Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy

Duggett, Natalie A; Griffiths, Lisa A.; McKenna, Olivia E; Santis, Vittorio De; Yongsanguanchai, Nutcha; Mokori, Esther B; Flatters, Sarah J.L.

doi:10.1016/j.neuroscience.2016.06.050

Cited by 154 publications

(128 citation statements)

References 49 publications

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“…This provides evidence that in vivo ROS scavenging may be an effective target in understanding and preventing BIPN. Neuronally derived mitochondrial ROS have previously been shown to have a significant role in painful neuropathy associated with another chemotherapeutic, paclitaxel (Flatters and Bennett, ; Fidanboylu et al, ; Griffiths and Flatters, ; Duggett et al, ). In conjunction with these data, the global ROS scavenger, PBN, has been shown to ameliorate paclitaxel‐induced pain in the rat (Kim et al, ; Fidanboylu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a rat model of bortezomib‐induced painful neuropathy

Duggett

Flatters

2017

British J Pharmacology

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Background and PurposeBortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first‐line treatment due to lack of treatment. The aim of this study was to characterize a clinically relevant rat model of bortezomib‐induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery.Experimental ApproachAdult male Sprague–Dawley rats were injected i.p. with 0.1 and 0.2 mg·kg−1 bortezomib, or its vehicle, on days 0, 3, 7 and 10. Multiple behavioural approaches were utilized: mechanical hypersensitivity, cold allodynia, heat hypersensitivity, motor co‐ordination, burrowing and voluntary wheel running. At maximal bortezomib‐induced mechanical hypersensitivity, 200 mg·kg−1 ethosuximide/vehicle and 100 mg·kg−1 phenyl N‐tert‐butylnitrone (PBN)/vehicle were administered i.p. in separate experiments, and mechanical hypersensitivity assessed 1, 3 and 24 h later.Key ResultsBortezomib induced dose‐related mechanical hypersensitivity for up to 80 days. Bortezomib induced short‐term cold allodynia, but no significant change in heat hypersensitivity, motor co‐ordination, voluntary wheel running and burrowing behaviour compared to vehicle‐treated controls. Systemic PBN and ethosuximide significantly ameliorated bortezomib‐induced mechanical hypersensitivity.Conclusions and ImplicationsThese data characterize a reproducible rat model of clinical‐grade bortezomib‐induced neuropathy demonstrating long‐lasting pain behaviours to evoked stimuli. Inhibition by ethosuximide and PBN suggests involvement of calcium and/or ROS in bortezomib‐induced painful neuropathy. These drugs could be used as preclinical positive controls to assess novel analgesics. As ethosuximide is widely used clinically, translation to the clinic to treat bortezomib‐induced painful neuropathy may be possible.

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Section: Discussionmentioning

confidence: 99%

Characterization of a rat model of bortezomib‐induced painful neuropathy

Duggett

Flatters

2017

British J Pharmacology

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“…These changes in turn are accompanied by increased ROS production in sensory neurons and spinal cord, although the mechanisms leading to altered mitochondrial function are relatively poorly understood (Doyle et al, 2012; Areti et al, 2014; Griffiths and Flatters, 2015; Duggett et al, 2016). …”

Section: Pathological Mechanisms Contributing To Cipnmentioning

confidence: 99%

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Starobova

Vetter

2017

Front. Mol. Neurosci.

473

400

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Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

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“…Numerous inflammatory mediators also increase the production of reactive oxygen (ROS) and nitrogen species (RNS) during inflammation and in animal models of chronic neuropathic pain, which can alter excitability of sensory neurons (Bauerova and Bezek, 1999, Babior, 2000, Kim et al, 2004, Wang et al, 2004, Remans et al, 2005, Fidanboylu et al, 2011, Salvemini et al, 2011). Furthermore, several studies demonstrate that antioxidants can reverse changes in neuronal sensitivity (Khattab, 2006, Keeble et al, 2009, Fidanboylu et al, 2011, Duggett et al, 2016). The mechanisms by which ROS and RNS alter the sensitivity of sensory neurons remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1

et al. 2017

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Although inflammation-induced peripheral sensitization oftentimes resolves as an injury heals, this sensitization can be pathologically maintained and contribute to chronic inflammatory pain. Numerous inflammatory mediators increase the production of reactive oxygen (ROS) and nitrogen species (RNS) during inflammation and in animal models of chronic neuropathic pain. Our previous studies demonstrate that ROS/RNS and subsequent DNA damage mediate changes in neuronal sensitivity induced by anticancer drugs and by ionizing radiation in sensory neurons, thus we investigated whether inflammation and inflammatory mediators also could cause DNA damage in sensory neurons and whether that DNA damage alters neuronal sensitivity. DNA damage was assessed by pH2A.X expression and the release of the neuropeptide, calcitonin gene-related peptide (CGRP), was measured as an index of neuronal sensitivity. Peripheral inflammation or exposure of cultured sensory neurons to the inflammatory mediators, LPS and MCP-1, elicited DNA damage. Moreover, exposure of sensory neuronal cultures to LPS or MCP-1 resulted in changes in the stimulated release of CGRP, without altering resting release or CGRP content. Genetically enhancing the expression of the DNA repair enzyme, apurinic/apyrimidinic endonuclease (APE1) or treatment with a small-molecule modulator of APE1 DNA repair activity, both which enhance DNA repair, attenuated DNA damage and the changes in neuronal sensitivity elicited by LPS or MCP-1. In conclusion, our studies demonstrate that inflammation or exposure to inflammatory mediators elicits DNA damage in sensory neurons. By enhancing DNA repair, we demonstrate that this DNA damage mediates the alteration of neuronal function induced by inflammatory mediators in peptidergic sensory neurons.

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Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy

Cited by 154 publications

References 49 publications

Characterization of a rat model of bortezomib‐induced painful neuropathy

Characterization of a rat model of bortezomib‐induced painful neuropathy

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1

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