title: Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). Thus, CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of peroxynitrite (PN) in response to activation of nitric oxide synthases and NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10 and IL-4) cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted glutamate transporters and glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of paclitaxel-induced neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of neuropathic pain in rats using known PNDCs (FeTMPyP(5+) and MnTE-2-PyP(5+)). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics.
authors.affiliation: Department of Pharmacological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Concetta
authors.initials: C
authors.lastname: Dagostino
authors.forename: Jan
authors.initials: J
authors.lastname: Ryerse
authors.forename: Smita
authors.initials: S
authors.lastname: Rausaria
authors.forename: Andrew
authors.initials: A
authors.lastname: Kamadulski
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D030421:Peroxynitrous Acid; D017239:Paclitaxel