Therapeutic Effect of a Novel Fatty Acid Amide Hydrolase Inhibitor PF04457845 in the Repetitive Closed Head Injury Mouse Model
Therapeutic Effect of a Novel Fatty Acid Amide Hydrolase Inhibitor PF04457845 in the Repetitive Closed Head Injury Mouse Model
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DOI：
10.1089/neu.2018.6226
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发表时间：
2019-05-15
影响因子：
4.2
通讯作者：
Zhang, Yumin
中科院分区：
文献类型：
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作者：
Selvaraj, Prabhuanand;Wen, Jie;Zhang, Yumin
脑震荡创伤性脑损伤是青壮年脑损伤的主要类型，也是导致慢性创伤性脑病和其他神经退行性疾病的危险因素。利用重复性闭合性脑损伤小鼠模型，我们发现，PF04457845是一种新型脂肪酸酰胺水解酶(FAAH)抑制剂，可以选择性地提高脑组织中ANANDAME的水平，改善通过光束行走、Y迷宫和Morris水迷宫测试检测的脑损伤小鼠的运动功能、学习和记忆。药物治疗可显著减少小鼠同侧脑损伤后皮质和海马区小胶质细胞和星形胶质细胞的聚集，减少致炎细胞因子IL-1β、IL-6和肿瘤坏死因子α(TNF-α)的表达。经PF04458745治疗后，脑内淀粉样前体蛋白(APP)、磷酸化Tau(p-Tau)、磷酸化糖原合成酶3β(pGSK3β)和p35/p25亚单位表达增加，突触前蛋白突触素、25 kDa突触体相关蛋白(SNAP25)和半胱氨酸串蛋白α(α-CSP)表达降低。运动功能和工作记忆的改善部分是通过激活大麻素(CB)1和CB2受体来实现的，而对空间学习和记忆的改善似乎依赖于CB1受体。有趣的是，在CB1受体拮抗剂的共同作用下，PF04457845对突触素表达减少的阻断作用被逆转，但对SNAP25和α-CSP的阻断作用不明显。这些结果表明，PF04457845的治疗作用既有依赖大麻素受体的机制，也有独立的机制，选择性抑制FAAH在脑外伤的治疗中具有很大的潜力。
Concussive traumatic brain injury (TBI) is the predominant type of brain injury in young adults and is a risk factor for the development of chronic traumatic encephalopathy and other neurodegenerative diseases late in life. Using a repetitive closed head injury mouse model, we found that treatment with PF04457845, a novel fatty acid amide hydrolase (FAAH) inhibitor that selectively elevated the brain levels of anandamide, improved locomotor function, learning, and memory in TBI mice examined by beam walk, Y-maze, and Morris water maze tests. The accumulation of microglia and astrocytes and the expression of proinflammatory cytokines, including interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), in the ipsilateral TBI mouse cortex and hippocampus were significantly reduced by drug treatment. The increased expression of amyloid precursor protein (APP), phosphorylated Tau (p-Tau), phosphorylated glycogen synthase kinase 3 beta (pGSK3 beta) and p35/p25 subunits and the decreased expression of the pre-synaptic proteins, synaptophysin, synaptosome-associated protein of 25 kDa (SNAP25), and cysteine string protein alpha (alpha-CSP), in TBI mouse brain were also normalized by PF04458745 treatment. The improved locomotor function and working memory were partially mediated by activation of both cannabinoid (CB)1 and CB2 receptors, whereas the improvement on spatial learning and memory seemed to be CB1 receptor dependent. Interestingly, the blockage of PF04457845 on the reduced expression of synaptophysin, but not SNAP25 and alpha-CSP, was reversed by coadministration of the CB1 receptor antagonist. These results suggest that the therapeutic effect of PF04457845 is mediated by both cannabinoid receptor dependent and independent mechanisms, and selective inhibition of FAAH possesses a great potential for the treatment of TBI.