Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment

Abstract

Activation of the cannabinoid 2 receptor (CB(2)) reduces ischemic injury in several organs. However, the mechanisms underlying this protective action are unclear. In a mouse model of ischemic stroke, we show that the CB(2) agonist JWH-133 (1 mg . kg(-1) . d(-1)) decreases the infarct size measured 3 d after onset of ischemia. The neuroprotective effect of JWH-133 was lost in CB(2)-deficient mice, confirming the specificity of JWH-133. Analysis of bone marrow chimeric mice revealed that bone marrow-derived cells mediate the CB(2) effect on ischemic brain injury. CB(2) activation reduced the number of neutrophils in the ischemic brain as shown by FACS analysis and by measuring the levels of the neutrophil marker enzyme myeloperoxidase. Indeed, we found in vitro that CB(2) activation inhibits adherence of neutrophils to brain endothelial cells. JWH-133 (1 microM) also interfered with the migration of neutrophils induced by the endogenous chemokine CXCL2 (30 ng/ml) through activation of the MAP kinase p38. This effect on neutrophils is likely responsible for the neuroprotection mediated by JWH-133 because JWH-133 was no longer protective when neutrophils were depleted. In conclusion, our data demonstrate that by activating p38 in neutrophils, CB(2) agonists inhibit neutrophil recruitment to the brain and protect against ischemic brain injury.-Murikinati, S., Jüttler, E., Keinert, T., Ridder, D. A., Muhammad, S., Waibler, Z., Ledent, C., Zimmer, A., Kalinke, U., Schwaninger, M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment.

Pannexins in ischemia-induced neurodegeneration

“…The mice were subjected to left MCAO as previously described (36). Briefly, the mice were anesthetized by intraperitoneal injection of 25 μL 1.5% tribromoethanol per gram of body weight.…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…In the case of TBI, damage is most commonly caused either by closed (concussion) or open head injury (stab wound). The cannabinoids having beneficial effects in these models included 1) dexanabinol (HU-211) [8][9][10][11], which is a synthetic compound having a chemical structure of a classic cannabinoid but no activity at cannabinoid receptors; 2) nonselective synthetic cannabinoid agonists such as HU-210, the active enantiomer of HU-211 [12], WIN 55,212-2 [13,14], TAK-937 [15,16], and BAY 38-7271 [17,18]; 3) phytocannabinoids such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) [19], which binds not only CB 1 R and CB 2 R, but also cannabidiol (CBD), which has no affinity at these receptors but was highly active against brain ischemia [20][21][22]; 4) endocannabinoids such as 2-arachidonoylglycerol (2-AG), in particular in TBI induced by closed head injury [23][24][25], but also in experimental ischemia [26], and also anandamide [27] and its related signaling lipids palmitoylethanolamide (PEA) [28], oleoylethanolamide [27], and N-arachidonoyl-L-serine (AraS) [29]; and 5) selective CB 2 R targeting ligands such as O-3853, O-1966, and JWH-133 [30][31][32][33][34][35]. Most of these studies were conducted with the cannabinoid administered at least after the cytotoxic insult [12-19, 21-26, 28-35].…”

“…In most cases, the benefits obtained with these cannabinoid-related compounds (e.g., improved neurological performance, reduced infarct size, edema, BBB disruption, inflammation and gliosis, and control of immunomodulatory responses) involved the activation of CB 1 R (e.g., HU-210 [12], WIN55,212-2 [13,14], TAK-937 [15,16], BAY 38-7271 [17,18], Δ 9 -THC [19], and PEA [36]) and/or CB 2 R (e.g., AraS [29], O-3853, O-1966, and JWH-133 [30][31][32][33][34][35] mice with a genetic deficiency in CB 1 R or, to a lesser extent, CB 2 R. For example, CB 1 -/-mice showed increased infarct size and neurological deficits after tMCAO, concomitant with a reduction in cerebral blood flow and NMDA excitotoxicity [37], and a similar greater vulnerability was also found in TBI models [24], then supporting the protective role of CB 1 R against both pathological conditions. In the case of CB 2 -/-mice, results were controversial, with a study reporting larger cerebral infarction and a worsened neurological function after tMCAO [30], but others describing no differences using permanent MCAO [32,33], despite the notable effects found in pharmacological experiments with compounds selectively activating the CB 2 R [30][31][32][33][34][35]. These types of agonists are particularly interesting for a possible therapeutic application in stroke and TBI because of the lack of psychoactivity of their selective agonists.…”

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

“…20,33 Our results are in partial contrast with previous studies indicating that the abrogation of poststroke neutrophil cerebral infiltration might be a promising therapeutic target to reduce brain injury during reperfusion. 21,35 However, although the majority of the article focused on neutrophil infiltration, less is known on the selective release and expression of neutrophilic products that might increase the cerebral ischemic injury. 36 Finally, no evidence on a direct protective role of CXC chemokine inhibition on neurons or microglial cells has been clearly shown in the animal models of ischemic stroke.…”