title: A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain.
abstract: Neuropathic pain (NeP) is generally considered an intractable problem, which becomes compelling in clinical practice when caused by highly effective chemotherapeutics, such as in the treatment of cancer with oxaliplatin (OXA) and related drugs. In the present work we describe a structurally new compound, ADM_09, which proved to effectively revert OXA-induced NeP in vivo in rats without eliciting the commonly observed negative side-effects. ADM_09 does not modify normal behavior in rats, does not show any toxicity toward astrocyte cell cultures, nor any significant cardiotoxicity. Patch-clamp recordings demonstrated that ADM_09 is an effective antagonist of the nociceptive sensor channel TRPA1, which persistently blocks mouse as well as human variants of TRPA1. A dual-binding mode of action has been proposed for ADM_09, in which a synergic combination of calcium-mediated binding of the carnosine residue and disulphide-bridge-forming of the lipoic acid residue accounts for the observed persistent blocking activity toward the TRPA1 channel.
authors.affiliation: Dipartimento di Chimica, Università di Firenze, Polo Scientifico e Tecnologico, Sesto Fiorentino, Firenze, Italy. cristina.nativi@unifi.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Nativi
authors.forename: Roberta
authors.initials: R
authors.lastname: Gualdani
authors.forename: Elisa
authors.initials: E
authors.lastname: Dragoni
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Sostegni
authors.forename: Martina
authors.initials: M
authors.lastname: Norcini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gabrielli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.forename: Barbara
authors.initials: B
authors.lastname: Richichi
authors.forename: Oscar
authors.initials: O
authors.lastname: Francesconi
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Moncelli
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Stefano
authors.initials: S
authors.lastname: Roelens
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D009437:Neuralgia / Q000139:chemically induced / Q000517:prevention & control*; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D000077150:Oxaliplatin