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

• Published in: International journal of molecular sciences 2019-02, Vol.20 (4), p.811
• Main Authors: Kwan, Mei Yee, Choo, Anthony, Hanania, Taleen, Ghavami, Afshin, Beltran, Jose, Shea, John, Barboza, Amidi, Hu, Andrew, Fowler, Marcie, Neelagiri, Venugopal Rao, Sucholeiki, Irving
• Format: Article
• Language: English
• Subjects: allodynia; Animals; Anticonvulsants; Attenuation; Biomarkers; Biomarkers - metabolism; Caspase 3 - genetics; Caspase-3; Cytokines; Dehydrogenases; dorsal root ganglion; Fuel consumption; Gabapentin; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Gelatinase B; Gene expression; Gene Expression Regulation - drug effects; Humans; IL-1β; Indoles - administration & dosage; inhibitor; Interleukin 6; Ligation; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase Inhibitors - administration & dosage; Matrix metalloproteinases; Metalloproteinase; MMP-2; MMP-9; Molecular weight; Neuralgia - drug therapy; Neuralgia - genetics; Neuralgia - pathology; neuropathic; Neurotransmission; Oral administration; Pain; Pain perception; Propionates - administration & dosage; Proteins; Rats; Rodents; Spinal cord; spinal nerve ligation; Spinal nerves; Spinal Nerves - drug effects; Spinal Nerves - injuries; Surgery; Thiophenes - administration & dosage; Western blotting
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20040811

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.