Targeting the Overproduction of Peroxynitrite for the Prevention and Reversal of Paclitaxel-Induced Neuropathic Pain

被引:137
作者
Doyle, Timothy [1 ]
Chen, Zhoumou [1 ]
Muscoli, Carolina [1 ,3 ,4 ]
Bryant, Leesa [1 ]
Esposito, Emanuela [5 ]
Cuzzocrea, Salvatore [5 ]
Dagostino, Concetta [4 ]
Ryerse, Jan [2 ]
Rausaria, Smita [6 ]
Kamadulski, Andrew [6 ]
Neumann, William L. [6 ]
Salvemini, Daniela [1 ]
机构
[1] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA
[2] St Louis Univ, Sch Med, Dept Pathol, St Louis, MO 63104 USA
[3] Magna Graecia Univ Catanzaro, Fac Pharm, I-88100 Catanzaro, Italy
[4] IRCCS, I-00163 Rome, Italy
[5] IRCCS Ctr Neurolesi Pulejo, Dept Clin & Expt Med & Pharmacol, I-98125 Messina, Italy
[6] So Illinois Univ, Sch Pharm, Dept Pharmaceut Sci, Edwardsville, IL 62026 USA
关键词
NITRIC-OXIDE SYNTHASE; MECHANICAL ALLODYNIA; SUPEROXIDE-DISMUTASE; DECOMPOSITION CATALYSTS; PERIPHERAL NEUROPATHY; INDUCED HYPERALGESIA; TYROSINE NITRATION; REACTIVE OXYGEN; BREAST-CANCER; UP-REGULATION;
D O I
10.1523/JNEUROSCI.6343-11.2012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-alpha and IL-1 beta) 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 (FeTMPyP5+ and MnTE-2-PyP5+). 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.
引用
收藏
页码:6149 / 6160
页数:12
相关论文
共 82 条
  • [1] Aldskogius H, 1999, J NEUROSCI RES, V58, P33, DOI 10.1002/(SICI)1097-4547(19991001)58:1<33::AID-JNR5>3.0.CO
  • [2] 2-M
  • [3] Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential
    Batinic-Haberle, Ines
    Reboucas, Julio S.
    Spasojevic, Ivan
    [J]. ANTIOXIDANTS & REDOX SIGNALING, 2010, 13 (06) : 877 - 918
  • [4] APPARENT HYDROXYL RADICAL PRODUCTION BY PEROXYNITRITE - IMPLICATIONS FOR ENDOTHELIAL INJURY FROM NITRIC-OXIDE AND SUPEROXIDE
    BECKMAN, JS
    BECKMAN, TW
    CHEN, J
    MARSHALL, PA
    FREEMAN, BA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (04) : 1620 - 1624
  • [5] Terminal arbor degeneration - a novel lesion produced by the antineoplastic agent paclitaxel
    Bennett, Gary J.
    Liu, Guo K.
    Xiao, Wen H.
    Jin, Hai W.
    Siau, Chiang
    [J]. EUROPEAN JOURNAL OF NEUROSCIENCE, 2011, 33 (09) : 1667 - 1676
  • [6] Pathophysiology and Animal Models of Cancer-Related Painful Peripheral Neuropathy
    Bennett, Gary J.
    [J]. ONCOLOGIST, 2010, 15 : 9 - 12
  • [7] LUMINOL ASSAY FOR SUPEROXIDE-DISMUTASE
    BENSINGER, RE
    JOHNSON, CM
    [J]. ANALYTICAL BIOCHEMISTRY, 1981, 116 (01) : 142 - 145
  • [8] Cata JP, 2006, MINERVA ANESTESIOL, V72, P151
  • [9] Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia
    Cata, JP
    Weng, HR
    Chen, JH
    Dougherty, PM
    [J]. NEUROSCIENCE, 2006, 138 (01) : 329 - 338
  • [10] The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats
    Cata, Juan P.
    Weng, Han-Rong
    Dougherty, Patrick M.
    [J]. BRAIN RESEARCH, 2008, 1229 : 100 - 110