A cannabinoid type 2 receptor agonist attenuates blood–brain barrier damage and neurodegeneration in a murine model of traumatic brain injury

Abstract

After traumatic brain injury (TBI), inflammation participates in both the secondary injury cascades and the repair of the CNS, both of which are influenced by the endocannabinoid system. This study determined the effects of repeated treatment with a cannabinoid type 2 receptor (CB(2) R) agonist on blood-brain barrier integrity, neuronal degeneration, and behavioral outcome in mice with TBI. We also looked for the presence of a prolonged treatment effect on the macrophage/microglial response to injury. C57BL/6 mice underwent controlled cortical impact (CCI) and received repeated treatments with a CB(2) R agonist, 0-1966, or vehicle. After euthanasia at 6 hr or 1, 2, 3, or 7 days postinjury, brains were removed for histochemical analysis. Blood-brain barrier permeability changes were evaluated by using sodium fluorescein (NaF). Perilesional degenerating neurons, injury volumes, and macrophage/microglia cells were quantified by stereological methods. Rota-rod and open-field testing were performed to evaluate motor function and natural exploratory behavior in mice. 0-1966 Treatment resulted in a significant reduction in NaF uptake and number of degenerating neurons compared with the vehicle-treated group. 0-1966-Treated mice demonstrated improvement on rota-rod and open-field testing compared with vehicle-treated mice. These changes in CCI mice treated with 0-1966 were associated with a prolonged reduction in macrophage/microglia cell counts. In conclusion, repeated treatments with a CB(2) R agonist, 0-1966, result in attenuated blood-brain barrier disruption and neuronal degeneration. In addition, repeated treatment with 0-1966 shows prolonged treatment effects on behavior and the macrophage/microglia cell response over several days.

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…58 Mild or severe traumatic brain injury induces hyperactivity in male and female mice Significant hyperactive exploration in the OF is a frequently reported effect of CCI delivered over parietal cortex in mice. 33,[59][60][61][62][63] In the current experiment, hyperactivity in injured mice ( Fig. 2A,B) was the result of more-continuous exploration in mice with TBI (fewer starts and stops; Fig.…”

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).…”