Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Fibrosis Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Pharmacol Res. 2023 Jan;187:106611. doi: 10.1016/j.phrs.2022.106611. Epub 2022 Dec 14.
Brain inflammation and apoptosis contribute to neuronal damage and loss following ischaemic stroke, leading to cognitive and functional disability. It is well-documented that the human gene-2 (H2)-relaxin hormone exhibits pleiotropic properties via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), including anti-inflammatory and anti-apoptotic effects, thus making it a potential therapeutic for stroke. Hence, the current study investigated whether post-stroke H2-relaxin administration could improve functional and histological outcomes. 8-12-week-old male C57BL/6 mice were subjected to sham operation or photothrombotic stroke and intravenously-administered with either saline (vehicle) or 0.02, 0.2 or 2 mg/kg doses of recombinant H2-relaxin at 6, 24 and 48 h post-stroke. Motor function was assessed using the hanging wire and cylinder test pre-surgery, and at 24 and 72 h post-stroke. Brains were removed after 72 h and infarct volume was assessed via thionin staining, and RXFP1 expression, leukocyte infiltration and apoptosis were determined by immunofluorescence. RXFP1 was identified on neurons, astrocytes and macrophages, and increased post-stroke. Whilst H2-relaxin did not alter infarct volume, it did cause a dose-dependent improvement in motor function at 24 and 72 h post-stroke. Moreover, 2 mg/kg H2-relaxin significantly decreased the number of apoptotic cells as well as macrophages and neutrophils within the ischaemic hemisphere, but did not alter T or B cells numbers. The anti-inflammatory and anti-apoptotic effects of H2-relaxin when administered at 6 h post-cerebral ischaemia may provide a novel therapeutic option for patients following ischaemic stroke.
脑炎症和细胞凋亡导致缺血性中风后神经元损伤和丢失，导致认知和功能障碍。有大量文献记载，人类基因-2（H2）-松弛素激素通过其同源受体松弛素家族肽受体 1（RXFP1）表现出多效性，包括抗炎和抗细胞凋亡作用，因此它是中风的潜在治疗方法。因此，本研究探讨了中风后给予 H2-松弛素是否可以改善功能和组织学结果。8-12 周龄雄性 C57BL/6 小鼠接受假手术或光血栓性中风，并在中风后 6、24 和 48 小时静脉给予生理盐水（载体）或 0.02、0.2 或 2mg/kg 剂量的重组 H2-松弛素。手术前使用悬挂线和圆筒测试评估运动功能，并在中风后 24 和 72 小时进行评估。中风后 72 小时取出大脑，通过硫堇染色评估梗死体积，并通过免疫荧光测定 RXFP1 表达、白细胞浸润和细胞凋亡。RXFP1 鉴定为神经元、星形胶质细胞和巨噬细胞，并在中风后增加。虽然 H2-松弛素没有改变梗死体积，但它确实导致中风后 24 和 72 小时运动功能的剂量依赖性改善。此外，2mg/kg H2-松弛素可显著减少缺血半球内的凋亡细胞以及巨噬细胞和中性粒细胞的数量，但不改变 T 或 B 细胞的数量。在脑缺血后 6 小时给予 H2-松弛素的抗炎和抗细胞凋亡作用可能为缺血性中风后患者提供新的治疗选择。
