Pyruvate dehydrogenase inhibition suppresses paclitaxel-induced nociceptive hypersensitivity in Drosophila and mice.

Abstract

Paclitaxel is widely used against solid tumors, but painful sensory neuropathy frequently limits its dosing, and no therapy has been approved to prevent or reverse this complication. Mitochondrial injury in sensory neurons is increasingly recognized as a contributor to paclitaxel-induced peripheral neuropathy (PIPN), although the metabolic sources of this injury remain poorly defined. We therefore asked whether blocking the pyruvate dehydrogenase complex (PDH), which releases hydrogen peroxide as a byproduct of acetyl-CoA synthesis, could prevent PIPN. In fruit fly larvae, dietary paclitaxel caused heat hypersensitivity together with excessive dendrite growth and branching in class IV dendritic arborization (C4da) nociceptors, and a small-molecule PDH inhibitor reversed these changes. The inhibitor also blocked the paclitaxel-driven rise in mitochondrial ROS and mitophagy within C4da neurons. Lowering PDH activity genetically, through knockdown of the PDH E1α subunit, mutation of the PDH phosphatase, or overexpression of PDH kinase, likewise protected larvae from paclitaxel-induced thermal hyperalgesia. In mice, systemic PDH inhibition attenuated mechanical allodynia caused by repeated paclitaxel injections. These findings indicate that PDH activity contributes to paclitaxel-induced sensory hypersensitivity, suggest that mitochondrial oxidative stress may be involved, and support PDH inhibition as a potential preventive strategy against chemotherapy-induced neuropathy.

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