MMP-13 inhibition improves adult paclitaxel-induced neurotoxicity. (A) Improved touch response upon coadministration of paclitaxel and either DB04760 or CL-82198 following four injections (n = 7, 7–12 fish per group) and complete rescue by day 14 in DB04760 coadministered animals (n = 2, 5 fish). (B and C) Axon branch density in distal caudal fin is rescued upon coadministration of paclitaxel and either DB04760 or CL-82198 when assessed 1 d (B) (n = 3, 7–12 fish per group) or 10 d (C) (n = 2, 5 fish per group) after the last injection. (D and E) MMP-13 immunofluorescence staining (red) 1 d after the last injection shows MMP-13 up-regulation specifically in basal keratinocytes (yellow arrowheads) of Tg(tp63:CAAX-GFP) fish injected with paclitaxel (E) and low MMP-13 expression in vehicle controls (D). Imaging was performed using identical settings. Dermal cells in both vehicle and paclitaxel-injected fish have similar MMP-13 expression levels. White arrowheads depict large distinctive MMP-13 clusters. (E) White arrows depict clusters of MMP-13–positive cellular debris at the skin surface, indicative of increased cell shedding. (Scale bar, 5 µm.) (F) MMP-13 staining (red) is adjacent to, but not within, DRG axons (green). (Scale bar, 10 µm.) *P < 0.05, ***P < 0.001, ****P < 0.0001. ac-tub, acetylated tubulin; Pctx, paclitaxel.
Discovery raises prospect of treatments for common painful/ numbing/tingling condition. Peripheral nerve damage is a common condition affecting nearly 8M people in the US, but until now a lack of understanding of the underlying mechanisms has held back the development of treatments. Drugs exist for the treatment of symptoms – pain relievers, for instance – but not for the condition itself, which can be caused by chemotherapy, diabetes, traumatic injury, heredity and other conditions.
“Our goal is to develop treatments that activate the repair and regeneration of damaged tissues,” said Kevin Strange, Ph.D., president of the MDI Biological Lab. Rieger conducted her research in zebrafish exposed to paclitaxel, a chemotherapeutic agent used for ovarian, breast, lung, pancreatic and other cancers. Paclitaxel-induced peripheral neuropathy affects the majority of treated patients; however, those who are most severely affected (about 30%) have to terminate chemotherapy or reduce the dose because of this condition. Zebrafish embryos develop rapidly and are translucent, making them ideal for studying the progression of nerve degeneration in live animals.
Paclitaxel induces the degeneration of sensory nerve endings by damaging the outer layer of the skin, or epidermis. The epidermis is innervated by free sensory nerve endings that establish direct contact with skin cells. Her research showed that degeneration is caused by perturbations in the epidermis due to an increase in matrix-metalloproteinase 13 (MMP-13), an enzyme that degrades the collagen, or “glue,” between the cells. The increase in MMP-13 activity could be triggered by oxidative stress, which is also a hallmark of diabetic peripheral neuropathy.
In the research, Rieger treated the zebrafish with pharmacological agents that reduce MMP-13 activity, with the result that skin defects were improved and chemotherapy-induced nerve damage was reversed. The treatment of neuropathy with MMP-13- targeting compounds is the subject of a provisional patent filed by the MDI Biological Laboratory in January. MMP-13 over-activation has also been linked to various other disease conditions, such as tendon injury, intestinal inflammatory and cancer, raising the possibility that drugs developed to treat peripheral neuropathy could yield other health benefits as well.
The next step is to study the effect of MMP-13 on peripheral neuropathy in mammalian models. Studies are also underway in collaboration with the Mayo Clinic in Rochester, Minn., to test the clinical relevance of these findings in humans. https://mdibl.org/press-release/mdi-biological-laboratory-scientist-identifies-mechanism-underlying-peripheral-neuropathy/ http://www.pnas.org/content/113/15/E2189.full
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