Abstract
BackgroundIn the peripheral nerve, pro-inflammatory matrix metalloproteinase (MMP)-9 performs essential functions in the acute response to injury. Whether MMP-9 activity contributes to late-phase injury or whether MMP-9 expression or activity after nerve injury is sexually dimorphic remains unknown.MethodsPatterns of MMP-9 expression, activity and excretion were assessed in a model of painful peripheral neuropathy, sciatic nerve chronic constriction injury (CCI), in female and male rats. Real-time Taqman RT-PCR for MMP-9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) of nerve samples over a 2-month time course of CCI was followed by gelatin zymography of crude nerve extracts and purified MMP-9 from the extracts using gelatin Sepharose-beads. MMP excretion was determined using protease activity assay of urine in female and male rats with CCI.ResultsThe initial upsurge in nerve MMP-9 expression at day 1 post-CCI was superseded more than 100-fold at day 28 post-CCI. The high level of MMP-9 expression in late-phase nerve injury was accompanied by the reduction in TIMP-1 level. The absence of MMP-9 in the normal nerve and the presence of multiple MMP-9 species (the proenzyme, mature enzyme, homodimers, and heterodimers) was observed at day 1 and day 28 post-CCI. The MMP-9 proenzyme and mature enzyme species dominated in the early- and late-phase nerve injury, consistent with the high and low level of TIMP-1 expression, respectively. The elevated nerve MMP-9 levels corresponded to the elevated urinary MMP excretion post-CCI. All of these findings were comparable in female and male rodents.ConclusionThe present study offers the first evidence for the excessive, uninhibited proteolytic MMP-9 activity during late-phase painful peripheral neuropathy and suggests that the pattern of MMP-9 expression, activity, and excretion after peripheral nerve injury is universal in both sexes.
Highlights
In the peripheral nerve, pro-inflammatory matrix metalloproteinase (MMP)-9 performs essential functions in the acute response to injury
In the present study, utilizing a well-established model of sciatic nerve constriction injury (CCI) mononeuropathy in male and female rats, we tested whether MMP-9 contributes to late-phase painful peripheral nerve trauma or whether the changes in MMP-9 expression, proteolytic activity, or excretion post-CCI are sexually dimorphic
After CCI injury, MMP-9 mRNA level at the nerve injury site increased within 1 day and persisted for several weeks, escalating again at day 28 post-CCI
Summary
Pro-inflammatory matrix metalloproteinase (MMP)-9 performs essential functions in the acute response to injury. There are over 100 peripheral neuropathy types associated with metabolic disease, nutritional deficiencies, trauma and exposure to Remacle et al Journal of Neuroinflammation (2018) 15:89 formation of collateral axonal sprouting, cortical connectivity, and the activities of brain-derived neurotrophic factor, N-methyl-D-aspartate, and opioid receptors in the damaged nervous system (reviewed in [3]). In the damaged adult peripheral nerve, pro-inflammatory MMP-9 (gelatinase B) is produced uniquely and immediately after injury by Schwann, endothelial, and immune cells to regulate the blood-nerve barrier breakdown, immune cell recruitment, glial activation, demyelination, remyelination, and pain [6,7,8,9,10,11,12,13,14,15,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
