title: A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.
abstract: Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina 98122, Italy Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Janes
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Dillip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D058909:Adenosine A3 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology; D008297:Male; D009249:NADP / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009437:Neuralgia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D009457:Neuroglia / Q000378:metabolism; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D058909:Adenosine A3 Receptor Agonists; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D027342:Excitatory Amino Acid Transporter 2; D016328:NF-kappa B; C493395:Slc1a2 protein, rat; D014409:Tumor Necrosis Factor-alpha; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D009249:NADP; D000241:Adenosine; D017239:Paclitaxel
keywords: A3; Adenosine; Chemotherapy-induced peripheral neuropathy; Neuroinflammation; Neuropathic pain; Paclitaxel; Spinal cord