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 percent) have to terminate chemotherapy or reduce the dose because of this condition, which can impact cancer survival.
The research showed that 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.
The 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, the zebrafish treated 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.
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.
Mechanism underlying peripheral neuropathy
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