Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain

Daniela Salvemini, Timothy Doyle, Zhoumou Chen, Carolina Muscoli, Leesa Bryant, Emanuela Esposito, Salvatore Cuzzocrea, Concetta Dagostino, Jan Ryerse, Smita Rausaria, Andrew Kamadulski, William L. Neumann

Research output: Contribution to journalArticle

79 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)6149-6160
Number of pages12
JournalJournal of Neuroscience
Volume32
Issue number18
DOIs
Publication statusPublished - May 2 2012

Fingerprint

Peroxynitrous Acid
Neuralgia
Paclitaxel
Peripheral Nervous System Diseases
Drug Therapy
Superoxides
Spinal Cord
Amino Acid Transport System X-AG
Glutamate-Ammonia Ligase
NADPH Oxidase
Post Translational Protein Processing
Interleukin-1
Nitric Oxide Synthase
Synaptic Transmission
Neuroglia
Chronic Pain
Astrocytes
Interleukin-4
Interleukin-10
Reactive Oxygen Species

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Salvemini, D., Doyle, T., Chen, Z., Muscoli, C., Bryant, L., Esposito, E., ... Neumann, W. L. (2012). Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. Journal of Neuroscience, 32(18), 6149-6160. https://doi.org/10.1523/JNEUROSCI.6343-11.2012

Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. / Salvemini, Daniela; Doyle, Timothy; Chen, Zhoumou; Muscoli, Carolina; Bryant, Leesa; Esposito, Emanuela; Cuzzocrea, Salvatore; Dagostino, Concetta; Ryerse, Jan; Rausaria, Smita; Kamadulski, Andrew; Neumann, William L.

In: Journal of Neuroscience, Vol. 32, No. 18, 02.05.2012, p. 6149-6160.

Research output: Contribution to journalArticle

Salvemini, D, Doyle, T, Chen, Z, Muscoli, C, Bryant, L, Esposito, E, Cuzzocrea, S, Dagostino, C, Ryerse, J, Rausaria, S, Kamadulski, A & Neumann, WL 2012, 'Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain', Journal of Neuroscience, vol. 32, no. 18, pp. 6149-6160. https://doi.org/10.1523/JNEUROSCI.6343-11.2012
Salvemini, Daniela ; Doyle, Timothy ; Chen, Zhoumou ; Muscoli, Carolina ; Bryant, Leesa ; Esposito, Emanuela ; Cuzzocrea, Salvatore ; Dagostino, Concetta ; Ryerse, Jan ; Rausaria, Smita ; Kamadulski, Andrew ; Neumann, William L. / Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 18. pp. 6149-6160.
@article{3048b4a729504f53876bd3a422e8347a,
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 (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.",
author = "Daniela Salvemini and Timothy Doyle and Zhoumou Chen and Carolina Muscoli and Leesa Bryant and Emanuela Esposito and Salvatore Cuzzocrea and Concetta Dagostino and Jan Ryerse and Smita Rausaria and Andrew Kamadulski and Neumann, {William L.}",
year = "2012",
month = "5",
day = "2",
doi = "10.1523/JNEUROSCI.6343-11.2012",
language = "English",
volume = "32",
pages = "6149--6160",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "18",

}

TY - JOUR

T1 - Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain

AU - Salvemini, Daniela

AU - Doyle, Timothy

AU - Chen, Zhoumou

AU - Muscoli, Carolina

AU - Bryant, Leesa

AU - Esposito, Emanuela

AU - Cuzzocrea, Salvatore

AU - Dagostino, Concetta

AU - Ryerse, Jan

AU - Rausaria, Smita

AU - Kamadulski, Andrew

AU - Neumann, William L.

PY - 2012/5/2

Y1 - 2012/5/2

N2 - 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 (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.

AB - 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 (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.

UR - http://www.scopus.com/inward/record.url?scp=84860333152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860333152&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.6343-11.2012

DO - 10.1523/JNEUROSCI.6343-11.2012

M3 - Article

C2 - 22553021

AN - SCOPUS:84860333152

VL - 32

SP - 6149

EP - 6160

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 18

ER -