中国科学院深圳先进技术研究所科研团队报道了MMP-9抑制剂SB-3CT通过调节星形细胞脂质代谢改善缺血性卒中小鼠的神经预后。这一研究成果发表在2025年3月11日出版的国际学术期刊《中国药理学报》上。

在这项研究中，该研究组研究了通过SB-3CT抑制MMP-9对星形细胞脂质代谢的影响，以及它对缺血性卒中后神经元存活和恢复的潜力。小鼠短暂性大脑中动脉闭塞（tMCAO） 60然后给小鼠注射SB-3CT (25毫克/公斤,注射)。在tMCAO后D3，评估神经学结果，并收集全脑进行分析。脑组织脂质组学分析显示，SB-3CT治疗通过调节鞘脂和甘油磷脂途径，显著抑制星形胶质细胞胆固醇代谢。具体来说，SB-3CT减少了神经酰胺的积累，促进了神经保护性己糖神经酰胺的增加，从而提高了神经元的存活率和突触的完整性。此外，SB-3CT治疗降低了星形细胞和小胶质细胞的反应性，从而减轻了神经炎症。为了优化抑制MMP-9的时间和剂量，使治疗效果最大化，在造模后7天内，分别在D0、D2、D4三次注射SB-3CT。研究组发现，延长MMP-9抑制可减轻星形胶质细胞增生，同时损害神经恢复并抑制血管生成。这些结果证明了脂质代谢在mmp -9介导的脑损伤中的关键作用，以及SB-3CT通过靶向星形细胞脂质代谢作为缺血性卒中治疗策略的潜力。

据介绍，急性期缺血性中风的特点是基质金属蛋白酶-9 （MMP-9）活性的激增。虽然是自然修复过程的一部分，但MMP-9通过破坏血脑屏障（BBB）和促进水肿和炎症加重了损伤。MMP-9主要由炎症细胞如中性粒细胞、巨噬细胞和小胶质细胞在中风发作后不久分泌。

附：英文原文

Title: MMP-9 inhibitor SB-3CT improves neurological outcomes in ischemic stroke mice by modulation of astrocytic lipid metabolism

Author: Du, Li-da, Fang, Cheng, Wang, Yue-qing, Feng, Zi-ying, Abiola, Ogunleye Femi, Gao, Zhao-lin, Huang, Ju-yang, Ma, Yin-zhong

Issue&Volume: 2025-03-11

Abstract: The acute phase of ischemic stroke is marked by a surge in matrix metalloproteinase-9 (MMP-9) activity. While integral to natural repair processes, MMP-9 exacerbates injury by breaking down the blood-brain barrier (BBB) and promoting edema and inflammation. MMP-9 is predominantly secreted by inflammatory cells such as neutrophils, macrophages and microglia soon after stroke onset. In this study we investigated the effects of MMP-9 inhibition via SB-3CT on astrocytic lipid metabolism, and its potential to enhance neuronal survival and recovery following ischemic stroke. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60min, mice then were injected with SB-3CT (25mg/kg, i.v.). On D3 post tMCAO, neurological outcomes were assessed, and whole brains were collected for analysis. Lipidomic analysis of brain tissue showed that SB-3CT treatment significantly restrained astrocytic cholesterol metabolism by modulating the sphingolipid and glycerophospholipid pathways. Specifically, SB-3CT reduced ceramide accumulation and promoted an increase in neuroprotective hexosylceramides, leading to enhanced neuronal survival and synaptic integrity. In addition, SB-3CT treatment reduced astrocytic and microglial reactivity, thereby mitigating neuroinflammation. In order to optimize the timing and dosage of MMP-9 inhibition to maximize the therapeutic efficacy, tMCAO mice were given three injections of SB-3CT on D0, D2 and D4 within 7 days after modeling. We found that prolonged MMP-9 inhibition alleviated astrogliosis, concurrently impaired neurological recovery and inhibited angiogenesis. These results demonstrate the critical role of lipid metabolism in MMP-9-mediated brain injury and the potential of SB-3CT as a therapeutic strategy for ischemic stroke by targeting astrocytic lipid metabolism.

DOI: 10.1038/s41401-025-01505-x

Source: https://www.nature.com/articles/s41401-025-01505-x