The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients’ lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

“…However, most of these therapies exhibited moderate efficacy and significant side effects such as somnolence, constipation, tolerance, and dizziness [ 60 ]. In addition, some treatments only improved neuropathy or one of the emotional disorders associated with chemotherapy-induced neuropathic pain [ 61 , 62 , 63 ], but only a few studies evaluated the possible effects of different treatments in the management of PIPN-associated mood disorders [ 13 , 64 , 65 ]. In this line, this study demonstrated that treatment with HRW inhibited neuropathy and avoided the cognitive and emotional deficits associated.…”

Exploring Outcome Priorities and Real-Life Management of Chemotherapy-Induced Peripheral Neurotoxicity: A Survey of the Italian Association for the Study of Pain members

“… 17 , 18 Furthermore, as many other neuropathic conditions, neuroinflammation and microglial phenotypic change are fundamental mechanisms in the pathogenesis of CIPN. 19 , 20 PEA modulates the cannabinoid receptors 2 (CB2) expression and potentiates the activity of other endocannabinoid mediators, and its role as a preventive or therapeutic has been demonstrated in animal models of CIPN induced by oxaliplatin and taxanes. 20–22 Furthermore, in a small clinical study, PEA administration to patients affected by painful CIPN has shown a beneficial effect on myelinated nerve fibers function and pain.…”

“… 19 , 20 PEA modulates the cannabinoid receptors 2 (CB2) expression and potentiates the activity of other endocannabinoid mediators, and its role as a preventive or therapeutic has been demonstrated in animal models of CIPN induced by oxaliplatin and taxanes. 20–22 Furthermore, in a small clinical study, PEA administration to patients affected by painful CIPN has shown a beneficial effect on myelinated nerve fibers function and pain. 23 As confirmed by the results of this survey, most respondents consider PEA as a first line agent for CIPN management, despite no robust evidence is available and this nutraceutical is not mentioned in CIPN guidelines.…”

Prevention and therapy of chemotherapy-induced peripheral neuropathy: a review of recent findings

“…The well-known anti-inflammatory and antinociceptive effects of PEA (palmitoylethanolamide) are considered a beneficial strategy in the management of the oxaliplatin- [148] and paclitaxel- [149] induced CIPN model, as well as in osteoarthritis [150] and fibromyalgia studies [151]. Cristiano et al, 2022 demonstrated that um-PEA (ultramicronized PEA) reduced the development of hypersensitivity with an effect associated with the reduction of spinal cord and hippocampal proinflammatory cytokines, as well as antidepressant and anxiolytic effects [152].…”