A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways |
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| Affiliation: | 1. Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA;2. Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina 98122, Italy;3. 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;1. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;3. Geriatric Research, Education and Clinical Center, James J. Peters VAMC, Bronx, NY, USA;4. Medical University of South Carolina, Charleston, SC, USA;5. Department of Emergency Medicine, Oregon Health & Science University, Portland, SC, USA;6. Department of Emergency Medicine, George Washington University Medical Center, Washington, DC, USA;7. Department of Emergency Medicine, University of Colorado, Aurora, CO, USA;8. Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;9. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;1. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA;2. Department of Pediatrics and Children’s Research Institute, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA;3. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA;1. Clermont Université, Université d’Auvergne, Pharmacologie fondamentale et clinique de la douleur, Clermont-Ferrand, France;2. Inserm, U 1107, Neuro-Dol, Clermont-Ferrand, France;3. CHU Clermont-Ferrand, Service de pharmacologie, Clermont-Ferrand, France;4. Université de Nice Sophia Antipolis, Nice, France;5. CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Valbonne, France;6. Universités de Montpellier 1 et 2, Montpellier, France;7. CNRS, Institut de Génomique Fonctionnelle, UMR-5203, Département de Physiologie, Montpellier, France;8. LabEx Ion Channel Science and Therapeutics, Valbonne, France;1. Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University Medical Center, Stanford, CA, USA;2. Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA;3. Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA;4. Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, Pain and Interoception Network (PAIN), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;5. Department of Radiology, University of Alabama, Birmingham Medical Center, Birmingham, AL, USA;6. Department of Anesthesiology, University of Alabama, Birmingham Medical Center, Birmingham, AL, USA;1. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA;2. The Synthetic Neurobiology Group, Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA |
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| 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. |
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| Keywords: | A3 Adenosine Chemotherapy-induced peripheral neuropathy Neuroinflammation Neuropathic pain Paclitaxel Spinal cord |
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