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.

Mei Kwan,Irving Sucholeiki,John Shea,Afshin Ghavami,Amidi Barboza,Anthony Choo,Marcie Fowler,Taleen Hanania,Venugopal Neelagiri,Jose Beltran,Andrew Hu

doi:10.3390/ijms20040811

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.

Highlights

The population suffering from neuropathic pain is large; neuropathic pain is a significant problem for patients and the healthcare system
Many biomarkers are associated with neuropathic pain, we focused on those whose expression and/or protein levels have been reported to change within the dorsal root ganglion (DRG) or dorsal horn following spinal nerve injuries [12,13,16,17,18]
This study presents for the first time biomarker data for an orally administered, dual active matrix metalloproteinases (MMPs)-2/MMP-9 inhibitor in the spinal nerve ligation (SNL) rat model for neuropathic pain

Summary

Introduction

The population suffering from neuropathic pain is large; neuropathic pain is a significant problem for patients and the healthcare system. This type of pain is difficult to treat effectively with currently available pharmacological agents, in part due to the fact that the aetiologies that drive the neuropathic pain states are varied, complex, and not well-understood. Surgically-induced rodent models of neuropathic pain cause the levels of various inflammatory proteins such as cytokines and, in particular, certain matrix metalloproteinases (MMPs), to become elevated within the spinal nerves [3,4,5,6,7,8,9]. Increased expression of MMPs or an imbalance of different MMPs has been observed in a variety of pathological conditions, including various neurodegenerative diseases [10,11]

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