N‐acylethanolamine‐hydrolyzing acid amidase: a new potential target to treat paclitaxel‐induced neuropathy

Abstract

Background

Although paclitaxel is an effective chemotherapeutic agent used to treat multiple types of cancer (e.g., breast, ovarian, neck, and lung), it also elicits paclitaxel‐induced peripheral neuropathy (PIPN), which represents a major dose‐limiting side effect of this drug.

Methods

As the endogenously produced N‐acylethanolamine, palmitoylethanolamide (PEA), reverses paclitaxel‐induced mechanical hypersensitivity in mice, the main goals of this study were to examine if paclitaxel affects levels of endogenous PEA in the spinal cord of mice and whether exogenous administration of PEA provides protection from the occurrence of paclitaxel‐induced mechanical hypersensitivity. We further examined whether inhibition of N‐acylethanolamine‐hydrolyzing acid amidase (NAAA), a hydrolytic PEA enzyme, would offer protection in mouse model of PIPN.

Results

Paclitaxel reduced PEA levels in the spinal cord, suggesting that dysregulation of this lipid signaling system may contribute to PIPN. Consistent with this idea, repeated administration of PEA partially prevented the paclitaxel‐induced mechanical hypersensitivity. We next evaluated whether the selective NAAA inhibitor, AM9053, would prevent paclitaxel‐induced mechanical hypersensitivity in mice. Acute administration of AM9053 dose‐dependently reversed mechanical hypersensitivity through a PPAR‐α mechanism, whereas repeated administration of AM9053 fully prevented the development of PIPN, without any evidence of tolerance. Moreover, AM9053 produced a conditioned place preference in paclitaxel treated mice, but not in control mice. This pattern of findings suggests a lack of intrinsic rewarding effects, but a reduction in the pain aversiveness induced by paclitaxel. Finally, AM9053, did not alter paclitaxel‐induced cytotoxicity in lung tumor cells.

Conclusions

Collectively, these studies suggest that NAAA represents a promising target to treat and prevent PIPN.

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