Anandamide (AEA) played potent neuroprotective activities via cannabinoid type 1 (CB1) and 2 (CB2) receptor. N-Linoleyltyrosine (NITyr), as an AEA analogue, was synthesized in our laboratory and evaluated the neuroprotective effects and mechanisms for the first time. NITyr was synthesized via substitution reaction. The neuroprotective effects of NITyr were evaluated in a gerbil model of transient cerebral ischemia. Each gerbil was subjected to open field test (OFT), Rotard rod test (RRT), Morris water maze (MWM) successively and executed after animal behaviors. Part of the brain was stained with hematoxylin and eosin (HE) and Nissl staining, and the rest for biochemical analysis. NITyr could not increase spontaneous locomotor activity and ameliorate the anxiety behavior in the OFT but could improve the motor coordination in the RRT and the spatial memory impairment in the MWM. Immunohistochemically, NITyr could attenuate the ischemia-induced neural loss in the hippocampus. The Enzyme-linked immunosorbent assay (ELISA) suggested that NITyr ameliorated the inflammation and oxidative stress. Consistently, NITyr could up-regulate the expressions of p-phosphadylinositol 3-kinase (PI3K) and p-Akt but not PI3K and Akt in the hippocampus. In addition to oxidative stress, CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251 could reverse the above phenomena. However, CB1 receptor antagonist AM251 could reverse oxidative stress. Accordingly, NITyr could up-regulate the expressions of CB2 but not CB1. NITyr could improve the motor coordination, learning and memory impairments, neural loss in the hippocampus and the inflammation of the mice via CB2 receptor involvement of PI3K/Akt signaling pathway.
阿南酰胺(AEA)通过
大麻素类型1(CB1)和2(CB2)受体发挥强效的神经保护活性。我们的实验室合成了作为AEA类似物的N-亚麻酰
酪氨酸(NITyr),并首次评估了其神经保护效果及机制。NITyr是通过取代反应合成的。在一项暂时性脑缺血的沙鼠模型中评估了NITyr的神经保护效果。每只沙鼠依次接受了开放场测试(OFT)、旋转杆测试(RRT)和莫里斯
水迷宫(MWM)测试,随后进行了行为观察。部分脑组织用苏木素-伊红(HE)和尼氏染色进行染色,余下部分用于生化分析。NITyr并未增加自发运动活动,也未改善OFT中的焦虑行为,但能够改善RRT中的运动协调性和MWM中的空间记忆损伤。在免疫组织
化学上,NITyr能够减轻缺血引起的海马神经损失。酶联免疫吸附测定(ELI
SA)显示,NITyr改善了炎症和氧化应激。一致地,NITyr能够上调海马中
磷酸化的
磷脂酰肌醇3-激酶(
PI3K)和
磷酸化的Akt的表达,但对
PI3K和Akt本身没有影响。除了氧化应激外,CB2受体拮抗剂
AM630可以逆转上述现象,而CB1受体拮抗剂
AM251则无法。尽管如此,CB1受体拮抗剂
AM251能够逆转氧化应激。因此,NITyr可以上调CB2的表达,而不影响CB1。NITyr可通过CB2受体介入
PI3K/Akt信号通路,改善运动协调性、学习和记忆损伤、海马神经损失及小鼠的炎症。