Elsevier

Neuroscience

Volume 129, Issue 3, 2004, Pages 743-750
Neuroscience

Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia

https://doi.org/10.1016/j.neuroscience.2004.08.044Get rights and content

Abstract

The role of endocannabinoid signaling in the response of the brain to injury is tantalizing but not clear. In this study, transient middle cerebral artery occlusion (MCAo) was used to produce ischemia/reperfusion injury. Brain content of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol were determined during MCAo. Whole brain AEA content was significantly increased after 30, 60 and 120 min MCAo compared with sham-operated brain. The increase in AEA was localized to the ischemic hemisphere after 30 min MCAo, but at 60 and 120 min, was also increased in the contralateral hemisphere. 2-Arachidonoylglycerol content was unaffected by MCAo. In a second set of studies, injury was assessed 24 h after 2 h MCAo. Rats administered a single dose (3 mg/kg) of the cannabinoid receptor type 1 (CB1) receptor antagonist SR141716 prior to MCAo exhibited a 50% reduction in infarct volume and a 40% improvement in neurological function compared with vehicle control. A second CB1 receptor antagonist, LY320135 (6 mg/kg), also significantly improved neurological function. The CB1 receptor agonist, WIN 55212-2 (0.1–1 mg/kg) did not affect either infarct volume or neurological score.

Section snippets

Focal cerebral ischemia–reperfusion

All experiments performed were approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin and conform to the National Institutes of Health International guidelines on the ethical use of animals. All measures were taken to minimize the number of animals used and their suffering. Transient focal cerebral ischemia by left MCA occlusion (MCAo) was induced in 270–300 g male Wistar rats using published methods (Longa et al., 1989). Animals were administered

Results

Brain endocannabinoid content was determined following MCAo for 30, 60 and 120 min as well as from sham operated animals 2 h after sham surgery. LC-APCI-MS revealed that the content of the endocannabinoid 2-AG did not change significantly during MCAo (Fig. 1). In contrast, the endocannabinoid AEA was significantly increased in MCA occluded ischemic brain compared with sham controls (Fig. 2). Total brain AEA content from MCA occluded animals was increased by 2.5-fold as early as 30 min following

Discussion

The first goal of the present study was to determine whether a brief period of focal ischemia would alter brain endocannabinoid content. The second goal was to investigate the role of the endocannabinoids in the outcome of a transient, focal ischemic episode using antagonists of the CB1 receptor. We found that AEA, but not 2-AG, was elevated in brain during a 120 min period of MCAo. We also demonstrated that the presence of the CB1 receptor antagonists, SR141716 and LY320135, during the

Acknowledgments

This study was funded by NIDA grants DA08098 and DA09155. The authors wish to thank the late Dr. Julio Garcia for helpful input and Mr. Frank Ceyda-Pommersheim for technical assistance.

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