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

Jun Hong; Vijaya Nandiwada; Victoria Jones; Miaomiao Lu; David S Warner; Somnath Mukhopadhyay; Huaxin Sheng

doi:10.1016/j.neulet.2015.04.016

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

Neurosci Lett. 2015 Jun 15:597:19-24. doi: 10.1016/j.neulet.2015.04.016. Epub 2015 Apr 14.

Authors

Jun Hong¹, Vijaya Nandiwada², Victoria Jones², Miaomiao Lu³, David S Warner⁴, Somnath Mukhopadhyay², Huaxin Sheng⁵

Affiliations

¹ The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, Tangshan Gongren Hospital, Hebei, China.
² Department of Chemistry, North Carolina Central University, Durham, NC, USA; Neuroscience Research Program, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
³ The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Anesthesiology, Second Affiliated Hospital, Zhengzhou University, China.
⁴ The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
⁵ The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: huaxin.sheng@duke.edu.

PMID: 25881484
DOI: 10.1016/j.neulet.2015.04.016

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.

Keywords: ACEA; Agonist; Cannabinoid receptor 1; Matrix metalloproteinase 9; Spinal cord injury.

MeSH terms

Animals
Arachidonic Acids / pharmacology*
Arachidonic Acids / therapeutic use
Male
Matrix Metalloproteinase 9 / metabolism*
Matrix Metalloproteinase Inhibitors / pharmacology*
Matrix Metalloproteinase Inhibitors / therapeutic use
Mice, Inbred C57BL
Receptor, Cannabinoid, CB1 / agonists*
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB2 / antagonists & inhibitors
Spinal Cord / drug effects
Spinal Cord / enzymology
Spinal Cord / pathology
Spinal Cord / physiopathology
Spinal Cord Injuries / drug therapy*
Spinal Cord Injuries / enzymology
Spinal Cord Injuries / pathology
Spinal Cord Injuries / physiopathology

Substances

Arachidonic Acids
Matrix Metalloproteinase Inhibitors
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
arachidonyl-2-chloroethylamide
Matrix Metalloproteinase 9