Acute Effects of a Selective Cannabinoid-2 Receptor Agonist on Neuroinflammation in a Model of Traumatic Brain Injury

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

“…One hypothesis is that microglia have a harmful effect on pericontusional axonal injury, and that reduction in the microglial response is the proximal mechanism by which COG1410 affects TAI. Additional interventions targeting microglia will be necessary to directly address this hypothesis (Elliott et al, 2011;Grathwohl et al, 2009;Namas et al, 2009). By analogy, minocycline, which may also inhibit microglial activation, has been shown to improve outcomes in other experimental injury models (Kim and Suh 2009).…”

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.…”

CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

“…By contrast, chronic CP55,940, at a dose that produced CB 2 -mediated antiallodynic efficacy, failed to decrease body temperature in CB 1 KO mice, documenting that prolonged activation of CB 2 receptors does not result in hypothermia (Malan et al, 2001;Valenzano et al, 2005;Yao et al, 2009;Elliott et al, 2011;Kinsey et al, 2011;Amenta et al, 2012). Chronic CP55,940-treated WT, but not CB 1 KO mice, showed profound withdrawal signs when challenged with the CB 1 antagonist rimonabant, suggesting precipitation at CB 1 receptors produces withdrawal symptoms (Tsou et al, 1995;Aceto et al, 1996;Cook et al, 1998;Rubino et al, 1998;Lichtman et al, 2001).…”