Preventive Hypothermia as a Neuroprotective Strategy for Paclitaxel-induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse effect that occurs secondary to chemotherapeutic treatments and has no known preventive or therapeutic strategy Therapeutic hypothermia has been shown to be effective in protecting against central and peripheral nervous system injuries However the effects of therapeutic hypothermia on CIPN have rarely been explored We induced lower back hypothermia (LBH) in an established paclitaxel-induced CIPN rat model and found that the paclitaxel-induced impairments observed in behavioral electrophysiological and histological impairments were inhibited by LBH when applied at an optimal setting of 24°C to the sciatic nerve and initiated 90 minutes before paclitaxel infusion Lower back hypothermia also inhibited the paclitaxel-induced activation of astroglia and microglia in the spinal cord macrophage infiltration into and neuronal injury in the dorsal root ganglia and sciatic nerves as well as the release of pro-inflammatory cytokines in the dorsal root ganglia sciatic nerves and spinal dorsal horn Furthermore LBH decreased the local blood flow and local tissue concentrations of paclitaxel Finally we induced unilateral hind limb hypothermia in paclitaxel-induced CIPN rat model and found that regional cooling is achieved with no effect on the contralateral side Importantly in NOD/SCID mice inoculated with cancer cells the antiproliferative effect of paclitaxel was not affected by the distal application of hypothermia In conclusion our findings indicate that early exposure to regional hypothermia alleviates paclitaxel-induced peripheral neuropathy Therapeutic hypothermia may therefore represent an economical and nonpharmaceutical preventive strategy for CIPN in patients with localized solid tumors

Date of Award	2019
Original language	English
Supervisor	Yu-Min Kuo (Supervisor)