Department of Neurology, State-Level Regional Children's Medical Ceter, Children's Hospital of Fudan University at Xiamen, Xiamen Children's Hospital, 92-98 Yibin Road, Huli District, Xiamen, 361006, Fujian, China.
Department of Emergency, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, 361001, Fujian, China.
Sci Rep. 2024 Sep 11;14(1):21236. doi: 10.1038/s41598-024-72097-5.
Ulinastatin, a broad-spectrum inflammatory inhibitor widely employed in the management of severe pancreatitis and sepsis, has not been extensively investigated for its therapeutic potential in bacterial meningitis. This study aims to assess the neuroprotective effects of ulinastatin on bacterial meningitis and elucidate its underlying mechanism. The rat model of bacterial meningitis was established by intracerebral injection of Escherichia coli. 3-week-old SD rats were randomly divided into 5 groups with 8 rats in each group, including control group, E.coli group, E.coli + UTI group (ulinastatin 50000IU/kg), E.coli + UTI + PMA group (ulinastatin 50000IU/kg + PMA 200 ug/kg), and E.coli + PMA group(PMA 200 ug/kg). Behavioral changes were assessed by Loeffler neurobehavioral score. Histomorphologic changes and apoptosis were assessed by hematoxylin and eosin staining, Nissl staining and TUNEL staining. Immunohistochemistry and immunofluorescence and western blotting were used to detect the expression levels of zonula occludens-1 (ZO-1) and phosphorylation protein kinase C (PKCα).It was found that ulinastatin treatment in Escherichia coli meningitis rats improved neurological function, alleviated meningeal inflammatory infiltration, reduced neuronal death, promoted the integrity of the blood-brain barrier structure. Moreover, phorbol myristate acetate (PMA, a protein kinase C activator), blocked the effective action of ulinastatin. These findings suggest that ulinastatin had neuroprotective effects on bacterial meningitis by inhibiting PKCα phosphorylation and reducing ZO-1 degradation, demonstrating that ulinastatin may be a promising strategy in the treatment of bacterial meningitis.
尿胰蛋白酶抑制剂（ulinastatin）是一种广泛应用于重症胰腺炎和脓毒症治疗的广谱炎症抑制剂，但其在细菌性脑膜炎治疗中的潜在疗效尚未得到广泛研究。本研究旨在评估尿胰蛋白酶抑制剂对细菌性脑膜炎的神经保护作用，并阐明其作用机制。通过脑内注射大肠杆菌建立细菌性脑膜炎大鼠模型。3 周龄 SD 大鼠随机分为 5 组，每组 8 只，包括对照组、大肠杆菌组、大肠杆菌+UTI 组（尿胰蛋白酶抑制剂 50000IU/kg）、大肠杆菌+UTI+PMA 组（尿胰蛋白酶抑制剂 50000IU/kg+PMA 200ug/kg）和大肠杆菌+PMA 组（PMA 200ug/kg）。采用 Loeffler 神经行为评分评估行为变化。通过苏木精-伊红染色、尼氏染色和 TUNEL 染色评估组织形态学变化和细胞凋亡。采用免疫组化、免疫荧光和 Western blot 检测闭锁蛋白-1（ZO-1）和磷酸化蛋白激酶 C（PKCα）的表达水平。结果发现，尿胰蛋白酶抑制剂治疗大肠杆菌性脑膜炎大鼠可改善神经功能，减轻脑膜炎症浸润，减少神经元死亡，促进血脑屏障结构的完整性。此外，佛波醇肉豆蔻酸乙酯（PMA，蛋白激酶 C 激活剂）阻断了尿胰蛋白酶抑制剂的有效作用。这些发现表明，尿胰蛋白酶抑制剂通过抑制 PKCα 磷酸化和减少 ZO-1 降解对细菌性脑膜炎具有神经保护作用，表明尿胰蛋白酶抑制剂可能是治疗细菌性脑膜炎的一种有前途的策略。
