Activation of CB2R with AM1241 ameliorates neurodegeneration via the Xist/miR‐133b‐3p/Pitx3 axis

Abstract

Activation of cannabinoid receptor type II (CB2R) by AM1241 has been demonstrated to protect dopaminergic neurons in Parkinson's disease (PD) animals.However, the specific mechanisms of the action of the CB2R agonist AM1241 for PD treatment have not been characterized. Wild-type (WT), CB1R knockout (CB1-KO), and CB2R knockout (CB2-KO) mice were exposed to 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) for 1 week to obtain a PD mouse model. The therapeutic effects of AM1241 were evaluated in each group. Behavioral tests, analysis of neurotransmitters, and immunofluorescence results demonstrated that AM1241 ameliorated PD in WT animals and CB1-KO animals. However, AM1241 did not ameliorate PD symptoms in CB2-KO mice. RNA-seq analysis identified the lncRNA Xist as an important regulator of the protective actions of AM1241.Specifically, AM1241 allowed WT and CB1-KO animals treated with MPTP to maintain normal expression of Xist, which affected the expression of miR-133b-3p and Pitx3. In vitro, overexpression of Xist or AM1241 protected neuronal cells from death induced by 6-hydroxydopamine and increased Pitx3 expression. The CB2 receptor agonist AM1241 alleviated PD via regulation of the Xist/miR-133b-3p/Pitx3 axis, and revealed a new approach for PD treatment.

Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration

“…Similar observations were found in a study of CB 2 receptors in cerebral malaria, where the benefits were reached by blocking the receptor or ablating its gene expression [2]. However, this contrasts with most of the literature on CB 2 receptor in other neurodegenerative/neuroinflammatory disorders, in which the benefits were reached after the activation of this receptor [6,14,25,28,32,50]. The difference compared with our current study may be in the cell type where the CB 2 receptor is located: glial versus neuronal location.…”

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

“…The number of registered clinical trials indicated in https://clinicaltrials.gov/ for testing cannabidiol in a variety of pathological conditions is 321 (date: 1 July 2021). As commented in the introduction, the CB 2 R is, also, an attractive target to afford neuroprotection in Parkinson's disease [3,[7][8][9][10][11][12][13][14].…”

“…The CB 2 R is considered a target for neuroprotection, especially in diseases coursing with neuroinflammation. For instance, cannabinoids acting on the CB 2 R in striatal neural cells reduce the neuronal loss in synucleinopathies such as Parkinson's disease [8][9][10][11][12][13]. The underlying mechanism is mainly related to the reduction of inflammation, but the CB 2 R expressed in some striatal neurons may also have a relevant role [3,7,[14][15][16].…”

Biological Function of Long Non-coding RNA (LncRNA) Xist

“…Trisomy 21, Pitx3, TLR5, TNFAIP1, STAT3, ZEB1 Jin et al, 2018;Yan et al, 2018;Wei et al, 2019 Neurodegeneration miR-133b-3p Pitx3 He et al, 2020 Alzheimer's disease miR-132, miR-124 BACE1 Wang et al, 2018b;Du Y. et al, 2020Osteoarthritis miR-211, miR-214-3p, miR-17-5p, miR-1277 CXCR4, MAPK, AHNAK, BMP2, TIMP-3, MMP-13, ADAMTS5, OPN, SGTB, DNMT3A, GNG5 Liao et al, 2019;Wang et al, 2019e;Feng et al, 2020;Ghaderian et al, 2020;Li et al, 2020b;Liu et al, 2020e;Shen X.F. et al, 2020 Bone marrow miR-9-5p ALPL, ALP, Bglap, Runx2 Zheng C. et al, 2020 Inflammation miR-27a-3p, miR-34a, miR-30c-5p, miR-146a NF−κB, NLRP3, Smurf1, YY1, PTEN, Nav1.7 Shenoda et al, 2018;Sun W.B.…”

“…In Down’s syndrome, lncRNA Xist ( Czerminski and Lawrence, 2020 ), which fully corrects trisomy 21 dosage in neural cells, promotes differentiation of trisomic NSCs (neural stem cells) to neurons by silencing Trisomy 21 and activating Notch signaling pathway. In Parkinson’s disease (PD) animals, it has been shown that lncRNA Xist/miR-133b-3p/Pitx3 axis protect dopaminergic neurons through activation of CB2R with AM1241, which alleviates PD ( He et al, 2020 ). In addition, lncRNA Xist participated in neuropathic pain though interacting with miRNAs in CCI (chronic constriction injury) rat models, including miR-154-5p, miR-137, miR-544, and miR-150.…”