Elsevier

Neuroscience

Volume 152, Issue 3, 27 March 2008, Pages 753-760
Neuroscience

Neuropharmacology
Modulation of the balance between cannabinoid CB1 and CB2 receptor activation during cerebral ischemic/reperfusion injury

https://doi.org/10.1016/j.neuroscience.2008.01.022Get rights and content

Abstract

Cannabinoid receptor activation has been shown to modulate both neurotransmission (CB1) and neuroinflammatory (CB2) responses. There are conflicting reports in the literature describing the influence of cannabinoid receptor activation on ischemic/reperfusion injury. The goal of this study was to evaluate how changing the balance between CB1 and CB2 activation following cerebral ischemia influences outcome. CB1 and CB2 expression were tested at different times after transient middle cerebral artery occlusion (MCAO) in mice by real-time RT-PCR. Animals subjected to 1 h MCAO were randomly assigned to receive different treatments: a CB1 antagonist, a CB2 antagonist, a CB2 agonist, a CB1 antagonist plus CB2 agonist, a CB2 antagonist plus CB2 agonist or an equal volume of vehicle as control. Cerebral blood flow was continuously monitored during ischemia; cerebral infarction and neurological deficit were tested 24 h after MCAO. Cerebral CB1 and CB2 mRNA expression undertook dynamic changes during cerebral ischemia. The selective CB1 antagonist significantly decreased cerebral infarction by 47%; the selective CB2 antagonist increased infarction by 26% after 1 h MCAO followed by 23 h reperfusion in mice. The most striking changes were obtained by combining a CB1 antagonist with a CB2 agonist. This combination elevated the cerebral blood flow during ischemia and reduced infarction by 75%. In conclusion, during cerebral ischemia/reperfusion injury, inhibition of CB1 receptor activation is protective while inhibition of CB2 receptor activation is detrimental. The greatest degree of neuroprotection was obtained by combining an inhibitor of CB1 activation with an exogenous CB2 agonist.

Section snippets

Animals and surgical procedures

The cerebral ischemia/reperfusion studies were carried out in 8-week-old male C57BL/6 mice (weighing 23–27 g; Taconic, Hudson, NY, USA) and conducted in accordance with the guidelines approved by the Institutional Animal Care and Use Committee at Temple University and followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the number of animals used and their suffering.

Middle cerebral artery occlusion and reperfusion (MCAO/R)

The animals were anesthetized by i.p. injection of a

CB1 and CB2 mRNA expression in brain during MCAO

There were no differences in CB1 mRNA expression in the non-ischemic hemisphere compared with normal control at 1, 3, 6 and 24 h after MCAO. CB1 expression in the ischemic hemisphere increased at 1 h after ischemia and was maximal at 6 h. Similarly there were no significant differences in CB2 mRNA expression in the non-ischemic hemispheres compared with control. However, CB2 expression in the ischemic hemispheres decreased during first 3 h following ischemia, followed by a gradual increase

Discussion

The primary goal of this study was to investigate whether modification of the endocannabinoid system could influence outcome following cerebral ischemia/reperfusion injury. The hypothesis that modification of the endocannabinoid system could influence outcome following ischemia was based upon prior reports that this system can have direct effects on neuronal function and can also modify inflammatory responses (Baker et al 2001, van der Stelt et al 2001, Muthian et al 2004, McCollum et al 2007).

Conclusion

In conclusion, the results of this investigation demonstrate dynamic changes in the expression of CB1 and CB2 receptors during cerebral ischemic/reperfusion injury in mice. The effects of stimulation of these receptors on damage ischemia/reperfusion injury differed dramatically. Stimulation of the CB2 receptor was found to be neuroprotective, while inhibition of the CB1 receptor was also protective. The combination of a CB2 agonist and a CB1 antagonist provided the greatest degree of protection

Acknowledgments

This project is funded, in part, under a grant with the Pennsylvania Department of Health, a contract from BTG (London) and grants from DA P30 13429, DA 03672 and DA 05488 from the National Institute on Drug Abuse.

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