Biotechnology Research and Training Center, University of North Carolina Pembroke, 115 Livermore Drive, Pembroke, NC 28372-1510, USA.
J Mol Neurosci. 2011 Mar;43(3):493-502. doi: 10.1007/s12031-010-9472-4. Epub 2010 Nov 11.
Endocannabinoids, including anandamide (AEA), have been implicated in neuroprotective on-demand responses. Related to such a response to injury, an excitotoxic kainic acid (KA) injection (i.p.) was found to increase AEA levels in the brain. To modulate the endocannabinoid response during events of excitotoxicity in vitro and in vivo, we utilized a new generation compound (AM5206) that selectively inhibits the AEA deactivating enzyme fatty acid amide hydrolase (FAAH). KA caused calpain-mediated spectrin breakdown, declines in synaptic markers, and disruption of neuronal integrity in cultured hippocampal slices. FAAH inhibition with AM5206 protected against the neurodegenerative cascade assessed in the slice model 24 h postinsult. In vivo, KA administration induced seizures and the same neurodegenerative events exhibited in vitro. When AM5206 was injected immediately after KA in rats, the seizure scores were markedly reduced as were levels of cytoskeletal damage and synaptic protein decline. The pre- and postsynaptic proteins were protected by the FAAH inhibitor to levels comparable to those found in healthy control brains. These data support the idea that endocannabinoids are released and converge on pro-survival pathways that prevent excitotoxic progression.
内源性大麻素，包括花生四烯酸乙醇胺（AEA），被认为与神经保护按需反应有关。与这种损伤反应相关，发现兴奋性海人酸（KA）注射（ip）会增加大脑中的 AEA 水平。为了在体外和体内的兴奋性毒性事件中调节内源性大麻素反应，我们利用了一种新一代化合物（AM5206），它选择性抑制 AEA 失活酶脂肪酸酰胺水解酶（FAAH）。KA 引起钙蛋白酶介导的血影蛋白分解，突触标志物下降，并破坏培养的海马切片中的神经元完整性。FAAH 抑制用 AM5206 可防止在损伤后 24 小时的切片模型中评估的神经退行性级联反应。在体内，KA 给药诱导癫痫发作和体外表现出的相同神经退行性事件。当 AM5206 在大鼠中 KA 给药后立即注射时，癫痫发作评分明显降低，细胞骨架损伤和突触蛋白下降的水平也降低。FAAH 抑制剂保护前突触和后突触蛋白，使其水平与健康对照大脑中的水平相当。这些数据支持内源性大麻素被释放并集中在防止兴奋性进展的存活途径上的观点。
