Lovelace Biomedical Research Institute, Albuquerque, NM, USA.
Department of Neurology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Adv Exp Med Biol. 2024;1463:109-112. doi: 10.1007/978-3-031-67458-7_19.
An early event in the pathology of traumatic brain injury (TBI) is a reduction in cerebral blood flow (CBF), which exacerbates secondary injury development and inhibits brain recovery. The endogenous cannabinoid system signalling (eCBs) might be critical in TBI recovery due to modulating synaptic activity and exerting neuroprotective and anti-inflammatory effects. In the brain, eCBs predominantly occur at cannabinoid receptor type 1 via the eCB 2-arachidonoylglycerol (2-AG). The aim of this work was to test the efficacy of potentiating 2-AG signalling by monoacylglycerol lipase (MAGL) inhibition using ABX-1431 immediately following TBI. Laser speckle contrast imaging (LSCI) was used to create a high-resolution map of regional cerebral blood flow (CBF) over the pericontusion cortical surface. In-vivo two-photon laser scanning microscopy (2PLSM) was used to monitor cerebral microcirculation (i.v. fluorescein isothiocyanate dextran, FITC) and mitochondrial respiration and brain tissue oxygen supply (nicotinamide adenine dinucleotide autofluorescence, NADH) during 4 hours after CHI. After baseline imaging, male C57BL/6 J mice (10-12 weeks, >28 g) were subjected to a modified moderate Shohami weight-drop closed-head injury (CHI) followed by i.p. injection of ABX-1431 (5 mg/kg) or vehicle 30 min after the insult (10 mice per group). Differences between groups and between time points were determined using two-way repeated measures (ANOVA) for multiple comparisons and post hoc testing with the statistical significance level set at p < 0.05. Optical imaging revealed that CHI caused a decrease in regional CBF, arteriole diameters (vasospasm), and blood flow volume, leading to capillary microthrombosis and a reduction in capillary flow velocity. Compromised cerebral microcirculation led to the development of tissue hypoxia. ABX-1431 application, in a ~30-minute delay, mitigated the development of microvascular dysfunction, microthrombosis formation, and tissue hypoxia compared to the saline control group (p < 0.05, starting 1 hour after CHI). Therefore, MAGL inhibition by ABX-1431 attenuates cerebral ischaemia early after TBI. The observed 2-AG-mediated cerebrovascular relaxation might involve both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium.
创伤性脑损伤 (TBI) 病理过程中的早期事件是脑血流 (CBF) 的减少，这会加剧继发性损伤的发展并抑制大脑的恢复。内源性大麻素系统信号 (eCBs) 可能在 TBI 恢复中至关重要，因为它可以调节突触活动并发挥神经保护和抗炎作用。在大脑中，eCBs 主要通过内源性大麻素受体 1 型 (CB1R) 存在于大麻素 2-花生四烯酸甘油 (2-AG) 中。本工作的目的是测试在 TBI 后立即使用 ABX-1431 抑制单酰基甘油脂肪酶 (MAGL) 增强 2-AG 信号的疗效。激光散斑对比成像 (LSCI) 用于在创伤性皮质表面上创建局部脑血流 (CBF) 的高分辨率图。在体内，使用双光子激光扫描显微镜 (2PLSM) 在 CHI 后 4 小时内监测脑微循环 (静脉内荧光素异硫氰酸酯葡聚糖，FITC) 和线粒体呼吸以及脑组织氧供应 (烟酰胺腺嘌呤二核苷酸自发荧光，NADH)。在基线成像后，雄性 C57BL/6 J 小鼠 (10-12 周龄，>28g) 接受改良的中度 Shohami 重物跌落闭合性颅脑损伤 (CHI)，然后在损伤后 30 分钟通过腹腔注射 ABX-1431(5mg/kg)或载体 (每组 10 只小鼠)。使用双向重复测量 (ANOVA) 进行多组比较和事后测试，以确定组间和时间点之间的差异，并将统计学显著性水平设置为 p<0.05。光学成像显示，CHI 导致局部 CBF、小动脉直径 (血管痉挛) 和血流体积减少，导致毛细血管微血栓形成和毛细血管血流速度降低。受损的脑微循环导致组织缺氧的发展。与盐水对照组相比，ABX-1431 的应用 (约 30 分钟延迟) 减轻了微血管功能障碍、微血栓形成和组织缺氧的发展 (p<0.05，从 CHI 后 1 小时开始)。因此，ABX-1431 通过 MAGL 抑制减轻了 TBI 后早期的脑缺血。观察到的 2-AG 介导的脑血管舒张可能涉及平滑肌收缩的直接抑制和内皮释放血管扩张介质。
