Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats

Shearer, Jennifer A. and Coker, Susan J. and Carswell, Hilary V. O. (2018) Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats. American Journal of Physiology - Heart and Circulatory Physiology, 314 (5). pp. 967-977. ISSN 0363-6135 (https://doi.org/10.1152/ajpheart.00299.2017)

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Abstract

2-Arachidonoylglycerol (2-AG) is a major modulator of blood flow and platelet aggregation and a potential neuroprotectant. The present study investigated the effects of 2-AG on cerebral blood flow (CBF) in the first critical hours during middle cerebral artery occlusion (MCAO) and on platelet aggregation for the first time in rats. Adult male Sprague Dawley rats (n=30) underwent permanent MCAO under isoflurane anaesthesia and were randomly assigned to receive either 2-AG (6 mgkg-1, i.v.), monoacylglycerol lipase inhibitor JZL184 (10 mgkg-1, i.v.), or vehicle (n=6 per group). CBF and cardiovascular responses were measured, by a blinded investigator, for up to 4 hours. In separate experiments, platelet aggregation by 2-AG (19-300µM) was assessed by whole blood aggregometry (n=40). 2-AG and JZL184 significantly increased the severity of the CBF deficit versus vehicle (20.2+/-8.8% and 22.7+/-6.4% versus 56.4+/-12.1% of pre-MCAO baseline, respectively, P<0.05) but had no effect on blood pressure or heart rate. Whilst JZL184 significantly increased the number of thrombi after MCAO, this did not reach significance by 2-AG. 2-AG induced platelet aggregation in rat whole blood in a similar manner to arachidonic acid and was significantly reduced by COX inhibitors, indomethacin and flurbiprofen, and thromboxane receptor antagonist, ICI 192,605 (P<0.05). This is the first study showing that 2-AG increases the severity of the CBF deficit during MCAO and further interrogation confirmed 2-AG-induced platelet aggregation in rats. These findings are important because 2-AG has previously been shown to exert neuroprotective actions and therefore force us to re-evaluate the circumstances under which 2-AG is beneficial.

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