<i>N</i>-Linoleyltyrosine Protects against Transient Cerebral Ischemia in Gerbil <i>via</i> CB2 Receptor Involvement in PI3K/Akt Signaling Pathway

Abstract

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.

N‑linoleyltyrosine protects PC12 cells against oxidative damage via autophagy: Possible�involvement of CB1 receptor regulation

“…Therefore, the activation of the Akt pathway induced by H 2 O 2 leads to cell proliferation or cell death, which may be related the concentration and time of H 2 O 2 stimulation ( 26 ). In a previous study, NITyr activated the Akt signaling pathway to delay cell injury in the ischemia-reperfusion model ( 13 ). NITyr was demonstrated to markedly suppress H 2 O 2 -induced cellular damage and ROS generation, and this protective effect was amplified with NITyr treatement.…”

“…NITyr was previously independently synthesized (13). The following additional reagents were used in the present study: Polyclonal antibodies against Lc3, beclin-1, autophagy-related protein (ATG) 5 and the cB1 receptor (1:1,000, cat.…”

“…Based on the chemical structure of AEA ( Fig. 1), its analogue, N-linoleyl tyrosine (NITyr), was previously synthesized in our laboratory (13). To the best of our knowledge, the present study aimed to demonstrate for the first time, the effects and potential mechanisms of NITyr on autophagy in rat pheochromocytoma (Pc12) cells under conditions of oxidative stress.…”

Differential contribution of CB1, CB2, 5‐HT1A, and PPAR‐γ receptors to cannabidiol effects on ischemia‐induced emotional and cognitive impairments

“…In gerbils submitted to GCI, the N‐Linoleytyrosine, an anandamide analog, improved hippocampal neurodegeneration and inflammation via CB 2 receptor involvement of PI3K/Akt signaling pathway. This mechanism was related to the amelioration of animal behavior after the brain insult (Cheng et al., 2019). However, it remains to be determined the role of CB 2 receptors in emotional impairments, like anxiety induced by BCCAO.…”

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

“…Among these, it should be mentioned that several N-acyl alanines (Ala) exhibited antiproliferative effect in vitro [12] as well as N-oleoyl phenylalanine (Phe) regulated energy homeostasis [13]. Moreover, stearoyl derivates of tyrosine (Tyr), serine (Ser), and threonine (Thr) exerted neuroprotection activity [14] and N-linoleoyl Tyr, by activating CB 2 receptor, protected against transient cerebral ischemia [15].…”