Neurosci Lett. 2015 Apr 14. pii: S0304-3940(15)00297-9. doi: 10.1016/j.neulet.2015.04.016. [Epub ahead of print]
CB1 cannabinoid receptor agonist inhibits matrix metalloproteinase activity in spinal cord injury: A possible mechanism of improved recovery.
Hong J1, Nandiwada V2, Jones V2, Lu M3, Warner DS4, Mukhopadhyay S2, Sheng H5.
1The Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, Tangshan Gongren Hospital, Hebei, China.
2Department of Chemistry, North Carolina Central University, Durham, NC, USA; Neuroscience Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
3The Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Anesthesiology, Second Affiliated Hospital, Zhengzhou University, China.
4The Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
5The Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: huaxin.sheng@duke.edu.
Increased matrix metalloproteinase (MMP) activity contributes to glial scar formation that inhibits the repair path after spinal cord injury (SCI). We examined whether treatment with N-?(2-?chloroethyl)-?5Z,?8Z,?11Z,?14Z-?eicosatetraenamide (ACEA), a selective synthetic cannabinoid receptor (CB1R) agonist, inhibits MMP and improves functional and histological recovery in a mouse spinal cord compression injury model. Injured mice randomly received either intraperitoneal ACEA (3mg/kg/day) or vehicle for up to 3 weeks. Behavioral, histological and biochemical assays were performed. Rotarod assessment and the Basso Mouse Scale score showed an improved performance following ACEA treatment concomitant with a decrease in compression lesion volume. MMP-9 and MMP-2 activity was measured at 1, 7 and 14 days post-SCI. SCI markedly increased MMP-9, but had negligible effect on MMP-2 activity. ACEA-treatment decreased MMP-9 activity by 80%, 49%, and 56%, respectively (P<0.05) and had a smaller effect on MMP-2 activity. The CB1R antagonist SR141716, but not the CB2R antagonist SR144528, blocked ACEA-mediated decrease in MMP-9 activity confirming the role of the CB1R in the process. Collectively these data demonstrate that post-injury CB1R agonism can improve SCI outcome and also indicate marked attenuation of MMP-9 proteolytic enzyme activity as a biochemical mechanism.
J Neuroimmune Pharmacol. 2015 Apr 16. [Epub ahead of print]
Effects of Cannabinoids on T-cell Function and Resistance to Infection.
Eisenstein TK1, Meissler JJ.
1Center for Substance Abuse Research, Temple University School of Medicine, Room 859, 3500 N. Broad St., Philadelphia, PA, 19140, USA, tke@temple.edu.
This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of ?9-THC extracted from the marijuana plant, and synthetic cannabinoids. Of particular interest are synthetic compounds that are CB2 receptor (CB2R) selective agonists. As the CB2R is principally expressed on cells of the immune system, agonists that target this receptor, and not CB1 (which is mainly expressed on neurons), have the possibility of altering immune function without psychoactive effects. The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including ?9-THC and CB2 selective agonists are immunosuppressive. The studies provide objective evidence for potentially beneficial effects of marijuana and ?9-THC on the immune system in conditions where it is desirable to dampen immune responses. Evidence is also reviewed supporting the conclusion that these same compounds can sensitize to some infections through their immunosuppressive activities, but not to others. An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects. |
