Research Identifies Underlying Mechanism of Chemotherapy-Induced Peripheral Neuropathy

A previously unidentified avenue exists for potential therapies for peripheral neuropathy induced by the chemotherapeutic agent paclitaxel.1

Nearly 8 million people in the United States are affected by peripheral nerve damage. Treatment development has been held back by a lack of understanding of its underlying mechanisms. Although treatments exist for the symptoms of peripheral neuropathy, treatments of the condition itself do not exist. Speculations were that its underlying biology was too complex to target.

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This research on the mechanisms underlying peripheral neuropathy was conducted by Sandra Rieger, PhD, of the MDI Biological Laboratory in Bar Harbor, Maine. MDI Biological Laboratory is an independent, nonprofit biomedical research institution focused on increasing healthy lifespan and harnessing our natural ability to repair and regenerate tissues damaged by injury or disease. The institution develops solutions to human health problems through research, education, and ventures that transform discoveries into cures.

"The general thinking is that no single drug can be effective for the treatment of all peripheral neuropathies, which stem from multiple causes," Rieger said. "But our research indicates that there may potentially be a common underlying mechanism for some neuropathies affecting the sensory nervous system that could be manipulated with drugs targeting a single enzyme."

Zebrafish were exposed to paclitaxel, which is used to treat ovarian, breast, lung, pancreatic, and other cancers. The majority of treated patients are affected by paclitaxel-induced peripheral neuropathy. The most severely affected patients (approximately 30%) discontinue chemotherapy or reduce the dose due to peripheral neuropathy, which can affect survival.

Peripheral neuropathy was modeled with zebrafish larvae, since the embryos develop rapidly and the larval fish are translucent, so nerve degeneration can be studied.

Paclitaxel was found to induce the degeneration of sensory nerve endings by damaging the outer layer of the skin (epidermis). The epidermis has free sensory nerve endings that establish direct contact with skin cells. Degeneration is 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, also a hallmark of diabetic peripheral neuropathy.

Treatments to reduce MMP-13 activity improved skin defects and reversed the chemotherapy-induced nerve damage in the zebrafish.

Next, the researchers will test the effect of MMP-13 on mammalian model of peripheral neuropathy.

REFERENCE

1. Lisse TS, Middleton LJ, Pellegrini AD, et al. Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish [published online ahead of print March 28, 2016]. PNAS Plus. doi:10.1073/pnas.1525096113.

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