ABSTRACT
Title
Cannabinoid CB2 Receptor Modulates Microglial Cell Activation: Role of ERK-1/2 Kinase Signaling
Authors
S. Merighi1,S. Gessi1, K. Varani1, D. Fazzi1, A. Stefanelli1, P. Mirandola2, P.A. Borea1
1Dept. of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Italy; 2Dept. of Human Anatomy, Pharmacology and Forensic Medicine, Institute of Normal Human Anatomy, University of Parma, Italy.
1Dept. of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Italy; 2Dept. of Human Anatomy, Pharmacology and Forensic Medicine, Institute of Normal Human Anatomy, University of Parma, Italy.
Abstract
Cannabinoid (CB) receptor agonists have potential utility as anti-inflammatory drugs for the treatment of many disease conditions (Atwood et al., 2010). In the present study, we characterized the signal transduction pathways mediated by CB2 receptors in resting and lipopolysaccharide (LPS)-stimulated murine microglia. We examined the effects of the synthetic CB2 ligand, JWH-015 (Merighi et al., 2010), on phosphorylation of MAPKs and on nitric oxide (NO) production. Stimulation of CB2 receptors by JWH-015 activates JNK-1/2 and ERK-1/2 in resting microglial cells. Furthermore, CB2 receptor activationincreased p-ERK-1/2 at 15 minutes in LPS-stimulated microglia. Surprisingly, in the presence of both LPS and JWH-015, phosphorylation of ERK-1/2 was reduced after 30 minutes. The NO synthetase inhibitor L-NAME blocked the ability of JWH-015 to downregulate LPS-induced p-ERK increase, indicating that CB2 reduces LPS-effects on ERK-1/2 phosphorylation through NO. JWH-015 increased LPS-induced NO release at 15 minutes, while at 48 hours CB2 receptor stimulation had an inhibitory effect. All of the effects of JWH-015 were significantly blocked by the CB2 antagonist AM 630 and were mediated specifically by activation of CB2 receptors since the inhibition of CB2 expression by siRNA abolished the agonist’s effects. Our results demonstrate that CB2 receptor stimulation activates MAPK pathway, but the presence of a second stimulus switches off MAPK signal transduction then inhibiting pro-inflammatory LPS-induced NO production. Therefore, CB2 receptor agonists may promote anti-inflammatory therapeutic response in activated microglia.
Atwood et al. (2010). Br J Pharmacol 160, 467-479.
Merighi et al. (2010). Biochem Pharmacol 79, 471-477.
Atwood et al. (2010). Br J Pharmacol 160, 467-479.
Merighi et al. (2010). Biochem Pharmacol 79, 471-477.