Highlights
- •Antioxidants ameliorate OXA-induced peripheral neuropathy in tumor-bearing mice.
- •OXA promotes ROS production and inflammation in the spinal cord of mice.
- •Antioxidants abrogate ROS-induced spinal cord inflammation in OXA-treated mice.
- •Tlr4 knockout decreases spinal cord inflammation and mechanical allodynia.
- •Antioxidants do not impair the antitumor efficacy of OXA.
Abstract
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat,
and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this
study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic
acid and vitamin E – upon nociceptive parameters and antitumor efficacy of OXA in
a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both
mechanical and cold allodynia when concomitantly administrated with OXA (preventive
protocol), as well as in animals with previously established CIPN (therapeutic protocol).
OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented
the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the
astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation,
and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4)
and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced
levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord,
which were associated with resistance to OXA-induced mechanical allodynia. Lastly,
antioxidants affected neither antitumor activity nor hematological toxicity of OXA
in vivo. The herein presented results are provocative for further evaluation of antioxidants
in clinical management of chemotherapy-induced peripheral neuropathy.
Perspective
This study reports preventive and therapeutic efficacy of orally administrated antioxidants
(N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced
peripheral neuropathy in tumor-bearing mice. Antioxidants’ anti-nociceptive effects
are associated with inhibition of ROS-dependent neuroinflammation, and occur at no
detriment of OXA antitumor activity, therefore indicating a translational potential
of these compounds.
Graphical abstract
Graphical Abstract
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
REFERENCES
- Antineoplastic effect of pectic polysaccharides from green sweet pepper (Capsicum annuum) on mammary tumor cells in vivo and in vitro.Carbohydr Polym. 2018; 201: 280-292
- Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.Pain. 2014; 155: 1802-1813
- Interventions for preventing neuropathy caused by cisplatin and related compounds.Cochrane Database Syst Rev. 2014; 3CD005228
- Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy.Redox Biol. 2014; 2: 289-295
- preventing paclitaxel-induced peripheral neuropathy: A Phase II trial of Vitamin E supplementation.J Pain Symptom Manage. 2006; 32: 237-244
- N-acetylcysteine (NAC) in neurological disorders: Mechanisms of action and therapeutic opportunities.Brain Behav. 2014; 4: 108-122
- Chemotherapy-induced neurotoxicity: The value of neuroprotective strategies.Neth J Med. 2012; 70: 18-25
- TRPA1 is a major oxidant sensor in murine airway sensory neurons.J Clin Invest. 2008; 118: 1899-1910
- Dietary supplementation with α-tocopherol reduces neuroinflammation and neuronal degeneration in the rat brain after kainic acid-induced status epilepticus.Free Radic Res. 2011; 45: 1136-1142
- Impact of antioxidant supplementation on chemotherapeutic toxicity: A systematic review of the evidence from randomized controlled trials.Int J Cancer. 2008; 123: 1227-1239
- Broad expression of Toll-like receptors in the human central nervous system.J Neuropathol Exp Neurol. 2002; 61: 1013-1021
- Pathogenesis of platinum-induced peripheral neurotoxicity: Insights from preclinical studies.Exp Neurol. 2020; 325113141
- Quantitative assessment of tactile allodynia in the rat paw.J Neurosci Methods. 1994; 53: 55-63
- Characterization of cancer-induced nociception in a murine model of breast carcinoma.Cell Mol Neurobiol. 2019; 39: 605-617
- Glial role in oxaliplatin-induced neuropathic pain.Exp Neurol. 2014; 261: 22-33
- Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: Could it correlate with in vivo neuropathy?.Free Radic Biol Med. 2013; 61: 143-150
- Oxaliplatin-induced neuropathy: Oxidative stress as pathological mechanism. Protective effect of silibinin.J Pain. 2012; 13: 276-284
- Methods for detection of mitochondrial and cellular reactive oxygen species.Antioxidants Redox Signal. 2014; 20: 372-382
- N -acetylcysteine for antioxidant therapy: Pharmacology and clinical utility.Expert Opin Biol Ther. 2008; 8: 1955-1962
- Malondialdehyde determination as index of lipid Peroxidation.Methods Enzymol. 1990; 186: 421-431
- Neuroinflammation and the generation of neuropathic pain.Br J Anaesth. 2013; 111: 26-37
- Oxamate potentiates taxol chemotherapeutic efficacy in experimentally-induced solid ehrlich carcinoma (SEC) in mice.Biomed Pharmacother. 2017; 95: 1565-1573
- The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol. 2009; 10: 241-247
- An acute mouse spinal cord slice preparation for studying glial activation ex vivo.Bio Protoc. 2017; 7: e2102
- A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.J Clin Oncol. 2004; 22: 23-30
- Lipoic acid - Biological activity and therapeutic potential.Pharmacol Reports. 2011; 63: 849-858
- Recent advances in understanding chemotherapy-induced peripheral neuropathy.F1000Research. 2020; 9: 177-190
- Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways.Glia. 2011; 59: 242-255
- High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy.Int J Cancer. 2020; 146: 2810-2821
- A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.Pain. 1988; 32: 77-88
- A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylxpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat.J Pharmacol Exp Ther. 2006; 319: 1376-1385
- A modified hot-plate test sensitivie to mild analgesics.Behav Brain Res. 1986; 21: 101-108
- Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase.Pain. 2013; 154: 2432-2440
- Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy.Brain Behav Immun. 2015; 44: 91-99
- The cold plate as a test of nociceptive behaviours: description and application to the study of chronic neuropathic and inflammatory pain models.Pain. 1998; 75: 367-382
- Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke.J Neurosci Res. 2004; 76: 519-527
- Up-regulation of tumor necrosis factor-alpha in spinal cord contributes to vincristine-induced mechanical allodynia in mice.Neurosci Lett. 2008; 445: 140-143
- Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme.Science. 1995; 267: 2000-2003
- Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats.Brain Behav Immun. 2007; 21: 686-698
- Immune-mediated processes implicated in chemotherapy-induced peripheral neuropathy.Eur J Cancer. 2017; 73: 22-29
- Determination of carbonyl content in oxidatively modified Proteins.Methods Enzymol. 1990; 186: 464-478
- Resveratrol inhibits paclitaxel-induced neuropathic pain by the activation of Pi3K/akt and siRT1/Pgc1α pathway.J Pain Res. 2019; 12: 879-890
- The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.J Neurosci. 2015; 35: 13487-13500
- Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy.J Pain. 2014; 15: 712-725
- N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: Preliminary data.Support Care Cancer. 2006; 14: 484-487
- Protein measurement with the Folin phenol reagent.J Biol Chem. 1951; 193: 265-275
- The role of oxidative stress in peripheral neuropathy.J Mol Neurosci. 2020; 70: 1009-1017
- TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism.Pflugers Arch Eur J Physiol. 2012; 463: 561-569
- Temporal dissociation of striatum and prefrontal cortex uncouples anhedonia and defense behaviors relevant to depression in 6-OHDA-Lesioned Rats.Mol Neurobiol. 2016; 53: 3891-3899
- Factors affecting grip strength testing.Neurotoxicol Teratol. 2003; 25: 543-553
- Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: A potential mechanism for neurotoxicity.Neurobiol Dis. 2005; 18: 305-313
- Cisplatin-induced apoptosis of DRG neurons involves bax redistribution and cytochrome c release but not fas receptor signaling.Neurobiol Dis. 2002; 9: 220-233
- Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice.Br J Pharmacol. 2016; 173: 3502-3521
- Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.Exp Neurol. 2008; 214: 276-284
- Reactive oxygen species in inflammation and tissue injury.Antioxidants Redox Signal. 2014; 20: 1126-1167
- Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy.Diabetes Care. 1995; 18: 1160-1167
- Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation.Pain. 2011; 152: 1621-1631
- Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: Old perspective with a new angle.Biochem Biophys Res Commun. 2011; 408: 1-5
- Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats.J Surg Res. 2006; 131: 124-130
- Vitamin e neuroprotection for cisplatin neuropathy: A randomized, placebo-controlled trial.Neurology. 2010; 74: 762-766
- Clinical course of oxaliplatin-induced neuropathy: Results from the randomized phase III trial N08CB (Alliance).J Clin Oncol. 2015; 33: 3416-3422
- Oxaliplatin-DNA adduct formation in white blood cells of cancer patients.Br J Cancer. 2008; 98: 1959-1965
- The involvement of the TRPA1 receptor in a mouse model of sympathetically maintained neuropathic pain.Eur J Pharmacol. 2015; 747: 105-113
- Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat.Neuroscience. 2014; 274: 308-317
- Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies.J Investig Med. 2003; 51: 261-283
- Effect of vitamin E on oxaliplatin-induced peripheral neuropathy prevention: A randomized controlled trial.Int J Prev Med. 2015; 6: 104
- Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.Pain. 2014; 155: 2461-2470
- Gut microbiota is critical for the induction of chemotherapy-induced pain.Nat Neurosci. 2017; 20: 1213-1216
- Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 2.Altern Ther Health Med. 2007; 13: 40-47
- Neuroinflammation, Mast cells, and Glia: Dangerous liaisons.Neuroscientist. 2017; 23: 478-498
- Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial.J Am Med Assoc. 2013; 309: 1359-1367
- Chemotherapy-induced peripheral neuropathy: A current review.Ann Neurol. 2017; 81: 772-781
- Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding.Neurotoxicology. 2006; 27: 992-1002
- A novel and selective poly (ADP-Ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.PLoS One. 2013; 8: e54161
- Oxaliplatin-induced oxidative stress provokes toxicity in isolated rat liver mitochondria.Arch Med Res. 2015; 46: 597-603
- Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.Immunity. 1999; 11: 443-451
- The protective effect of alpha lipoic acid against traumatic brain injury in rats.Free Radic Res. 2009; 43: 658-667
- Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade.Cancer Res. 2013; 73: 3120-3131
- Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms.Pain. 2018; 159: 1025-1034
- Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy.Cytokine. 2012; 59: 3-9
- Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway.Mol Pain. 2018; 14: 1-10
- Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function.Free Radic Biol Med. 2018; 120: 13-24
- Spinal astrocyte gap junctions contribute to oxaliplatin-induced mechanical hypersensitivity.J Pain. 2013; 14: 205-214
- Oxaliplatin neurotoxicity involves peroxisome alterations. PPARc agonism as preventive pharmacological approach.PLoS One. 2014; 9102758
- Alkylating agent–induced NRF2 blocks endoplasmic reticulum stress–mediated apoptosis via control of glutathione pools and protein thiol homeostasis.Mol Cancer Ther. 2016; 15: 3000-3014
- Curcumin alleviates oxaliplatin-induced peripheral neuropathic pain through inhibiting oxidative stress-mediated activation of nf-κb and mitigating inflammation.Biol Pharm Bull. 2020; 43: 348-355
Article info
Publication history
Published online: March 24, 2021
Accepted:
March 8,
2021
Received in revised form:
February 25,
2021
Received:
November 10,
2020
Footnotes
Supported by grants from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) – Finance code 001, and Programa de Pesquisa para o SUS (PPSUS 17/2551-0001-408-1) grants to JCFM and AZF. CNPq (National Council for Scientific and Technological Development) and CAPES provided PhD fellowships to JPA, RMG, MD, RNN, SM, CSG, DDL, MAF, SJMJ and SCL; Scientific Initiation (CNPq-PIBIC) fellowship to VWS; and Research Productivity Scholar Fellowship (CNPq-PQ) to AZF [310665/2017-5].
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
