质金属蛋白酶（MMP）和/或肿瘤坏死因子（TNF）转换酶（TACE）已显示可减少脑损伤和相关的神经认知功能损害。但是，这些研究中评估的化合物均未进入临床开发阶段。在这里，我们评估了两种第二代MMP和TACE抑制剂，它们具有更高的选择性和改善的口服利用率。 Ro 32-3555（Trocade，cipemastat）优先抑制胶原酶（MMP-1，-8和-13）和明胶酶B（MMP-9），而Ro 32-7315是TACE的有效抑制剂。通过活体内肺活链球菌的脑池内注射在幼鼠中诱发PM。从感染后3小时开始腹膜内注射Ro 32-3555和Ro 32-7315。感染后18小时开始抗生素（头孢曲松）治疗，并记录临床参数（体重，临床评分，死亡率）。测量脑脊髓液中的髓过氧化物酶活性，细胞因子和趋化因子的浓度，MMP-2和MMP-9的浓度以及胶原蛋白的浓度。在感染后42小时处死动物，并通过组织形态计量学评估其大脑的海马细胞凋亡和皮质坏死。两种化合物均表现出不同的MMP和TACE抑制特性，但减少了海马细胞凋亡和皮质损伤。 Ro 32-3555降低死亡率和脑脊髓液TNF，白介素1β（IL-1β）和胶原蛋白水平，而Ro 32-7315降低体重减轻和脑脊液TNF和IL-6水平。

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