Activation of CB2R with AM1241 ameliorates neurodegeneration via the Xist/miR-133b-3p/Pitx3 axis
Schematic representation showing the proposed mechanism by which the CBR2 agonist AM1241 exerts neuroprotective effects through the Xist/ miR-133b-3p/Pitx3 axis Parkinson’s disease (PD) is a common disorder of the nervous system that affects movement, often including tremors, affecting over 7 million people over 60 years of age worldwide. Activation of the cannabinoid receptor type II (CB2R), a member of the cannabinoid receptors family that can be activated by endocannabinoid, plant cannabinoids, and synthetic cannabinoids, were previously shown to protect dopaminergic neurons in PD animals. Here, researchers elucidated the pathway through which AM1241, an activator of CB2R, alleviated PD symptoms.
They found that in the PD mouse model with intact CB2R, AM1241 could promote motor function recovery, increase dopaminergic neurons, and norepinephrine level and prevent cell-death in the substantia nigra. Such protective effects were lost when CB2R was knocked out. Follow-up experiments indicated that upon entry to the cells through CB2R, AM1241 displayed neuroprotective action by upregulating the RNA Xist which, in turn, inhibited another RNA, miR-133b-3p. The ultimate result was an increase in the level of Pitx3, a protein involved in the production of dopaminergic neurons in the substantia nigra. In summary, these findings implied that the CB2R activator AM1241 could be a novel therapeutic drug candidate for PD treatment.