Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.
Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation.
['Braun|Molly|M|', 'Khan|Zenab T|ZT|', 'Khan|Mohammad B|MB|', 'Kumar|Manish|M|', 'Ward|Ayobami|A|', 'Achyut|Bhagelu R|BR|', 'Arbab|Ali S|AS|', 'Hess|David C|DC|', 'Hoda|Md Nasrul|MN|', 'Baban|Babak|B|', 'Dhandapani|Krishnan M|KM|', 'Vaibhav|Kumar|K|']
D000818:Animals D001930:Brain Injuries D000070642:Brain Injuries, Traumatic D002186:Cannabinoids D002188:Cannabis D004195:Disease Models, Animal D063388:Endocannabinoids D007192:Indenes D007249:Inflammation D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D015213:Neuroimmunomodulation D011720:Pyrazoles D043885:Receptor, Cannabinoid, CB2 D043882:Receptors, Cannabinoid
Macrophage Inflammation Controlled cortical impact Cannabinoid receptor 2 Marijuana