ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.
Summary. Background: The endocannabinoid 2-arachidonoylglycerol (2-AG) is an endogenous lipid that acts through the activation of G-protein-coupled cannabinoid receptors and plays essential roles in many physiological contexts. In the cardiovascular system 2-AG is generated by both activated endothelial cells and platelets, and participates in the regulation of inflammation and thrombosis. Although human platelets actively metabolize endocannabinoids, 2-AG also binds to platelet surface and leads to cell activation. Objective: To investigate the biological consequence of 2-AG interactions with human platelets and to clarify the role of cannabinoid receptors. Methods: Gel-filtered platelets were stimulated with 2-AG in the presence or absence of various inhibitors. Platelet aggregation and secretion were measured in a lumiaggregometer. Calcium ion movements were measured in FURA-2 loaded platelets. Thromboxane A 2 (TxA 2 ) generation was evaluated as Thromboxane B 2 accumulation with a commercial EIA assay. Results: 2-AG induced platelet shape change, aggregation and secretion with a dose-dependent mechanism that required engagement of platelet TxA 2 receptors. 2-AG caused also cytosolic calcium increase; however, it was totally dependent on availability of TxA 2 . Indeed 2-AG was able to induce a robust generation of TxA 2 through the cyclooxygenase pathway. Treatment of platelets with inhibitors of monoacylglycerol lipase and fatty acid amide hydrolase did not affect the activation induced by 2-AG. Moreover, neither CB 1 and CB 2 proteins nor CB 1 /CB 2 mRNAs were detected in platelets. Conclusions: 2-AG can be considered a new physiologic platelet agonist able to induce full platelet activation and aggregation with a non-CB 1 /CB 2 receptor-mediated mechanism.
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