Pfizer Worldwide Research & Development, Cambridge, MA, 02139, USA.
Present Address: Abbvie Inc., 200 Sidney St., Cambridge, MA, 02139, USA.
J Neuroinflammation. 2018 May 14;15(1):142. doi: 10.1186/s12974-018-1166-9.
Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential.
Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2.
Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult.
Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.
感染、全身炎症、缺血或创伤性损伤引起的急性神经损伤通常与血脑屏障 (BBB) 的破坏有关，随后外周免疫细胞、细胞毒性蛋白和水渗透。BBB 破坏和这些外周成分渗透到脑实质中会导致炎症、氧化应激、水肿、兴奋性毒性和神经退行性变。BBB 功能障碍的这些下游后果会驱动病理生理过程，并在急性和慢性神经损伤的发病率和死亡率中发挥重要作用，并导致长期后果。因此，维持或恢复 BBB 的完整性和内稳性代表了一个具有高治疗潜力的转化研究领域。
分别通过全身给予 LPS 和局部光血栓性缺血损伤，在存在和不存在单酰基甘油脂肪酶 (MAGL) 抑制剂 CPD-4645 的情况下，在小鼠中诱导全身性和局部 BBB 破坏。通过对富含神经血管的脑部分进行基因表达分析、细胞因子和炎症介质测量以及 BBB 通透性的功能评估，评估 CPD-4645 治疗的效果。使用大麻素受体 CB1 和 CB2 的反向激动剂/拮抗剂，从药理学上研究了 CPD-4645 的作用机制。
在这里，我们证明神经血管在炎症损伤后表现出独特的转录特征，并且使用新表征的抑制剂抑制 MAGL 可挽救脑血管的转录谱并恢复其功能内稳性。这种 MAGL 抑制对血脑屏障通透性的明显影响在全身炎症和局部缺血性损伤后都很明显。从机制上讲，MAGL 抑制剂的保护作用部分是通过缺血性脑损伤中的大麻素受体信号传导介导的。
我们的研究结果支持将 MAGL 抑制剂视为与炎症性脑损伤相关的 BBB 功能障碍和脑水肿的潜在治疗药物。
