Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 224-237 |
| Number of pages | 14 |
| Journal | Brain, Behavior, and Immunity |
| Volume | 68 |
| DOIs | |
| State | Published - Feb 1 2018 |
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Keywords
- Cannabinoid receptor 2
- Controlled cortical impact
- Inflammation
- Macrophage
- Marijuana
ASJC Scopus subject areas
- Immunology
- Endocrine and Autonomic Systems
- Behavioral Neuroscience
Cite this
Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization. / Braun, Molly; Khan, Zenab T.; Khan, Mohammad Badruzzaman; Kumar, Manish; Ward, Ayobami; Achyut, Bhagelu Ram; Arbab, Ali Syed; Hess, David C; Hoda, MD Nasrul; Baban, Babak; Dhandapani, Krishnan Michael; Vaibhav, Kumar.
In: Brain, Behavior, and Immunity, Vol. 68, 01.02.2018, p. 224-237.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization
AU - Braun, Molly
AU - Khan, Zenab T.
AU - Khan, Mohammad Badruzzaman
AU - Kumar, Manish
AU - Ward, Ayobami
AU - Achyut, Bhagelu Ram
AU - Arbab, Ali Syed
AU - Hess, David C
AU - Hoda, MD Nasrul
AU - Baban, Babak
AU - Dhandapani, Krishnan Michael
AU - Vaibhav, Kumar
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
KW - Cannabinoid receptor 2
KW - Controlled cortical impact
KW - Inflammation
KW - Macrophage
KW - Marijuana
UR - http://www.scopus.com/inward/record.url?scp=85032343375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032343375&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2017.10.021
DO - 10.1016/j.bbi.2017.10.021
M3 - Article
VL - 68
SP - 224
EP - 237
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
SN - 0889-1591
ER -