The CB1 antagonist, SR141716A, is protective in permanent photothrombotic cerebral ischemia

Abstract

Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5 mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research.

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

“…At the same time the CB 1 receptor inverse agonist SR141716A (rimonabant) and the CB 2 receptor antagonist SR144528 significantly reduced LPS-induced IL-1β production in the brain [ 191 ] whereas SR141716A was also shown to increase pro-inflammatory cytokines in an EAE model [ 192 ]. Neuroprotective effect of SR141716A was shown in the retinal degeneration model [ 193 ] and in permanent photothrombotic cerebral ischemia [ 194 ]. These findings indicate that manipulation of CB 1 or CB 2 receptors may have therapeutic value in neuroinflammation; however, due to the complexity of the ECS, this concept remains to be carefully considered.…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…However, there is some ambiguity over CB1R’s neuroprotective role in cerebral ischemia [ 417 ]. In two separate studies, CB1R antagonists SR141716A and AM251 were shown to have beneficial effects in attenuating neuronal damage caused by cerebral ischemia [ 418 , 419 ]. Interestingly, CB2R agonists have also been shown to mitigate inflammatory states and promote neurogenesis in post stroke and post intracerebral hemorrhage [ 420 , 421 ].…”

The endocannabinoid system and stroke: A focused review

“…have also found that CB1R antagonism used as both a pretreatment and a posttreatment is neuroprotective in a mouse model of permanent ischemia through photoinjury. [19] However, there is at least one recent study that suggests that CB1R agonism can also play a neuroprotective role in rodent models of stroke. Caltana et al .…”