PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis.

Michela Campolo,Marika Lanza,Alessia Filippone,Sarah A Scuderi,Lorenzo Memeo,Irene Paterniti,Alessio Ardizzone,Marzia Mare,Emanuela Esposito,Salvatore Cuzzocrea,Caterina Puglisi,Giovanna Casili

doi:10.3390/ijms22083927

Abstract

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0–4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15–20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.

Highlights

Introduction published maps and institutional affilChemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of common anticancer therapies [1]
CIPN develops during platinum drug treatment and the symptoms may persist for 2–6 months after cessation of chemotherapy [3]
Tests conducted in each compound group, prior to drug administration, confirmed that Mechanical Conflict System (MCS) escape latencies were consistent with those observed in L-OHP-treated rats in the stimulus response assessment for the 0 and 3 mm probe conditions

Summary

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of common anticancer therapies [1]. The chemotherapy drugs that can origin CIPN include vinca alkaloids, taxanes, and, above all, platinum analogues. CIPN develops during platinum drug treatment and the symptoms may persist for 2–6 months after cessation of chemotherapy [3]. Oxaliplatininduced peripheral neuropathy (OIPN) initiates through the accumulation of platinum adducts in dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons, leading to a modification of axon function, as well as myelin sheath, neuronal cell body, and glial structures [3]. The pathological mechanisms underlying CIPN are still unclear; a considerable involvement of oxidative stress and inflammation has been recently recognized, leading to an increase in nociceptive trigeminal ganglion excitability.

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