title: Antineuropathic profile of N-palmitoylethanolamine in a rat model of oxaliplatin-induced neurotoxicity.
abstract: Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg-1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg-1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Experimental and Clinical Medicine-DMSC-Anatomy and Histology Section, University of Florence, Florence, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Corti
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Messina, Italy; Young Against Pain (YAP) group, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000577:Amides; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009420:Nervous System / Q000187:drug effects / Q000473:pathology; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010169:Palmitic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley
chemical_list: D051700:Activating Transcription Factor 3; D000577:Amides; C497108:Atf3 protein, rat; D004983:Ethanolamines; D018836:Inflammation Mediators; D009944:Organoplatinum Compounds; D010169:Palmitic Acids; D000077150:Oxaliplatin; C005958:palmidrol