title: 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.
authors.affiliation: The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, Tangshan Gongren Hospital, Hebei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Chemistry, North Carolina Central University, Durham, NC, USA; Neuroscience Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Nandiwada
authors.affiliation: Department of Chemistry, North Carolina Central University, Durham, NC, USA; Neuroscience Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.affiliation: The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Anesthesiology, Second Affiliated Hospital, Zhengzhou University, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Lu
authors.affiliation: The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: Department of Chemistry, North Carolina Central University, Durham, NC, USA; Neuroscience Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: huaxin.sheng@duke.edu.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
chemical_list: D001095:Arachidonic Acids; D061965:Matrix Metalloproteinase Inhibitors; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119325:arachidonyl-2-chloroethylamide; D020780:Matrix Metalloproteinase 9
keywords: ACEA; Agonist; Cannabinoid receptor 1; Matrix metalloproteinase 9; Spinal cord injury