A Cannabinoid Type 2 (CB2) Receptor Agonist Augments NOS-Dependent Responses of Cerebral Arterioles During Type 1 Diabetes

Introduction: While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). The goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)- dependent dilation of cerebral arterioles during T1D.

Methods: In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to an eNOS-dependent agonist (adenosine 5′-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-Daspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 hour following JWH-133 (1 mg/kg IP). In a second series of experiments, to determine the role of CB2 receptors, rats were injected with AM-630 (3 mg/kg IP). AM-630 has been shown to be a specific antagonist to CB2 receptors. After 30 minutes, the nondiabetic and T1D rats were treated with JWH-133 (1 mg/kg IP). One hour after the injection of JWH-133, responses of arterioles to the agonists were again examined. In a third series of experiments, a potential time-dependency in reactivity of cerebral arterioles to the agonists was examined. Initially responses of arterioles to ADP, NMDA and nitroglycerin were examined. Then, one hour after injection of vehicle (ethanol) for JWH-133 and AM-630 responses of arterioles to the agonists were again examined.

Results: Baseline diameter of cerebral arterioles was similar in nondiabetic and T1D rats across all groups of rats. In addition, treatment of the rats with JWH-133, JWH-133 and AM-630 or vehicle (ethanol) did not produce a change in baseline diameter in either nondiabetic or T1D rats. Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in diabetic rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and diabetic rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and diabetic rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors.

Conclusions: This study showed that acute treatment with a specific activator of CB2 receptors could potentiate dilation of cerebral resistance arterioles to eNOS- and nNOS-dependent agonists in both nondiabetic and T1D rats. In addition, the influence of activation of CB2 receptors on cerebral vascular function could be attenuated by treatment with a specific antagonist of CB2 receptors (AM-630). Based on these findings, one could speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease that can contribute to the pathogenesis of stroke.