Lavayen Bianca P, Yang Changjun, Larochelle Jonathan, Liu Lei, Tishko Ryland J, de Oliveira Antonio Carlos Pinheiro, Muñoz Eduardo, Candelario-Jalil Eduardo
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Neuropharmacology Laboratory, Department of Pharmacology, Universidade Federal de Minas Gerais, Brazil.
Neurochem Int. 2023 May;165:105508. doi: 10.1016/j.neuint.2023.105508. Epub 2023 Feb 28.
Synthetic cannabidiol (CBD) derivative VCE-004.8 is a peroxisome proliferator-activated receptor gamma (PPARγ) and cannabinoid receptor type 2 (CB) dual agonist with hypoxia mimetic activity. The oral formulation of VCE-004.8, termed EHP-101, possesses anti-inflammatory properties and is currently in phase 2 clinical trials for relapsing forms of multiple sclerosis. The activation of PPARγ or CB receptors exerts neuroprotective effects by dampening neuroinflammation in ischemic stroke models. However, the effect of a dual PPARγ/CB agonist in ischemic stroke models is not known. Here, we demonstrate that treatment with VCE-004.8 confers neuroprotection in young mice subjected to cerebral ischemia. Male C57BL/6J mice, aged 3-4 months, were subjected to 30-min transient middle cerebral artery occlusion (MCAO). We evaluated the effect of intraperitoneal VCE-004.8 treatment (10 or 20 mg/kg) either at the onset of reperfusion or 4h or 6h after the reperfusion. Seventy-two hours after ischemia, animals were subjected to behavioral tests. Immediately after the tests, animals were perfused, and brains were collected for histology and PCR analysis. Treatment with VCE-004.8 either at the onset or 4h after reperfusion significantly reduced infarct volume and improved behavioral outcomes. A trend toward reduction in stroke injury was observed in animals receiving the drug starting 6h after recirculation. VCE-004.8 significantly reduced the expression of pro-inflammatory cytokines and chemokines involved in BBB breakdown. Mice receiving VCE-004.8 had significantly lower levels of extravasated IgG in the brain parenchyma, indicating protection against stroke-induced BBB disruption. Lower levels of active matrix metalloproteinase-9 were found in the brain of drug-treated animals. Our data show that VCE-004.8 is a promising drug candidate for treating ischemic brain injury. Since VCE-004.8 has been shown to be safe in the clinical setting, the possibility of repurposing its use as a delayed treatment option for ischemic stroke adds substantial translational value to our findings.
合成大麻二酚（CBD）衍生物VCE-004.8是一种过氧化物酶体增殖物激活受体γ（PPARγ）和2型大麻素受体（CB）双重激动剂，具有缺氧模拟活性。VCE-004.8的口服制剂称为EHP-101，具有抗炎特性，目前正处于复发型多发性硬化症的2期临床试验阶段。在缺血性中风模型中，激活PPARγ或CB受体会通过减轻神经炎症发挥神经保护作用。然而，双重PPARγ/CB激动剂在缺血性中风模型中的作用尚不清楚。在此，我们证明用VCE-004.8治疗可对遭受脑缺血的年轻小鼠起到神经保护作用。3至4个月大的雄性C57BL/6J小鼠接受30分钟的短暂大脑中动脉闭塞（MCAO）。我们评估了在再灌注开始时或再灌注后4小时或6小时腹腔注射VCE-004.8（10或20毫克/千克）的效果。缺血72小时后，对动物进行行为测试。测试结束后立即对动物进行灌注，并收集大脑用于组织学和PCR分析。在再灌注开始时或4小时后用VCE-004.8治疗可显著减少梗死体积并改善行为结果。在再循环6小时后开始接受药物治疗的动物中观察到中风损伤减轻的趋势。VCE-004.8显著降低了参与血脑屏障破坏的促炎细胞因子和趋化因子的表达。接受VCE-004.8的小鼠脑实质中渗出的IgG水平显著降低，表明对中风诱导的血脑屏障破坏具有保护作用。在接受药物治疗的动物大脑中发现活性基质金属蛋白酶-9水平较低。我们的数据表明，VCE-004.8是治疗缺血性脑损伤的有前景的候选药物。由于VCE-004.8在临床环境中已被证明是安全的，将其重新用作缺血性中风的延迟治疗选择的可能性为我们的研究结果增添了重要的转化价值。
