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Int. J. Mol. Sci. 2019, 20(4), 811; https://doi.org/10.3390/ijms20040811

Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain

1
PsychoGenics Inc., 215 College Road, Paramus, NJ 07652, USA
2
United States Army of Surgical Research, Joint Base San Antonio (JBSA), Fort Sam Houston, TX 78234, USA
3
Aquilus Pharmaceuticals Inc., 3H Gill Street, Suite 300, Woburn, MA 01801, USA
*
Author to whom correspondence should be addressed.
Received: 23 December 2018 / Revised: 11 February 2019 / Accepted: 11 February 2019 / Published: 14 February 2019
(This article belongs to the Special Issue Matrix Metalloproteinase)
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Abstract

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG. View Full-Text
Keywords: matrix metalloproteinase; MMP-2; MMP-9; inhibitor; allodynia; caspase-3; neuropathic; pain; dorsal root ganglion; spinal nerve ligation matrix metalloproteinase; MMP-2; MMP-9; inhibitor; allodynia; caspase-3; neuropathic; pain; dorsal root ganglion; spinal nerve ligation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kwan, M.Y.; Choo, A.; Hanania, T.; Ghavami, A.; Beltran, J.; Shea, J.; Barboza, A.; Hu, A.; Fowler, M.; Neelagiri, V.R.; Sucholeiki, I. Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain. Int. J. Mol. Sci. 2019, 20, 811.

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