CB1 cannabinoid receptor agonist inhibits matrix metalloproteinase activity in spinal cord injury: A possible mechanism of improved recovery

Abstract

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.