Role of Matrix Metalloproteinases 2 in Spinal Cord Injury-Induced Neuropathic Pain

Abstract

Neuropathic pain (NP) affects approximately 4 million people in the United States with spinal cord injury (SCI) being a common cause. Matrix metalloproteinases (MMPs) play an integral role in mediating inflammatory responses, cellular signaling, cell migration, extracellular matrix degradation and tissue remodeling and repair. As such, they are major components in the pathogenesis of secondary injury within the central nervous system. Other gene regulatory pathways, specifically MAPK/extracellular signaling-regulated kinase (ERK) and Wnt/β-catenin, are also believed to participate in secondary injury likely intersect. The study aims to examine the MMP-2 signaling pathway associated with ERK and Wnt/β-catenin activity during contusion SCI (cSCI)-induced NP in a rat model. This is an experimental study investigating the implication of MMP-2 in SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase and β-catenin. Adult Sprague-Dawley rats received cSCI injury by NYU impactor by dropping 10 g weight from a height of 12.5 mm. Locomotor functional recovery of injured rats was measured on post cSCI day 1, and weekly thereafter for 6 weeks using Basso, Beattie and Bresnahan scores. Thermal hyperalgesia (TH) testing was performed on days 21, 28, 35 and 42 post cSCI. The expression and/or activity of MMP-2, β-catenin and ERK were studied following harvest of spinal cord tissues between 3 and 6 weeks post cSCI. All experiments were funded by the department of Neurological Surgery at the University of Wisconsin, School of Medicine and Public Health having no conflict of interest. MMP-2 and β-catenin expression were elevated and gradually increased from days 21 to 42 compared to sham-operated rats and injured rats that did not exhibit TH. The expression of phosphorylated ERK (phospho-ERK) increased on day 21 but returned to baseline levels on day 42 whereas total ERK levels remained relatively unchanged and constant. Chronic NP is associated with changes in the expression of MMP-2, β-catenin and ERK. Our data suggest that the transient upregulation of phospho-ERK is involved in the initial upregulation of both β-catenin and MMP-2 following cSCI-induced NP states.

Comparative Morphometry of the Wisconsin Miniature Swine^TM Thoracic Spine for Modeling Human Spine in Translational Spinal Cord Injury Research

“…To date, drug-based therapies for SCI and NP management have had limited efficacy in humans [23]. The heavy reliance on mouse [3][4][5][6]24] and rat [7][8][9][10] models for SCI research has led to inaccurate assessment of the effectiveness of therapies and delivery methods, especially of those administered into the spinal cord. The large surface area to volume ratio and the small axial plane of the spinal cord in small animals result in the distribution of therapies that is significantly different from that in humans.…”

“…While many promising molecular, gene, and cell therapies are being explored for SCI, advancement of these therapies to the clinical setting is hampered by a gap that exists between early research and clinical testing. Most SCI research occurs in small animal models such as mice [3][4][5][6] and rats [7][8][9][10]. However, no therapy shown to be safe and effective in rodent studies has advanced through clinical trials for treating human SCI [11].…”

Yoga: Can It Be Integrated with Treatment of Neuropathic Pain

“…Authors have speculated, through various grant proposals, that by inhibiting upregulation of such pain molecules in the early phase and/or late phase of injury, spinal cord damage and induced NP could be ameliorated. Our research findings from previous studies have helped in understanding novel mechanisms and treatments for SCI and NP employing a rat model [36][37][38][39][40][41][42] . This review aims to prompt new studies that examine the possible relationship of nociceptive proteins and its implications in translational approach of yogic processes in NP.…”

“…By using tissue inhibitors of MMPs and intrathecal injections of siRNAs, MMP levels are reduced, resulting in a decreased amount of inflammatory markers in comparison with wild-type mice [44] . Following induced cSCI in male adult Sprague-Dawley rats, we studied MMP2 in SCI-induced NP, the role of β-catenin in the WNT signaling pathway, and extracellular signaling kinase within the mitogen-activated protein kinase (MAPK) cascade [40] .…”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…Using Sprague Dawley rat, we have established a contusion SCI-induced NP model that demonstrates expression and activity of MMP9 in early phase and MMP2 in late phase of injury. These results are supported by molecular evidence of β-catenin involved in the WNT signaling pathway, and extracellular signaling kinase within the MAPK cascade (Miranpuri et al, 2016) [3]. Given the limitations of diffusion, larger animals with correspondingly larger spinal cords may require direct infusion of the therapeutics into the spinal cord parenchyma to realize results.…”