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

Jennifer A. Shearer, Susan J. Coker, Hilary V. O. Carswell

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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.
Original languageEnglish
Pages (from-to)967-977
Number of pages11
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume314
Issue number5
DOIs
Publication statusPublished - 1 May 2018

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Cerebrovascular Circulation
Platelet Aggregation
Blood Platelets
Middle Cerebral Artery Infarction
2-arachidonylglycerol
Monoacylglycerol Lipases
Thromboxane Receptors
Flurbiprofen
Isoflurane
Neuroprotective Agents
Arachidonic Acid
Indomethacin

Keywords

  • endocannabinoids
  • cerebral ischemia
  • stroke
  • thrombosis
  • anti-platelet

Cite this

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title = "Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats",
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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T1 - Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats

AU - Shearer, Jennifer A.

AU - Coker, Susan J.

AU - Carswell, Hilary V. O.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - endocannabinoids

KW - cerebral ischemia

KW - stroke

KW - thrombosis

KW - anti-platelet

UR - https://www.physiology.org/journal/ajpheart

U2 - 10.1152/ajpheart.00299.2017

DO - 10.1152/ajpheart.00299.2017

M3 - Article

VL - 314

SP - 967

EP - 977

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -