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Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence

Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Department of Pharmacy, Okayama University Hospital, Okayama 700-8558, Japan
Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(3), 1393;
Submission received: 30 December 2020 / Revised: 20 January 2021 / Accepted: 27 January 2021 / Published: 30 January 2021
(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)


Oxaliplatin is an essential drug in the chemotherapy of colorectal, gastric, and pancreatic cancers, but it frequently causes peripheral neuropathy as a dose-limiting factor. So far, animal models of oxaliplatin-induced peripheral neuropathy have been established. The mechanisms of development of neuropathy induced by oxaliplatin have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory effects on neuropathy. In this review, we summarize the basic and clinical evidence for the therapeutic effects of oxaliplatin. In basic research, there are many reports of neuropathy inhibitors that target oxidative stress, inflammatory response, sodium channel, transient receptor potential (TRP) channel, glutamate nervous system, and monoamine nervous system. Alternatively, very few drugs have clearly demonstrated the efficacy for oxaliplatin-induced peripheral neuropathy in clinical trials. It is important to activate translational research in order to translate basic research into clinical research.

1. Introduction

Oxaliplatin is a platinum-based chemotherapeutic agent that is widely used as a standard treatment for colorectal, gastric, and pancreatic cancers, usually combined with other therapeutic agents such as fluorouracil, irinotecan, capecitabine, or tegafur, gimeracil and oteracil, however it often causes severe peripheral neuropathy. Within a few hours to a few days after oxaliplatin administration, acute neuropathy, such as cold sensory disturbance in the limbs and perioral region, appears. In most cases, cold-related acute neuropathy is transient and reversible [1,2]. In addition, sensory deficits as chronic neuropathy, a dose-limiting factor, occur after repeated oxaliplatin administration [2,3]. These neuropathies remain a significant clinical problem with oxaliplatin chemotherapy because they can affect quality of life and lead to drug reductions or discontinuation. Previous reports have suggested that voltage-gated ion channels and transient receptor potential channels are involved in oxaliplatin-induced acute neuropathy [4,5,6]. Chronic neuropathy is thought to be caused by morphological changes in neurons, such as axonal degeneration and damage to neuronal cell bodies [7,8,9]. However, no drugs have been recommended to prevent chemotherapy-induced peripheral neuropathy [10]. Since around 2000, animal models of chemotherapy-induced peripheral neuropathy, including oxaliplatin-induced neuropathy, have been established and reported [11,12,13]. In this study, we reviewed the preclinical and clinical evidence for oxaliplatin-induced peripheral neuropathy.

2. Therapeutic Agents in Preclinical Evidence

All articles found in PubMed with the search term “oxaliplatin neuropathy or oxaliplatin neurotoxicity” were surveyed. The last search date was 1 August 2020. Reports that did not include information on therapeutic agents for oxaliplatin-induced peripheral neuropathy and clinical studies were excluded from the analysis. From the surveyed papers, we extracted information on the name and dosage of the drugs that showed statistically significant improvement, their mechanism of action, and the animal species in which they were used.
There were 1657 articles in PubMed for the search term “oxaliplatin neuropathy or oxaliplatin neurotoxicity”. Of these, 127 articles reported on drugs that inhibit oxaliplatin-induced peripheral neuropathy in animal studies. The following is a summary of the drugs had therapeutic effects on oxaliplatin-induced peripheral neuropathy in these basic studies (Table 1).

2.1. Antioxidants

Many previous preclinical reports support that oxidative stress plays a role in oxaliplatin-related peripheral neuropathy [27,140,141]. Vitamin C, vitamin E, acetyl L-carnitine, alpha-lipoic acid, and glutathione, which are widely known for their antioxidant effects, have been reported to alleviate the peripheral neuropathy of oxaliplatin in rodents [14,15,16,23,34]. Among the approved drugs, carvedilol, donepezil, dimethyl fumarate, and rosiglitazone have also been reported to reverse the neurotoxicity of oxaliplatin via their antioxidant effects [18,21,22,32]. Moreover, many agents, which have antioxidant effects, inhibit oxaliplatin-caused peripheral neuropathy in preclinical studies [17,19,20,24,25,26,28,29,30,31,33,35,36,37,38].

2.2. Anti-Inflammatory Agents

Inflammatory cytokines such as IL-1β, IL-6, and TNF-α were elevated in the dorsal root ganglion (DRG) and spinal cord of oxaliplatin-treated animals, and some agents reduced the peripheral neuropathy symptoms via their anti-inflammatory effects [39,41,42]. Activations of astrocytes and microglia were also observed in the spinal dorsal horn after oxaliplatin administrations, and minocycline, rapamycin, and fluorocitrate inhibited these spinal changes and prevented neurological damage [40,43,44].

2.3. Sodium Channel Inhibitors

Oxaliplatin-induced acute neuropathy is termed a ‘channelopathy’, as oxaliplatin and oxalate modulated voltage-gated Na+ and K+ channels in several types of neurons [3,142,143]. For example, oxaliplatin increases the amplitude and duration of compound action potentials interacting with voltage-gated Na+ channels in rat sensory neurons [142]. Furthermore, oxaliplatin prolongs the duration of the A-fiber compound action potential related to K+ channels [3]. Thus, the effect of oxaliplatin on Na+ and K+ channels is thought to be involved in acute neuropathy [4]. Many Na+ channel inhibitors, such as lidocaine, mexiletine, and lamotrigine have been reported to ameliorate the neuropathic symptoms of oxaliplatin, especially the acute neuropathy [11,45,46,47,48,49].

2.4. Potassium Channel Modulators

Glucosinolate glucoraphanin, isothiocyanate sulforaphane, allyl-isothiocyanate, phenyl-isothiocyanate and carboxyphenyl-isothiocyanate inhibited oxaliplatin-induced neuropathy by modulating Kv7 channels [50,51]. It has been reported that tandem pore domains in weak rectifying K+ channel (TWIK)-related K+ channel 1 (TREK-1) channels are partially involved in the inhibitory effect of riluzole on oxaliplatin-induced peripheral neuropathy [52].

2.5. Calcium Channel α2δ Ligands

In animal studies only, gabapentin and pregabalin, which act on α2δ, reduced the symptoms of oxaliplatin neuropathy [11,46,48,53,54].

2.6. Transient Receptor Potential (TRP) Modulators

It has been reported that temperature-sensitive cation channels, such as transient receptor potential ankyrin 1 (TRPA1), transient receptor potential melastatin 8 (TRPM8), and transient receptor potential vanilloid 1 (TRPV1), are involved in oxaliplatin-induced peripheral neuropathy [144,145,146]. It has also been reported that the amelioration of oxaliplatin neuropathy by topiramate, acetazolamide, shakuyakukanzoto, goshajinkigan, eel calcitonin, nifedipine, diltiazem, and mexiletine, is partly due to the downregulation or modulation of TRP channels [55,56,57,58,59,60].

2.7. Modulators of Glutamate Nervous System

Some studies indicated that the excessive spinal transmission activities, such as spinal glutamate uptake and spinal N-methyl-D-aspartate receptor subtype NR2B subunit overexpression, are involved in painful neuropathic symptoms related to oxaliplatin [64,69,71]. Riluzole, mirtazapine, ifenprodil, amitriptyline, trifluoperazine, dimiracetam, E2072, and Tat-HA-NR2B9c targeted these glutamatergic nervous systems and showed that oxaliplatin reduced neurotoxicity [64,65,66,67,68,69,70,71].

2.8. Modulators of Monoamine Nervous System

Monoamines, including noradrenalin and serotonin, play an important role in the descending pain inhibitory system [147]. In also the oxaliplatin peripheral neuropathy animal models, many drugs, such as, duloxetine, fluoxetine, vortioxetine, tandospirone, venlafaxine, xaliproden, clomipramine, and clonidine, also showed analgesic effects by modulating the monoamine nervous system [11,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94].

2.9. Others

In addition to the above, many other drugs have been identified to reduce oxaliplatin-induced peripheral neuropathy via several therapeutic targets, such as acetylcholine receptors [95,96,97,98], thrombin [106,107], protein kinase C/mitogen-activated protein kinase and extracellular signal-regulated kinase signal [103,104], organic cation transporter [99,100], opioid receptors [46,78,79,80], phosphodiesterase [72,73], hyperpolarization-activated, cyclic nucleotide-gated cation channel [61,62], imidazoline receptors [63], endothelin receptor [74], cannabinoid receptors [75], sigma-1 receptors [76,77], orexin receptors [101], histamine receptors [102], ceramide-sphingosine 1-phosphate [105], chelate of oxalate [11,13], vascular endothelial growth factor [108], and others [48,54,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139], at the basic research.

3. Therapeutic Agents in Clinical Evidence

We analyzed the articles found in PubMed with the search term “oxaliplatin neuropathy or oxaliplatin neurotoxicity” limited to “clinical trials”. The last search date was 25 June 2020. Reports other than randomized trials and meta-analyses were excluded. Moreover, Information such as the investigational drug and its dosage, chemotherapy received by the patient, study design, number of patients, and results was collected.
There were 533 articles in PubMed for the search term “oxaliplatin neuropathy or oxaliplatin neurotoxicity” limited to “clinical trials”. Of these, 127 articles reported on drugs that inhibit oxaliplatin-induced peripheral neuropathy in animal studies. After excluding reports other than randomized trials and meta-analyses, the authors found 16 reports that they considered to be clinically important. A summarized list of the representative randomized controlled trials and meta-analyses on prophylactic and therapeutic agents for oxaliplatin-induced peripheral neuropathy is shown below in Table 2.
Duloxetine was tested in a randomized, double-blind, placebo-controlled, cross-over trial, for its ability to treat neuropathy in patients with taxane or platinum [148]. In this study, relative risks (RRs) (95% confidence interval (CI)) of experiencing 30% and 50% pain reduction were 1.96 (1.15–3.35) and 2.43 (1.11–5.30), respectively. A sub-analysis of this study indicates that duloxetine is more effective than taxanes in treating platinum-induced neuropathy.
Intravenous injection of calcium and magnesium is thought to chelate oxalate, and the preventive effects for oxaliplatin-induced peripheral neurotoxicity have been investigated since before [149,150,151,152]. Some studies reported significant inhibitory effects on oxaliplatin-related neuropathy [149,150], some studies did not confirm significant effects [151,152]. The results of a meta-analysis including five studies showed that calcium and magnesium had no significant effect on neuropathy (relative risks (RRs) (95% CI) of incidence of ≥Grade 2 neuropathy and ≥Grade 1 chronic neuropathy were 0.81 (0.60–1.11) and 0.95 (0.69–1.32), respectively.) [153].
Goshajinkigan, a Japanese herbal medicine, has been studied in several clinical trials [154,155,156]. In a randomized controlled trial, goshajinkigan significantly reduced the incidence of Grade 2 or higher neuropathy [154]. In goshajinkigan oxaliplatin neurotoxicity evaluation (GONE) study, the incidence of Grade 2 or higher neuropathy until the 8th cycle was 39 and 51% in goshajinkigan and placebo groups, respectively, which was not statistically significant [155]. This study concluded that goshajinkigan appears to have an acceptable safety margin and a promising effect in delaying the onset of Grade 2 or greater peripheral neuropathy [155]. However, in the interim analysis of goshajinkigan effect for oxaliplatin neurotoxicity inhibition using mFOLFOX6 regimen (GENIUS) study, a multicenter randomized, double-blind, placebo-controlled trial, goshajinkigan significantly increased the incidence of neuropathy [156].
Alpha-lipoic acid and vitamin E, both of which have antioxidant properties, were also examined in clinical trials for their effects on neuropathy in patients using oxaliplatin [157,158,159]. However, neither has been reported to significantly improve neuropathy. Beside, glutathione and calmangafordipir, which also have antioxidant effects, were found to significantly improve neuropathy related oxaliplatin treatment in randomized trials [160,161]. However, the dose of glutathione used in this clinical trial was high (1.5 g/m2), and calmangafodipir is undergoing Phase III trials and not approved as a drug at this time. Other drugs such as pregabalin, a general-purpose drug for neuropathic pain, and minocycline, a glial attenuator, have also been tested in clinical trials, but no significant inhibitory effects have been reported [162,163].
As described above, few drugs have shown clear therapeutic effects on oxaliplatin-induced peripheral neuropathy in clinical trials. Thus, according to the clinical practice guideline updated by the American Society of Clinical Oncology in 2020, no agents have yet to be recommended for preventing chemotherapy-induced peripheral neuropathy and only duloxetine may be used as a treatment for neuropathy [10].

4. Discussion

Recently, the mechanism of oxaliplatin-induced peripheral neuropathy has been elucidated in basic studies, and many drugs and agents targeting this mechanism have been explored and identified for therapy for oxaliplatin-induced peripheral neuropathy. In particular, many inhibitors of neuropathy targeting oxidative stress, inflammatory response, sodium channel, TRP channel, glutamate nervous system, and monoamine nervous system have been identified as candidates for inhibiting oxaliplatin-induced neuropathy in animal research.
Alternatively, very few drugs have shown the efficacy of oxaliplatin for peripheral neuropathy in clinical trials. The American Society of Clinical Oncology’s clinical practice guideline states that only duloxetine can be used for the treatment of chemotherapy-induced peripheral neuropathy [10]. Since duloxetine has been shown to improve pain in clinical trials [148], its use in patients with pain may be beneficial. However, consideration should be given to side effects such as drowsiness, headache, and dizziness. Goshajinkigan and glutathione are drugs that have few side effects, thus they can be considered easy to treat in patients. Goshajinkigan has been reported both to have therapeutic effects on oxaliplatin-induced peripheral neuropathy and not to have the effects [154,155,156]. In an animal study, it has been reported that goshajinkigan does not inhibit the progression of chronic neuropathy, but rather relieves neuropathic symptoms [124]. Therefore, it may be used to relieve symptoms in patients with oxaliplatin-induce neuropathy.
While many drugs have been reported in basic research as having the potential to inhibit the neuropathy by oxaliplatin, few drugs have developed sufficient evidence in clinical studies. The “valley of death” between basic researches and clinical applications is considered caused by many issues, including the difference between clinical symptoms and animal assessment methods, the cost and time of conducting clinical research, safety considerations in clinical application, and the lack of collaboration between basic and clinical researchers. It is important to promote translational research, that is, to bridge basic research to clinical research.


This research received no external funding


This work was partly supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (JP20K07198).

Conflicts of Interest

The authors declare that they have no conflicts of interest to this work.


95% CI95% confidence interval
Aktprotein kinase B
ATF-3activating transcription factor 3
ATPadenosine triphosphate
CaMKIIcalmodulin-dependent protein kinase II
DRGdorsal root ganglia
ERKextracellular signal-regulated kinase
ETAendothelin A
ETBendothelin B
FACT/GOG-NTxFunctional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity
GENIUSgoshajinkigan effect for oxaliplatin neurotoxicity inhibition using mFOLFOX6 regimen
GFAPglial fibrillary acidic protein
GLT-1glutamate transporter 1
GONEgoshajinkigan oxaliplatin neurotoxicity evaluation
GPxglutathione peroxidase
HCN1hyperpolarization-activated, cyclic nucleotide-gated cation channel 1
HCN2hyperpolarization-activated, cyclic nucleotide-gated cation channel 2
HIF-1hypoxia inducible factor 1
HMGB1high mobility group box 1
Iba-1ionized calcium binding adaptor protein 1
IENFintra-epidermal nerve fibers
IL-1βinterleukin-1 beta
JSPSJapan Society for the Promotion of Science
MAPK14mitogen-activated protein kinase-14
MBPmyelin basic protein
MEK1/2mitogen-activated protein kinase kinases 1 and 2
MMP9/2matrix metalloproteinase-9 and -2
mTORmammalian target of rapamycin
nAChRnicotinic acetylcholine receptor
NF-κBnuclear factor kappa-B
OCT2organic cation transporter 2
OCTN1organic cation transporter novel type 1
PI3Kphosphatidylinositol-3 kinase
PKCprotein kinase C
RRrelative risk
SODsuperoxide dismutase
TAFIthrombin-activatable fibrinolysis inhibitor
TNF-αtumor necrosis factor-α
TREK-1tandem pore domains in weak rectifying K+ channel (TWIK)-related K+ channel 1
TRPA1transient receptor potential ankyrin 1
TRPM8transient receptor potential melastatin 8
TRPV1transient receptor potential vanilloid 1
VEGFvascular endothelial growth factor


  1. Wilson, R.H.; Lehky, T.; Thomas, R.R.; Quinn, M.G.; Floeter, M.K.; Grem, J.L. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J. Clin. Oncol. 2002, 20, 1767–1774. [Google Scholar] [CrossRef]
  2. Argyriou, A.A.; Bruna, J.; Marmiroli, P.; Cavaletti, G. Chemotherapy-induced peripheral neurotoxicity (CIPN): An update. Crit. Rev. Oncol. Hematol. 2012, 82, 51–77. [Google Scholar] [CrossRef]
  3. Pasetto, L.M.; D’Andrea, M.R.; Rossi, E.; Monfardini, S. Oxaliplatin-related neurotoxicity: How and why? Crit. Rev Oncol. Hematol. 2006, 59, 159–168. [Google Scholar] [CrossRef]
  4. Sittl, R.; Lampert, A.; Huth, T.; Schuy, E.T.; Link, A.S.; Fleckenstein, J.; Alzheimer, C.; Grafe, P.; Carr, R.W. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc. Natl. Acad. Sci. USA 2012, 24, 6704–6709. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Kagiava, A.; Tsingotjidou, A.; Emmanouilides, C.; Theophilidis, G. The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat. Neurotoxicology 2008, 29, 1100–1106. [Google Scholar] [CrossRef] [PubMed]
  6. Nakagawa, T.; Kaneko, S. Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy. Biol. Pharm. Bull. 2017, 40, 947–953. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Lehky, T.J.; Leonard, G.D.; Wilson, R.H.; Grem, J.L.; Floeter, M.K. Oxaliplatin-induced neurotoxicity: Acute hyperexcitability and chronic neuropathy. Muscle Nerve. 2004, 29, 387–392. [Google Scholar] [CrossRef] [PubMed]
  8. Jamieson, S.M.; Liu, J.; Connor, B.; McKeage, M.J. Oxaliplatin causes selective atrophy of a subpopulation of dorsal root ganglion neurons without inducing cell loss. Cancer Chemother. Pharmacol. 2005, 56, 391–399. [Google Scholar] [CrossRef]
  9. Tsutsumi, K.; Yamashita, Y.; Ushio, S.; Kawashiri, T.; Kaname, T.; Fujita, S.; Oishi, R.; Egashira, N. Oxaliplatin induces hypomyelination and reduced neuregulin 1 expression in the rat sciatic nerve. Neurosci. Res. 2014, 80, 86–90. [Google Scholar] [CrossRef] [PubMed]
  10. Loprinzi, C.L.; Lacchetti, C.; Bleeker, J.; Cavaletti, G.; Chauhan, C.; Hertz, D.L.; Kelley, M.R.; Lavino, A.; Lustberg, M.B.; Paice, J.A.; et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J. Clin. Oncol. 2020, 38, 3325–3348. [Google Scholar] [CrossRef]
  11. Ling, B.; Authier, N.; Balayssac, D.; Eschalier, A.; Coudore, F. Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat. Pain 2007, 128, 225–234. [Google Scholar] [CrossRef] [PubMed]
  12. Ta, L.E.; Low, P.A.; Windebank, A.J. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli. Mol. Pain 2009, 26, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Sakurai, M.; Egashira, N.; Kawashiri, T.; Yano, T.; Ikesue, H.; Oishi, R. Oxaliplatin-induced neuropathy in the rat: Involvement of oxalate in cold hyperalgesia but not mechanical allodynia. Pain 2009, 15, 165–174. [Google Scholar] [CrossRef] [PubMed]
  14. Ghirardi, O.; Lo Giudice, P.; Pisano, C.; Vertechy, M.; Bellucci, A.; Vesci, L.; Cundari, S.; Miloso, M.; Rigamonti, L.M.; Nicolini, G.; et al. Acetyl-L-Carnitine prevents and reverts experimental chronic neurotoxicity induced by oxaliplatin, without altering its antitumor properties. Anticancer. Res. 2005, 25, 2681–2687. [Google Scholar] [PubMed]
  15. Joseph, E.K.; Chen, X.; Bogen, O.; Levine, J.D. Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J. Pain. 2008, 9, 463–472. [Google Scholar] [CrossRef]
  16. Zheng, H.; Xiao, W.H.; Bennett, G.J. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp. Neurol. 2011, 232, 154–161. [Google Scholar] [CrossRef] [Green Version]
  17. Canta, A.; Chiorazzi, A.; Pozzi, E.; Fumagalli, G.; Monza, L.; Meregalli, C.; Cavaletti, G. Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fibers loss in a mouse model of oxaliplatin induced peripheral neurotoxicity. Antioxidants 2020, 9, 594. [Google Scholar] [CrossRef]
  18. Areti, A.; Komirishetty, P.; Kumar, A. Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy. Toxicol. Appl. Pharmacol. 2017, 322, 97–103. [Google Scholar] [CrossRef]
  19. Abdelhamid, A.M.; Mahmoud, S.S.; Abdelrahman, A.E.; Said, N.M.; Toam, M.; Samy, W.; Amer, M.A. Protective effect of cerium oxide nanoparticles on cisplatin and oxaliplatin primary toxicities in male albino rats. Naunyn Schmiedebergs Arch. Pharmacol. 2020, 393, 2411–2425. [Google Scholar] [CrossRef]
  20. Kawashiri, T.; Kobayashi, D.; Egashira, N.; Tsuchiya, T.; Shimazoe, T. Oral administration of Cystine and Theanine ameliorates oxaliplatin-induced chronic peripheral neuropathy in rodents. Sci. Rep. 2020, 10, 12665. [Google Scholar] [CrossRef]
  21. Miyagi, A.; Kawashiri, T.; Shimizu, S.; Shigematsu, N.; Kobayashi, D.; Shimazoe, T. Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents. Biol. Pharm Bull. 2019, 42, 638–644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kawashiri, T.; Shimizu, S.; Shigematsu, N.; Kobayashi, D.; Shimazoe, T. Donepezil ameliorates oxaliplatin-induced peripheral neuropathy via a neuroprotective effect. J. Pharmacol. Sci. 2019, 140, 291–294. [Google Scholar] [CrossRef] [PubMed]
  23. Lee, M.; Cho, S.; Roh, K.; Chae, J.; Park, J.H.; Park, J.; Lee, M.A.; Kim, J.; Auh, C.K.; Yeom, C.H.; et al. Glutathione alleviated peripheral neuropathy in oxaliplatin-treated mice by removing aluminum from dorsal root ganglia. Am. J. Transl. Res. 2017, 15, 926–939. [Google Scholar]
  24. Celik, H.; Kucukler, S.; Ozdemir, S.; Comakli, S.; Gur, C.; Kandemir, F.M.; Yardim, A. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology 2020, 80, 29–40. [Google Scholar] [CrossRef]
  25. Waseem, M.; Tabassum, H.; Parvez, S. Neuroprotective effects of melatonin as evidenced by abrogation of oxaliplatin induced behavioral alterations, mitochondrial dysfunction and neurotoxicity in rat brain. Mitochondrion 2016, 30, 168–176. [Google Scholar] [CrossRef]
  26. Janes, K.; Doyle, T.; Bryant, L.; Esposito, E.; Cuzzocrea, S.; Ryerse, J.; Bennett, G.J.; Salvemini, D. 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. [Google Scholar] [CrossRef] [Green Version]
  27. Di Cesare Mannelli, L.; Zanardelli, M.; Landini, I.; Pacini, A.; Ghelardini, C.; Mini, E.; Bencini, A.; Valtancoli, B.; Failli, P. Effect of the SOD mimetic MnL4 on in vitro and in vivo oxaliplatin toxicity: Possible aid in chemotherapy induced neuropathy. Free Radic. Biol. Med. 2016, 93, 67–76. [Google Scholar] [CrossRef] [Green Version]
  28. Cerles, O.; Benoit, E.; Chéreau, C.; Chouzenoux, S.; Morin, F.; Guillaumot, M.A.; Coriat, R.; Kavian, N.; Loussier, T.; Santulli, P.; et al. Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response. Mol. Cancer Ther. 2017, 16, 300–311. [Google Scholar] [CrossRef] [Green Version]
  29. Kim, S.T.; Chung, Y.H.; Lee, H.S.; Chung, S.J.; Lee, J.H.; Sohn, U.D.; Shin, Y.K.; Park, E.S.; Kim, H.C.; Bang, J.S.; et al. Protective effects of phosphatidylcholine on oxaliplatin-induced neuropathy in rats. Life Sci. 2015, 130, 81–87. [Google Scholar] [CrossRef]
  30. Schwingel, T.E.; Klein, C.P.; Nicoletti, N.F.; Dora, C.L.; Hadrich, G.; Bica, C.G.; Lopes, T.G.; da Silva, V.D.; Morrone, F.B. Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice. Naunyn Schmiedebergs Arch. Pharmacol. 2014, 387, 837–848. [Google Scholar] [CrossRef]
  31. Azevedo, M.I.; Pereira, A.F.; Nogueira, R.B.; Rolim, F.E.; Brito, G.A.; Wong, D.V.; Lima-Júnior, R.C.; de Albuquerque Ribeiro, R.; Vale, M.L. The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol. Pain 2013, 9, 53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Zanardelli, M.; Micheli, L.; Cinci, L.; Failli, P.; Ghelardini, C.; Di Cesare Mannelli, L. Oxaliplatin neurotoxicity involves peroxisome alterations. PPARγ agonism as preventive pharmacological approach. PLoS ONE 2014, 18, e102758. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Areti, A.; Komirishetty, P.; Kalvala, A.K.; Nellaiappan, K.; Kumar, A. Rosmarinic Acid Mitigates Mitochondrial Dysfunction and Spinal Glial Activation in Oxaliplatin-induced Peripheral Neuropathy. Mol. Neurobiol. 2018, 55, 7463–7475. [Google Scholar] [CrossRef] [PubMed]
  34. Di Cesare Mannelli, L.; Zanardelli, M.; Failli, P.; Ghelardini, C. Oxaliplatin-induced neuropathy: Oxidative stress as pathological mechanism. Prot. eff. silibinin. J. Pain. 2012, 13, 276–284. [Google Scholar] [CrossRef] [Green Version]
  35. Toyama, S.; Shimoyama, N.; Szeto, H.H.; Schiller, P.W.; Shimoyama, M. Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice. ACS Chem. Neurosci. 2018, 9, 1566–1571. [Google Scholar] [CrossRef]
  36. Toyama, S.; Shimoyama, N.; Ishida, Y.; Koyasu, T.; Szeto, H.H.; Shimoyama, M. Characterization of acute and chronic neuropathies induced by oxaliplatin in mice and differential effects of a novel mitochondria-targeted antioxidant on the neuropathies. Anesthesiology 2014, 120, 459–473. [Google Scholar] [CrossRef]
  37. Yang, Y.; Luo, L.; Cai, X.; Fang, Y.; Wang, J.; Chen, G.; Yang, J.; Zhou, Q.; Sun, X.; Cheng, X.; et al. Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. Free Radic. Biol. Med. 2018, 120, 13–24. [Google Scholar] [CrossRef]
  38. Micheli, L.; Mattoli, L.; Maidecchi, A.; Pacini, A.; Ghelardini, C.; Di Cesare Mannelli, L. Effect of Vitis vinifera hydroalcoholic extract against oxaliplatin neurotoxicity: In vitro and in vivo evidence. Sci. Rep. 2018, 8, 14364. [Google Scholar] [CrossRef] [Green Version]
  39. Li, D.; Kim, W.; Shin, D.; Jung, Y.; Bae, H.; Kim, S.K. Preventive Effects of Bee Venom Derived Phospholipase A2 on Oxaliplatin-Induced Neuropathic Pain in Mice. Toxins 2016, 8, 27. [Google Scholar] [CrossRef] [Green Version]
  40. Di Cesare Mannelli, L.; Pacini, A.; Micheli, L.; Tani, A.; Zanardelli, M.; Ghelardini, C. Glial role in oxaliplatin-induced neuropathic pain. Exp. Neurol. 2014, 261, 22–33. [Google Scholar] [CrossRef]
  41. Cheng, X.; Huo, J.; Wang, D.; Cai, X.; Sun, X.; Lu, W.; Yang, Y.; Hu, C.; Wang, X.; Cao, P. Herbal Medicine AC591 Prevents Oxaliplatin-Induced Peripheral Neuropathy in Animal Model and Cancer Patients. Front. Pharmacol. 2017, 8, 344. [Google Scholar] [CrossRef] [PubMed]
  42. Wan, C.F.; Zheng, L.L.; Liu, Y.; Yu, X. Houttuynia cordata Thunb reverses oxaliplatin-induced neuropathic pain in rat by regulating Th17/Treg balance. Am. J. Transl. Res. 2016, 8, 1609–1614. [Google Scholar] [PubMed]
  43. Robinson, C.R.; Zhang, H.; Dougherty, P.M. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience 2014, 274, 308–317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Duan, Z.; Su, Z.; Wang, H.; Pang, X. Involvement of pro-inflammation signal pathway in inhibitory effects of rapamycin on oxaliplatin-induced neuropathic pain. Mol. Pain 2018, 14, 1744806918769426. [Google Scholar] [CrossRef]
  45. Egashira, N.; Hirakawa, S.; Kawashiri, T.; Yano, T.; Ikesue, H.; Oishi, R. Mexiletine reverses oxaliplatin-induced neuropathic pain in rats. J. Pharmacol. Sci. 2010, 112, 473–476. [Google Scholar] [CrossRef] [Green Version]
  46. Zhao, M.; Nakamura, S.; Miyake, T.; So, K.; Shirakawa, H.; Tokuyama, S.; Narita, M.; Nakagawa, T.; Kaneko, S. Pharmacological characterization of standard analgesics on oxaliplatin-induced acute cold hypersensitivity in mice. J. Pharmacol. Sci. 2014, 124, 514–517. [Google Scholar] [CrossRef] [Green Version]
  47. Rapacz, A.; Obniska, J.; Koczurkiewicz, P.; Wójcik-Pszczoła, K.; Siwek, A.; Gryboś, A.; Rybka, S.; Karcz, A.; Pękala, E.; Filipek, B. Antiallodynic and antihyperalgesic activity of new 3,3-diphenyl-propionamides with anticonvulsant activity in models of pain in mice. Eur. J. Pharmacol. 2018, 821, 39–48. [Google Scholar] [CrossRef]
  48. Deuis, J.R.; Lim, Y.L.; Rodrigues de Sousa, S.; Lewis, R.J.; Alewood, P.F.; Cabot, P.J.; Vetter, I. Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. Neuro Oncol. 2014, 16, 1324–1332. [Google Scholar] [CrossRef] [Green Version]
  49. Furgała-Wojas, A.; Kowalska, M.; Nowaczyk, A.; Fijałkowski, Ł.; Sałat, K. Comparison of Bromhexine and its Active Metabolite—Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain—Pharmacodynamic and Molecular Docking Studies. Curr. Drug Metab. 2020, 21, 548–561. [Google Scholar] [CrossRef]
  50. Lucarini, E.; Micheli, L.; Trallori, E.; Citi, V.; Martelli, A.; Testai, L.; De Nicola, G.R.; Iori, R.; Calderone, V.; Ghelardini, C.; et al. Effect of glucoraphanin and sulforaphane against chemotherapy-induced neuropathic pain: Kv7 potassium channels modulation by H2 S release in vivo. Phytother. Res. 2018, 32, 2226–2234. [Google Scholar] [CrossRef] [Green Version]
  51. Di Cesare Mannelli, L.; Lucarini, E.; Micheli, L.; Mosca, I.; Ambrosino, P.; Soldovieri, M.V.; Martelli, A.; Testai, L.; Taglialatela, M.; Calderone, V.; et al. Effects of natural and synthetic isothiocyanate-based H2S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels. Neuropharmacology 2017, 121, 49–59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Poupon, L.; Lamoine, S.; Pereira, V.; Barriere, D.A.; Lolignier, S.; Giraudet, F.; Aissouni, Y.; Meleine, M.; Prival, L.; Richard, D.; et al. Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology 2018, 140, 43–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Ohsawa, M.; Otake, S.; Murakami, T.; Yamamoto, S.; Makino, T.; Ono, H. Gabapentin prevents oxaliplatin-induced mechanical hyperalgesia in mice. J. Pharmacol. Sci. 2014, 125, 292–299. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Aoki, M.; Kurauchi, Y.; Mori, A.; Nakahara, T.; Sakamoto, K.; Ishii, K. Comparison of the effects of single doses of elcatonin and pregabalin on oxaliplatin-induced cold and mechanical allodynia in rats. Biol. Pharm Bull. 2014, 37, 322–326. [Google Scholar] [CrossRef] [Green Version]
  55. Potenzieri, A.; Riva, B.; Rigolio, R.; Chiorazzi, A.; Pozzi, E.; Ballarini, E.; Cavaletti, G.; Genazzani, A.A. Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors. Pain 2020, 161, 405–415. [Google Scholar] [CrossRef]
  56. Andoh, T.; Mizoguchi, S.; Kuraishi, Y. Shakuyakukanzoto attenuates oxaliplatin-induced cold dysesthesia by inhibiting the expression of transient receptor potential melastatin 8 in mice. J. Tradit. Complement. Med. 2016, 7, 30–33. [Google Scholar] [CrossRef] [Green Version]
  57. Mizuno, K.; Kono, T.; Suzuki, Y.; Miyagi, C.; Omiya, Y.; Miyano, K.; Kase, Y.; Uezono, Y. Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat. J. Pharmacol. Sci. 2014, 125, 91–98. [Google Scholar] [CrossRef] [Green Version]
  58. Kato, Y.; Tateai, Y.; Ohkubo, M.; Saito, Y.; Amagai, S.Y.; Kimura, Y.S.; Iimura, N.; Okada, M.; Matsumoto, A.; Mano, Y.; et al. Gosha-jinki-gan reduced oxaliplatin-induced hypersensitivity to cold sensation and its effect would be related to suppression of the expression of TRPM8 and TRPA1 in rats. Anticancer Drugs. 2014, 25, 39–43. [Google Scholar] [CrossRef]
  59. Aoki, M.; Mori, A.; Nakahara, T.; Sakamoto, K.; Ishii, K. Effect of synthetic eel calcitonin, elcatonin, on cold and mechanical allodynia induced by oxaliplatin and paclitaxel in rats. Eur. J. Pharmacol. 2012, 696, 62–69. [Google Scholar] [CrossRef]
  60. Kawashiri, T.; Egashira, N.; Kurobe, K.; Tsutsumi, K.; Yamashita, Y.; Ushio, S.; Yano, T.; Oishi, R. L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. Mol. Pain 2012, 8, 7. [Google Scholar] [CrossRef] [Green Version]
  61. Resta, F.; Micheli, L.; Laurino, A.; Spinelli, V.; Mello, T.; Sartiani, L.; Di Cesare Mannelli, L.; Cerbai, E.; Ghelardini, C.; Romanelli, M.N.; et al. Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy. Neuropharmacology 2018, 131, 403–413. [Google Scholar] [CrossRef] [PubMed]
  62. Dini, L.; Del Lungo, M.; Resta, F.; Melchiorre, M.; Spinelli, V.; Di Cesare Mannelli, L.; Ghelardini, C.; Laurino, A.; Sartiani, L.; Coppini, R.; et al. Selective Blockade of HCN1/HCN2 Channels as a Potential Pharmacological Strategy against Pain. Front. Pharmacol. 2018, 9, 1252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Micheli, L.; Di Cesare Mannelli, L.; Del Bello, F.; Giannella, M.; Piergentili, A.; Quaglia, W.; Carrino, D.; Pacini, A.; Ghelardini, C. The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity. Neurotherapeutics 2020, 17, 1005–1015. [Google Scholar] [CrossRef] [PubMed]
  64. Yamamoto, S.; Ushio, S.; Egashira, N.; Kawashiri, T.; Mitsuyasu, S.; Higuchi, H.; Ozawa, N.; Masuguchi, K.; Ono, Y.; Masuda, S. Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: A possibility for riluzole as a prophylactic drug. Sci. Rep. 2017, 7, 9661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Fariello, R.G.; Ghelardini, C.; Di Cesare Mannelli, L.; Bonanno, G.; Pittaluga, A.; Milanese, M.; Misiano, P.; Farina, C. Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain. Neuropharmacology 2014, 81, 85–94. [Google Scholar] [CrossRef]
  66. Wozniak, K.M.; Wu, Y.; Vornov, J.J.; Lapidus, R.; Rais, R.; Rojas, C.; Tsukamoto, T.; Slusher, B.S. The orally active glutamate carboxypeptidase II inhibitor E2072 exhibits sustained nerve exposure and attenuates peripheral neuropathy. J. Pharmacol. Exp. Ther. 2012, 343, 746–754. [Google Scholar] [CrossRef] [Green Version]
  67. Zhou, H.H.; Zhang, L.; Zhang, H.X.; Xu, B.R.; Zhang, J.P.; Zhou, Y.J.; Qian, X.P.; Ge, W.H. Tat-HA-NR2B9c attenuate oxaliplatin-induced neuropathic pain. Exp. Neurol. 2019, 311, 80–87. [Google Scholar] [CrossRef]
  68. Liu, X.; Zhang, G.; Dong, L.; Wang, X.; Sun, H.; Shen, J.; Li, W.; Xu, J. Repeated administration of mirtazapine attenuates oxaliplatin-induced mechanical allodynia and spinal NR2B up-regulation in rats. Neurochem. Res. 2013, 38, 1973–1979. [Google Scholar] [CrossRef]
  69. Mihara, Y.; Egashira, N.; Sada, H.; Kawashiri, T.; Ushio, S.; Yano, T.; Ikesue, H.; Oishi, R. Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Mol. Pain 2011, 7, 8. [Google Scholar] [CrossRef] [Green Version]
  70. Sada, H.; Egashira, N.; Ushio, S.; Kawashiri, T.; Shirahama, M.; Oishi, R. Repeated administration of amitriptyline reduces oxaliplatin-induced mechanical allodynia in rats. J. Pharmacol. Sci. 2012, 118, 547–551. [Google Scholar] [CrossRef] [Green Version]
  71. Shirahama, M.; Ushio, S.; Egashira, N.; Yamamoto, S.; Sada, H.; Masuguchi, K.; Kawashiri, T.; Oishi, R. Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in rats. Mol. Pain 2012, 8, 26. [Google Scholar] [CrossRef] [Green Version]
  72. Ogihara, T.; Nakagawa, T.; Hayashi, M.; Koyanagi, M.; Yonezawa, A.; Omura, T.; Nakagawa, S.; Kitada, N.; Imai, S.; Matsubara, K. Improvement of peripheral vascular impairment by a phosphodiesterase type 5 inhibitor tadalafil prevents oxaliplatin-induced peripheral neuropathy in mice. J. Pharmacol. Sci. 2019, 141, 131–138. [Google Scholar] [CrossRef] [PubMed]
  73. Johnston, I.N.; Tan, M.; Cao, J.; Matsos, A.; Forrest, D.R.L.; Si, E.; Fardell, J.E.; Hutchinson, M.R. Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats. Behav. Brain Res. 2017, 334, 109–118. [Google Scholar] [CrossRef] [PubMed]
  74. Pontes, R.B.; Lisboa, M.R.P.; Pereira, A.F.; Lino, J.A.; de Oliveira, F.F.B.; de Mesquita, A.K.V.; de Freitas Alves, B.W.; Lima-Júnior, R.C.P.; Vale, M.L. Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice. Neurotox. Res. 2019, 36, 688–699. [Google Scholar] [CrossRef] [PubMed]
  75. King, K.M.; Myers, A.M.; Soroka-Monzo, A.J.; Tuma, R.F.; Tallarida, R.J.; Walker, E.A.; Ward, S.J. Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain. Br. J. Pharmacol. 2017, 174, 2832–2841. [Google Scholar] [CrossRef] [Green Version]
  76. Gris, G.; Portillo-Salido, E.; Aubel, B.; Darbaky, Y.; Deseure, K.; Vela, J.M.; Merlos, M.; Zamanillo, D. The selective sigma-1 receptor antagonist E-52862,enuates neuropathic pain of different aetiology in rats. Sci. Rep. 2016, 6, 24591. [Google Scholar] [CrossRef] [Green Version]
  77. Tomohisa, M.; Junpei, O.; Aki, M.; Masato, H.; Mika, F.; Kazumi, Y.; Teruo, H.; Tsutomu, S. Possible involvement of the Sigma-1 receptor chaperone in chemotherapeutic-induced neuropathic pain. Synapse 2015, 69, 526–532. [Google Scholar] [CrossRef]
  78. Kanbara, T.; Nakamura, A.; Takasu, K.; Ogawa, K.; Shibasaki, M.; Mori, T.; Suzuki, T.; Hasegawa, M.; Sakaguchi, G.; Kanemasa, T. The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model. J. Pharmacol. Sci. 2014, 126, 264–273. [Google Scholar] [CrossRef] [Green Version]
  79. Bedini, A.; Di Cesare Mannelli, L.; Micheli, L.; Baiula, M.; Vaca, G.; De Marco, R.; Gentilucci, L.; Ghelardini, C.; Spampinato, S. Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist. Front. Pharmacol. 2020, 11, 188. [Google Scholar] [CrossRef] [Green Version]
  80. Shidahara, Y.; Ogawa, S.; Nakamura, M.; Nemoto, S.; Awaga, Y.; Takashima, M.; Hama, A.; Matsuda, A.; Takamatsu, H. Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin-induced neuropathic cold hypersensitivity. Pharmacol. Res. Perspect. 2016, 4, e00216. [Google Scholar] [CrossRef]
  81. Furgała, A.; Sałat, R.; Sałat, K. Acute cold allodynia induced by oxaliplatin is attenuated by amitriptyline. Acta Neurobiol. Exp. (Wars) 2018, 78, 315–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Yeo, J.H.; Yoon, S.Y.; Kwon, S.K.; Kim, S.J.; Lee, J.H.; Beitz, A.J.; Roh, D.H. Repetitive Acupuncture Point Treatment with Diluted Bee Venom Relieves Mechanical Allodynia and Restores Intraepidermal Nerve Fiber Loss in Oxaliplatin-Induced Neuropathic Mice. J. Pain 2016, 17, 298–309. [Google Scholar] [CrossRef] [PubMed]
  83. Kim, W.; Kim, M.J.; Go, D.; Min, B.I.; Na, H.S.; Kim, S.K. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice. Toxins 2016, 8, 33. [Google Scholar] [CrossRef] [PubMed]
  84. Lim, B.S.; Moon, H.J.; Li, D.X.; Gil, M.; Min, J.K.; Lee, G.; Bae, H.; Kim, S.K.; Min, B.I. Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. Evid. Based Complement. Alternat. Med. 2013, 2013, 369324. [Google Scholar] [CrossRef]
  85. Li, D.; Lee, Y.; Kim, W.; Lee, K.; Bae, H.; Kim, S.K. Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain. Toxins 2015, 7, 2422–2434. [Google Scholar] [CrossRef] [Green Version]
  86. Yeo, J.H.; Yoon, S.Y.; Kim, S.J.; Oh, S.B.; Lee, J.H.; Beitz, A.J.; Roh, D.H. Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension. Int. J. Cancer. 2016, 138, 2466–2476. [Google Scholar] [CrossRef] [Green Version]
  87. Kim, W.; Chung, Y.; Choi, S.; Min, B.I.; Kim, S.K. Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents. Int. J. Mol. Sci. 2017, 18, 2626. [Google Scholar] [CrossRef] [Green Version]
  88. Balayssac, D.; Ling, B.; Ferrier, J.; Pereira, B.; Eschalier, A.; Authier, N. Assessment of thermal sensitivity in rats using the thermal place preference test: Description and application in the study of oxaliplatin-induced acute thermal hypersensitivity and inflammatory pain models. Behav. Pharmacol. 2014, 25, 99–111. [Google Scholar] [CrossRef]
  89. Baptista-de-Souza, D.; Di Cesare Mannelli, L.; Zanardelli, M.; Micheli, L.; Nunes-de-Souza, R.L.; Canto-de-Souza, A.; Ghelardini, C. Serotonergic modulation in neuropathy induced by oxaliplatin: Effect on the 5HT2C receptor. Eur. J. Pharmacol. 2014, 735, 141–149. [Google Scholar] [CrossRef]
  90. Choi, S.; Chae, H.K.; Heo, H.; Hahm, D.H.; Kim, W.; Kim, S.K. Analgesic Effect of Melittin on Oxaliplatin-Induced Peripheral Neuropathy in Rats. Toxins 2019, 11, 396. [Google Scholar] [CrossRef] [Green Version]
  91. Sałat, K.; Kołaczkowski, M.; Furgała, A.; Rojek, A.; Śniecikowska, J.; Varney, M.A.; Newman-Tancredi, A. Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT1A receptor selective agonist, NLX-112 in mouse models of pain. Neuropharmacology 2017, 125, 181–188. [Google Scholar] [CrossRef] [PubMed]
  92. Yoon, S.Y.; Lee, J.Y.; Roh, D.H.; Oh, S.B. Pharmacopuncture With Scolopendra subspinipes Suppresses Mechanical Allodynia in Oxaliplatin-Induced Neuropathic Mice and Potentiates Clonidine-induced Anti-allodynia Without Hypotension or Motor Impairment. J. Pain 2018, 19, 1157–1168. [Google Scholar] [CrossRef] [PubMed]
  93. Andoh, T.; Sakamoto, A.; Kuraishi, Y. 5-HT1A receptor agonists, xaliproden and tandospirone, inhibit the increase in the number of cutaneous mast cells involved in the exacerbation of mechanical allodynia in oxaliplatin-treated mice. J. Pharmacol. Sci. 2016, 131, 284–287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Micov, A.M.; Tomić, M.A.; Todorović, M.B.; Vuković, M.J.; Pecikoza, U.B.; Jasnic, N.I.; Djordjevic, J.D.; Stepanović-Petrović, R.M. Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy. Prog. Neuropsychopharmacol. Biol. Psychiatry 2020, 103, 109975. [Google Scholar] [CrossRef] [PubMed]
  95. Kanat, O.; Bagdas, D.; Ozboluk, H.Y.; Gurun, M.S. Preclinical evidence for the antihyperalgesic activity of CDP-choline in oxaliplatin-induced neuropathic pain. J. BUON 2013, 18, 1012–1018, Erratum in: J BUON 2014, 19, 323. Kanat, D [corrected to Kanat, O]. [Google Scholar] [PubMed]
  96. Di Cesare Mannelli, L.; Pacini, A.; Matera, C.; Zanardelli, M.; Mello, T.; De Amici, M.; Dallanoce, C.; Ghelardini, C. Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: Effects of selective activation. Neuropharmacology 2014, 79, 37–48. [Google Scholar] [CrossRef]
  97. Wang, H.; Li, X.; Zhangsun, D.; Yu, G.; Su, R.; Luo, S. The α9α10 Nicotinic Acetylcholine Receptor Antagonist αO-Conotoxin GeXIVA[1,2] Alleviates and Reverses Chemotherapy-Induced Neuropathic Pain. Mar. Drugs 2019, 17, 265. [Google Scholar] [CrossRef] [Green Version]
  98. Pacini, A.; Micheli, L.; Maresca, M.; Branca, J.J.; McIntosh, J.M.; Ghelardini, C.; Di Cesare Mannelli, L. The α9α10 nicotinic receptor antagonist α-conotoxin RgIA prevents neuropathic pain induced by oxaliplatin treatment. Exp. Neurol. 2016, 282, 37–48. [Google Scholar] [CrossRef]
  99. Huang, K.M.; Leblanc, A.F.; Uddin, M.E.; Kim, J.Y.; Chen, M.; Eisenmann, E.D.; Gibson, A.A.; Li, Y.; Hong, K.W.; DiGiacomo, D.; et al. Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice. J. Clin. Investig. 2020, 130, 4601–4606. [Google Scholar] [CrossRef]
  100. Nishida, K.; Takeuchi, K.; Hosoda, A.; Sugano, S.; Morisaki, E.; Ohishi, A.; Nagasawa, K. Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats. Life Sci. 2018, 207, 516–524. [Google Scholar] [CrossRef]
  101. Toyama, S.; Shimoyama, N.; Shimoyama, M. The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain. Neuropeptides 2017, 61, 95–100. [Google Scholar] [CrossRef] [PubMed]
  102. Chaumette, T.; Chapuy, E.; Berrocoso, E.; Llorca-Torralba, M.; Bravo, L.; Mico, J.A.; Chalus, M.; Eschalier, A.; Ardid, D.; Marchand, F.; et al. Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats. Eur. J. Pain. 2018, 22, 127–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Tsubaki, M.; Takeda, T.; Matsumoto, M.; Kato, N.; Asano, R.T.; Imano, M.; Satou, T.; Nishida, S. Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation. Am. J. Cancer Res. 2018, 8, 1239–1248. [Google Scholar] [PubMed]
  104. Tsubaki, M.; Takeda, T.; Tani, T.; Shimaoka, H.; Suzuyama, N.; Sakamoto, K.; Fujita, A.; Ogawa, N.; Itoh, T.; Imano, M.; et al. PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects. Int. J. Cancer 2015, 137, 243–250. [Google Scholar] [CrossRef] [PubMed]
  105. Janes, K.; Little, J.W.; Li, C.; Bryant, L.; Chen, C.; Chen, Z.; Kamocki, K.; Doyle, T.; Snider, A.; Esposito, E.; et al. The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J. Biol. Chem. 2014, 289, 21082–21097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Minami, T.; Takeda, M.; Sata, M.; Kato, H.; Yano, K.; Sakai, T.; Tsujita, R.; Kawasaki, K.; Ito, A. Thrombomodulin alfa prevents oxaliplatin-induced neuropathic symptoms through activation of thrombin-activatable fibrinolysis inhibitor and protein C without affecting anti-tumor activity. Eur. J. Pharmacol. 2020, 880, 173196. [Google Scholar] [CrossRef]
  107. Tsubota, M.; Fukuda, R.; Hayashi, Y.; Miyazaki, T.; Ueda, S.; Yamashita, R.; Koike, N.; Sekiguchi, F.; Wake, H.; Wakatsuki, S.; et al. Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: Negative impact of anticoagulants. J. NeuroInflamm. 2019, 16, 199. [Google Scholar] [CrossRef]
  108. Di Cesare Mannelli, L.; Tenci, B.; Micheli, L.; Vona, A.; Corti, F.; Zanardelli, M.; Lapucci, A.; Clemente, A.M.; Failli, P.; Ghelardini, C. Adipose-derived stem cells decrease pain in a rat model of oxaliplatin-induced neuropathy: Role of VEGF-A modulation. Neuropharmacology 2018, 131, 166–175. [Google Scholar] [CrossRef] [Green Version]
  109. Miguel, C.A.; Raggio, M.C.; Villar, M.J.; Gonzalez, S.L.; Coronel, M.F. Anti-allodynic and anti-inflammatory effects of 17α-hydroxyprogesterone caproate in oxaliplatin-induced peripheral neuropathy. J. Peripher. Nerv. Syst. 2019, 24, 100–110. [Google Scholar] [CrossRef] [Green Version]
  110. Taleb, O.; Bouzobra, F.; Tekin-Pala, H.; Meyer, L.; Mensah-Nyagan, A.G.; Patte-Mensah, C. Behavioral and electromyographic assessment of oxaliplatin-induced motor dysfunctions: Evidence for a therapeutic effect of allopregnanolone. Behav. Brain Res. 2017, 320, 440–449. [Google Scholar] [CrossRef]
  111. Shigematsu, N.; Kawashiri, T.; Kobayashi, D.; Shimizu, S.; Mine, K.; Hiromoto, S.; Uchida, M.; Egashira, N.; Shimazoe, T. Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro. Sci. Rep. 2020, 10, 6734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Yi, J.M.; Shin, S.; Kim, N.S.; Bang, O.S. Neuroprotective Effects of an Aqueous Extract of Forsythia viridissima and Its Major Constituents on Oxaliplatin-Induced Peripheral Neuropathy. Molecules 2019, 24, 1177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Yi, J.M.; Shin, S.; Kim, N.S.; Bang, O.S. Ameliorative effects of aqueous extract of Forsythiae suspensa fruits on oxaliplatin-induced neurotoxicity in vitro and in vivo. BMC Complement. Altern. Med. 2019, 19, 339. [Google Scholar] [CrossRef]
  114. Cho, E.S.; Yi, J.M.; Park, J.S.; Lee, Y.J.; Lim, C.J.; Bang, O.S.; Kim, N.S. Aqueous extract of Lithospermi radix attenuates oxaliplatin-induced neurotoxicity in both in vitro and in vivo models. BMC Complement. Altern. Med. 2016, 16, 419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Sałat, K.; Furgała, A.; Sałat, R. Interventional and preventive effects of aripiprazole and ceftriaxone used alone or in combination on oxaliplatin-induced tactile and cold allodynia in mice. Biomed. Pharmacother. 2019, 111, 882–890. [Google Scholar] [CrossRef] [PubMed]
  116. Di Cesare Mannelli, L.; Pacini, A.; Micheli, L.; Femia, A.P.; Maresca, M.; Zanardelli, M.; Vannacci, A.; Gallo, E.; Bilia, A.R.; Caderni, G.; et al. Astragali radix: Could it be an adjuvant for oxaliplatin-induced neuropathy? Sci. Rep. 2017, 7, 42021. [Google Scholar] [CrossRef] [Green Version]
  117. Cerles, O.; Gonçalves, T.C.; Chouzenoux, S.; Benoit, E.; Schmitt, A.; Bennett Saidu, N.E.; Kavian, N.; Chéreau, C.; Gobeaux, C.; Weill, B.; et al. Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth. Acta Neuropathol. Commun. 2019, 7, 9. [Google Scholar] [CrossRef] [PubMed]
  118. Kim, C.; Lee, J.H.; Kim, W.; Li, D.; Kim, Y.; Lee, K.; Kim, S.K. The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats. Molecules 2016, 21, 1253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Di Cesare Mannelli, L.; Piccolo, M.; Maione, F.; Ferraro, M.G.; Irace, C.; De Feo, V.; Ghelardini, C.; Mascolo, N. Tanshinones from Salvia miltiorrhiza Bunge revert chemotherapy-induced neuropathic pain and reduce glioblastoma cells malignancy. Biomed. Pharmacother. 2018, 105, 1042–1049. [Google Scholar] [CrossRef]
  120. Al Moundhri, M.S.; Al-Salam, S.; Al Mahrouqee, A.; Beegam, S.; Ali, B.H. The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: Some behavioral, biochemical, and histopathological studies. J. Med. Toxicol. 2013, 9, 25–33. [Google Scholar] [CrossRef] [Green Version]
  121. Fujita, S.; Ushio, S.; Ozawa, N.; Masuguchi, K.; Kawashiri, T.; Oishi, R.; Egashira, N. Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats. PLoS ONE 2015, 10, e0141921. [Google Scholar] [CrossRef] [PubMed]
  122. Yamamoto, S.; Yamashita, T.; Ito, M.; Caaveiro, J.M.M.; Egashira, N.; Tozaki-Saitoh, H.; Tsuda, M. New pharmacological effect of fulvestrant to prevent oxaliplatin-induced neurodegeneration and mechanical allodynia in rats. Int. J. Cancer 2019, 145, 2107–2113. [Google Scholar] [CrossRef]
  123. Mizuno, K.; Shibata, K.; Komatsu, R.; Omiya, Y.; Kase, Y.; Koizumi, S. An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi. Cancer Biol. Ther. 2016, 17, 1206–1212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Ushio, S.; Egashira, N.; Sada, H.; Kawashiri, T.; Shirahama, M.; Masuguchi, K.; Oishi, R. Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents. Eur. J. Cancer. 2012, 48, 1407–1413. [Google Scholar] [CrossRef] [PubMed]
  125. Yang, Y.; Hu, L.; Wang, C.; Yang, X.; Song, L.; Jiang, C.; Li, Y.; Li, T.; Liu, W.T.; Feng, J. p38/TF/HIF-α Signaling Pathway Participates in the Progression of CIPN in Mice. Biomed Res. Int. 2019, 2019, 5347804. [Google Scholar] [CrossRef] [Green Version]
  126. Chiorazzi, A.; Wozniak, K.M.; Rais, R.; Wu, Y.; Gadiano, A.J.; Farah, M.H.; Liu, Y.; Canta, A.; Alberti, P.; Rodriguez-Menendez, V.; et al. Ghrelin agonist HM01 attenuates chemotherapy-induced neurotoxicity in rodent models. Eur. J. Pharmacol. 2018, 840, 89–103. [Google Scholar] [CrossRef]
  127. Areti, A.; Komirishetty, P.; Akuthota, M.; Malik, R.A.; Kumar, A. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J. Pineal. Res. 2017, 62. [Google Scholar] [CrossRef]
  128. Martinez, N.W.; Sánchez, A.; Diaz, P.; Broekhuizen, R.; Godoy, J.; Mondaca, S.; Catenaccio, A.; Macanas, P.; Nervi, B.; Calvo, M.; et al. Metformin protects from oxaliplatin induced peripheral neuropathy in rats. Neurobiol. Pain 2020, 8, 100048. [Google Scholar] [CrossRef]
  129. Pereira, A.F.; Pereira, L.M.S.; Silva, C.M.P.; Freitas Alves, B.W.; Barbosa, J.S.; Pinto, F.M.M.; Pereira, A.C.; Silva, K.O.; Pontes, R.B.; Alencar, N.M.N.; et al. Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice. Neurosci. Lett. 2019, 709, 134378. [Google Scholar] [CrossRef]
  130. Masuguchi, K.; Watanabe, H.; Kawashiri, T.; Ushio, S.; Ozawa, N.; Morita, H.; Oishi, R.; Egashira, N. Neurotropin® relieves oxaliplatin-induced neuropathy via Gi protein-coupled receptors in the monoaminergic descending pain inhibitory system. Life Sci. 2014, 98, 49–54. [Google Scholar] [CrossRef]
  131. Kawashiri, T.; Egashira, N.; Watanabe, H.; Ikegami, Y.; Hirakawa, S.; Mihara, Y.; Yano, T.; Ikesue, H.; Oishi, R. Prevention of oxaliplatin-induced mechanical allodynia and neurodegeneration by neurotropin in the rat model. Eur. J. Pain 2011, 15, 344–350. [Google Scholar] [CrossRef] [PubMed]
  132. Suzuki, T.; Yamamoto, A.; Ohsawa, M.; Motoo, Y.; Mizukami, H.; Makino, T. Effect of ninjin’yoeito and ginseng extracts on oxaliplatin-induced neuropathies in mice. J. Nat. Med. 2017, 71, 757–764. [Google Scholar] [CrossRef] [PubMed]
  133. Di Cesare Mannelli, L.; Pacini, A.; Corti, F.; Boccella, S.; Luongo, L.; Esposito, E.; Cuzzocrea, S.; Maione, S.; Calignano, A.; Ghelardini, C. Antineuropathic profile of N-palmitoylethanolamine in a rat model of oxaliplatin-induced neurotoxicity. PLoS ONE 2015, 10, e0128080. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Suzuki, T.; Miyamoto, K.; Yokoyama, N.; Sugi, M.; Kagioka, A.; Kitao, Y.; Adachi, T.; Ohsawa, M.; Mizukami, H.; Makino, T. Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain. J. Ethnopharmacol. 2016, 186, 44–52. [Google Scholar] [CrossRef] [PubMed]
  135. Aoki, M.; Mori, A.; Nakahara, T.; Sakamoto, K.; Ishii, K. Salmon calcitonin reduces oxaliplatin-induced cold and mechanical allodynia in rats. Biol. Pharm. Bull. 2013, 36, 326–329. [Google Scholar] [CrossRef] [Green Version]
  136. Cheng, W.; Xiang, W.; Wang, S.; Xu, K. Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion. Am. J. Transl. Res. 2019, 11, 3140–3149. [Google Scholar]
  137. Alberti, P.; Canta, A.; Chiorazzi, A.; Fumagalli, G.; Meregalli, C.; Monza, L.; Pozzi, E.; Ballarini, E.; Rodriguez-Menendez, V.; Oggioni, N.; et al. Topiramate prevents oxaliplatin-related axonal hyperexcitability and oxaliplatin induced peripheral neurotoxicity. Neuropharmacology 2020, 164, 107905. [Google Scholar] [CrossRef]
  138. Tenci, B.; Di Cesare Mannelli, L.; Maresca, M.; Micheli, L.; Pieraccini, G.; Mulinacci, N.; Ghelardini, C. Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats. Z. Naturforsch. C J. Biosci. 2017, 72, 449–457. [Google Scholar] [CrossRef]
  139. Deng, B.; Jia, L.; Pan, L.; Song, A.; Wang, Y.; Tan, H.; Xiang, Q.; Yu, L.; Ke, D. Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain. Evid. Based Complement. Alternat. Med. 2016, 2016, 3629489. [Google Scholar] [CrossRef]
  140. McQuade, R.M.; Carbone, S.E.; Stojanovska, V.; Rahman, A.; Gwynne, R.M.; Robinson, A.M.; Goodman, C.A.; Bornstein, J.C.; Nurgali, K. Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice. Br. J. Pharmacol. 2016, 173, 3502–3521. [Google Scholar] [CrossRef] [Green Version]
  141. Di Cesare Mannelli, L.; Zanardelli, M.; Failli, P.; Ghelardini, C. 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. [Google Scholar] [CrossRef] [PubMed]
  142. Adelsberger, H.; Quasthoff, S.; Grosskreutz, J.; Lepier, A.; Eckel, F.; Lersch, C. The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur. J. Pharmacol. 2000, 406, 25–32. [Google Scholar] [CrossRef]
  143. Grolleau, F.; Gamelin, L.; Boisdron-Celle, M.; Lapied, B.; Pelhate, M.; Gamelin, E. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J. Neurophysiol. 2001, 85, 2293–2297. [Google Scholar] [CrossRef] [PubMed]
  144. Gauchan, P.; Andoh, T.; Kato, A.; Kuraishi, Y. Involvement of increased expression of transient receptor potential melastatin 8 in oxaliplatin-induced cold allodynia in mice. Neurosci. Lett. 2009, 458, 93–95. [Google Scholar] [CrossRef] [PubMed]
  145. Ta, L.E.; Bieber, A.J.; Carlton, S.M.; Loprinzi, C.L.; Low, P.A.; Windebank, A.J. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol. Pain 2010, 6, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Descoeur, J.; Pereira, V.; Pizzoccaro, A.; Francois, A.; Ling, B.; Maffre, V.; Couette, B.; Busserolles, J.; Courteix, C.; Noel, J.; et al. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol. Med. 2011, 3, 266–278. [Google Scholar] [CrossRef] [PubMed]
  147. Yoshimura, M.; Furue, H. Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J. Pharmacol. Sci. 2006, 101, 107–117. [Google Scholar] [CrossRef] [Green Version]
  148. Smith, E.M.; Pang, H.; Cirrincione, C.; Fleishman, S.; Paskett, E.D.; Ahles, T.; Bressler, L.R.; Fadul, C.E.; Knox, C.; Le-Lindqwister, N.; et al. Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA 2013, 309, 1359–1367. [Google Scholar] [CrossRef]
  149. Grothey, A.; Nikcevich, D.A.; Sloan, J.A.; Kugler, J.W.; Silberstein, P.T.; Dentchev, T.; Wender, D.B.; Novotny, P.J.; Chitaley, U.; Alberts, S.R.; et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J. Clin. Oncol. 2011, 29, 421–427. [Google Scholar] [CrossRef]
  150. Grothey, A.; Hart, L.L.; Rowland, K.M.; Ansari, R.H.; Alberts, S.R.; Chowhan, N.M.; Hochster, H.S. Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. J. Clin. Oncol. 2008, 26, 4010. [Google Scholar] [CrossRef]
  151. Loprinzi, C.L.; Qin, R.; Dakhil, S.R.; Fehrenbacher, L.; Flynn, K.A.; Atherton, P.; Seisler, D.; Qamar, R.; Lewis, G.C.; Grothey, A. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J. Clin. Oncol. 2014, 32, 997–1005. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Han, C.H.; Khwaounjoo, P.; Kilfoyle, D.H.; Hill, A.; McKeage, M.J. Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients. BMC Cancer 2013, 13, 495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Jordan, B.; Jahn, F.; Beckmann, J.; Unverzagt, S.; Müller-Tidow, C.; Jordan, K. Calcium and Magnesium Infusions for the Prevention of Oxaliplatin-Induced Peripheral Neurotoxicity: A Systematic Review. Oncology 2016, 90, 299–306. [Google Scholar] [CrossRef] [PubMed]
  154. Nishioka, M.; Shimada, M.; Kurita, N.; Iwata, T.; Morimoto, S.; Yoshikawa, K.; Higashijima, J.; Miyatani, T.; Kono, T. The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. Int. J. Clin. Oncol. 2011, 16, 322–327. [Google Scholar] [CrossRef] [PubMed]
  155. Kono, T.; Hata, T.; Morita, S.; Munemoto, Y.; Matsui, T.; Kojima, H.; Takemoto, H.; Fukunaga, M.; Nagata, N.; Shimada, M.; et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): A phase 2, multicenter, randomized, double‑blind, placebo‑controlled trial of goshajinkigan to prevent oxaliplatin‑induced neuropathy. Cancer Chemother. Pharmacol. 2013, 72, 1283–1290. [Google Scholar] [CrossRef] [Green Version]
  156. Oki, E.; Emi, Y.; Kojima, H.; Higashijima, J.; Kato, T.; Miyake, Y.; Kon, M.; Ogata, Y.; Takahashi, K.; Ishida, H.; et al. Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): A placebo-controlled, double-blind, randomized phase III study. Int. J. Clin. Oncol. 2015, 20, 767–775. [Google Scholar] [CrossRef]
  157. Guo, Y.; Jones, D.; Palmer, J.L.; Forman, A.; Dakhil, S.R.; Velasco, M.R.; Weiss, M.; Gilman, P.; Mills, G.M.; Noga, S.J.; et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Support. Care Cancer 2014, 22, 1223–1231. [Google Scholar] [CrossRef]
  158. Salehi, Z.; Roayaei, M. Effect of Vitamin E on Oxaliplatin-induced Peripheral Neuropathy Prevention: A Randomized Controlled Trial. Int. J. Prev. Med. 2015, 6, 104. [Google Scholar] [CrossRef]
  159. Huang, H.; He, M.; Liu, L.; Huang, L. Vitamin E does not decrease the incidence of chemotherapy-induced peripheral neuropathy: A meta-analysis. Contemp. Oncol. 2016, 20, 237. [Google Scholar] [CrossRef]
  160. Cascinu, S.; Catalano, V.; Cordella, L.; Labianca, R.; Giordani, P.; Baldelli, A.M.; Beretta, G.D.; Ubiali, E.; Catalano, G. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: A randomized, double-blind, placebo-controlled trial. J. Clin. Oncol. 2002, 20, 3478–3483. [Google Scholar] [CrossRef]
  161. Glimelius, B.; Manojlovic, N.; Pfeiffer, P.; Mosidze, B.; Kurteva, G.; Karlberg, M.; Mahalingam, D.; Buhl Jensen, P.; Kowalski, J.; Bengtson, M.; et al. Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®): A placebo-controlled randomised phase II study (PLIANT). Acta Oncol. 2018, 57, 393–402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. de Andrade, D.C.; Jacobsen Teixeira, M.; Galhardoni, R.; Ferreira, K.S.L.; Braz Mileno, P.; Scisci, N.; Zandonai, A.; Teixeira, W.G.J.; Saragiotto, D.F.; Silva, V. Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial. Oncologist 2017, 22, 1154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Wang, X.S.; Shi, Q.; Bhadkamkar, N.A.; Cleeland, C.S.; Garcia-Gonzalez, A.; Aguilar, J.R.; Heijnen, C.; Eng, C. Minocycline for Symptom Reduction During Oxaliplatin-Based Chemotherapy for Colorectal Cancer: A Phase II Randomized Clinical Trial. J. Pain Symptom. Manag. 2019, 58, 662–671. [Google Scholar] [CrossRef] [PubMed]
Table 1. The therapeutic agents for oxaliplati-induced peripheral neuropathy in preclinical experiments.
Table 1. The therapeutic agents for oxaliplati-induced peripheral neuropathy in preclinical experiments.
Therapeutic TargetsTherapeutic AgentsDoseAnimalsSymptoms that Showed ImprovementMechanismsReferences
Oxidative stressAcetyl L-carnitine60–150 mg/kgRatsMechanical, thermal and cold allodyniaAntioxidant effect[14]
Acetyl L-carnitine50–100 mg/kgRatsMechanical, thermal and cold allodyniaAntioxidant effect[15]
Acetyl L-carnitine100 mg/kgRatsMechanical allodyniaPrevention of deficits in mitochondrial function[16]
Alpha-lipoic acid50–100 mg/kgRatsMechanical, thermal and cold allodyniaAntioxidant effect[15]
Calmangafodipir (PledOx®)2.5–10 mg/kgMiceMechanical allodynia and decrease in in IENF densityAntioxidant effect[17]
Carvedilol10 mg/kgRatsMechanical and cold allodyniaAntioxidant and mitoprotective effects[18]
Cerium oxide nanoparticles60 mg/kgRatsDecrease in MBP of sciatic nerve and increase in GFAP of spinal cordAntioxidant effect[19]
Cystine and Theanine280 mg/kgRatsMechanical allodynia and sciatic nervedenegerationsAntioxidant effect (upregulation of glutathione)[20]
Dimethyl fumarate200 mg/kgRatsMechanical allodynia and sciatic nervedenegerationsAntioxidant effect[21]
Donepezil1 mg/kgRatsMechanical allodyniaRecovery of reduction in SOD activity[22]
Glutathione33 mg/kgMiceCold allodyniaAluminum chelation and antioxidative effect[23]
Lycopene2–4 mg/kgRatsNeurodegenerative changes (increases in NCAM and BDNS), and decreases in GFAP and caspase-3) in brain and sciatic nerveAntioxidant effects (downregulation of SOD, CAT, and GPx), and antiinflamattory effects (downregulation of MAPK14, NF-κB and TNF-α)[24]
Melatonin10 mg/kgRatsLocomotor activity, muscular strength, thermal, and mechanical allodyniaAntioxidative effects and inactivations of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c release[25]
Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+))0.3–3 mg/kgRatsMechanical allodyniaInhibition of nitration and activation of superoxide dismutase in mitochondria, and increase in ATP production in primary nerve sensory axons[26]
MnL4 (SOD mimetic compound)15 mg/kgRatsMotor coordination, mechanical and cold allodyniaAntioxidative effects and inactivations of caspase 3/7 in astrocyte[27]
Niclosamide10 mg/kgMiceTactile hypoesthesia and thermal hyperalgesia, IENF density, and demyelinationAntioxidative and antiinflammatory effects[28]
Phosphatidylcholine300 mg/kgRatsMechanical and thermal allodyniaAntioxidative effects (downregulation of malondialdehyde, glutathione, GPx, and SOD in sciatic nerve) and modulation of microglial activities[29]
Quercetin20 mg/kgMiceMechanical allodyniaAntioxidant effect[30]
Quercetin25–100 mg/kgMiceMechanical and cold allodyniaDownregulation of nitric oxide and peroxynitrite[31]
Resveratrol100 mg/kgMiceMechanical allodyniaAntioxidant effect[30]
Rosiglitazone3–10 mg/kgRatsMechanical, cold allodynia and motor coordinationPrevention of catalase impairment[32]
Rosmarinic Acid25–50 mg/kgRatsMechanical and cold allodyniaReduction of oxidative stress, improvement of mitochondrial function, inhibition of spinal glial cell activation, and suppression of expression of inflammatory markers[33]
Rutin20 mg/kgMiceMechanical allodyniaAntioxidant effect[30]
Rutin25–100 mg/kgMiceMechanical and cold allodyniaDownregulation of nitric oxide and peroxynitrite[31]
Silibinin100 mg/kgRatsMechanical and cold allodyniaImprovement of oxidative alterations[34]
SS-20 (mitochondria-targeted peptide)5–10 mg/kgMiceMechanical allodynia and IENF densityMitochondrial protection[35]
SS-315 mg/kgMiceMechanical and cold allodyniaMitochondria-targeted antioxidant[36]
Sulforaphane5 mg/kgMiceMechanical allodynia and morphological alterations, mitochondrial dysfunction in DRGActivation of the Nrf2 signaling pathway[37]
Vitamin C50–100 mg/kgRatsMechanical, thermal and cold allodyniaAntioxidant effect[15]
Vitis vinifera extract300 mg/kgRatsMechanical and cold allodyniaAntioxidant effect[38]
α-tocopherol100 mg/kgRatsMechanical and cold allodyniaImprovement of oxidative alterations[34]
InflammatoryBee Venom derived phospholipase A20.2 mg/kgMiceMechanical and cold allodyniaSuppression of infiltration of macrophages and the increase in IL-1β level in the DRG[39]
Fluorocitrate1 nmol/h (i.t.)RatsMechanical allodyniaInactivation of microglia[40]
Herbal Medicine AC59110,000–20,000 mg/kgRatsMechanical, cold allodynia, and histological changes in sciatic nerve and DRGDownregulation of inflammation and immune response[41]
Houttuynia cordata Thunb1000 mg/kgRatsMechanical allodyniaModulation of Th17/Treg balance by regulating PI3K/Akt/mTOR signaling pathway[42]
Minocycline12.5 nmol/h (i.t.)RatsMechanical allodyniaInactivation of astrocyte[40]
Minocycline25 mg/kgRatsMechanical allodyniaInactivation of astrocyte[43]
Rapamycin5 mg/kgRatsMechanical and cold allodyniaBlocking mTOR and decreases in IL-1β, IL-6, and TNF-α[44]
Na channelLidocaine30 mg/kgRatsCold allodyniaN/A[45]
Lidocaine3–10 mg/kgRatsCold allodyniaN/A[11]
Mexiletine100 mg/kgRatsCold allodyniaN/A[45]
Mexiletine30 mg/kgMiceCold allodyniaN/A[46]
Lacosamide10–30 mg/kgMiceMechanical allodyniaN/A[47]
Lamotrigine5–10 mg/kgMiceCold allodyniaN/A[48]
Bromhexine150 mg/kgMiceTactile, cold allodyniaInhibition of Nav1.6, Nav1.7, and Nav1.9[49]
K channelGlucosinolate glucoraphanin4.43–119.79 µmol/kgMiceMechanical allodyniaReleasing H2S and modulating Kv7 channels[50]
Isothiocyanate sulforaphane1.33–13.31 µmol/kgMiceMechanical allodyniaReleasing H2S and modulating Kv7 channels[50]
Allyl-isothiocyanate1.33–13.31 µmol/kgMiceCold allodyniaReleasing H2S and modulating Kv7 channels[51]
Phenyl- and carboxyphenyl-isothiocyanate1.33–13.31 µmol/kgMiceCold allodyniaReleasing H2S and modulating Kv7 channels[51]
Riluzole7.5 mg/kgMiceMechanical and cold allodyniaInvolvement of TREK-1 potassium channel[52]
Ca channelGabapentin10–100 mg/kgMiceMechanical allodyniaAttenuation of cofilin phosphorylation in spinal cord[53]
Gabapentin100 mg/kgMiceCold allodyniaN/A[48]
Gabapentin30 mg/kgMiceCold allodyniaN/A[46]
Gabapentin300 mg/kgRatsCold allodyniaN/A[11]
Pregabalin30 mg/kgRatsMechanical and cold allodyniaN/A[54]
TRP channelTopiramate50 mg/kgMiceCold allodyniaPrevention of cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons[55]
Acetazolamide50 mg/kgMiceCold allodyniaPrevention of cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons[55]
Shakuyakukanzoto100–1000 mg/kgMiceCold allodyniaInhibition of TRPM8 expression in DRG[56]
Goshajinkigan300–1000 mg/kgRatsCold allodyniaSuppressions of increases in TRPA1 and TRPM8 in DRG[57]
Goshajinkigan1000 mg/kgRatsCold allodyniaSuppressions of increases in TRPA1 and TRPM8 in DRG[58]
Eel calcitonin20 U/kgRatsMechanical and cold allodyniaInhibition cellular signaling related to TRPA1 and TRPM8[59]
Nifedipine10–30 mg/kgRatsCold allodyniaDownregulation of TRPM8[60]
Diltiazem10–30 mg/kgRatsCold allodyniaDownregulation of TRPM8[60]
Mexiletine10–30 mg/kgRatsCold allodyniaDownregulation of TRPM8[60]
HCN1/HCN2MEL57A1–10 mg/kgRatsMechanical allodyniaHCN1 inhibitor[61]
MEL55A30 mg/kgMiceCold allodyniaBlockade of HCN1/HCN2 Channels[62]
Imidazoline receptor2-(1-([1,1’-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline)0.1–10 mg/kgMiceMechanical, cold allodynia, and increase in GFAP of spinal cordI1-imidazoline receptor agonist[63]
GlutamateRiluzole12 mg/kgRatsMechanical allodyniaSuppression of increase in glutamate concentration and decrease in GLT-1 in spinal cord[64]
Dimiracetam100–300 mg/kgRatsMechanical allodyniaCounteraction of NMDA-induced release of glutamate with highest potency in the spinal cord[65]
E20720.1–1 mg/kgMiceThermal hyperalgesiaGlutamate carboxypeptidase II inhibitor[66]
Tat-HA-NR2B9c50–100 ng (i.t.)Mice and ratsMechanical and cold allodyniaNMDA receptor antagonist[67]
Mirtazapine20–30 mg/kgRatsMechanical allodyniaDownregulation of NMDA receptor NR2B subunit[68]
Ifenprodil50 mg/kgRatsMechanical allodyniaNMDA receptor antagonist[69]
Amitriptyline5–10 mg/kgRatsMechanical allodyniaDownregulation of NMDA receptor NR2B subunit[70]
Trifluoperazine0.3 mg/kgRatsMechanical allodyniaInhibition of CaMKII[71]
PDETadalafil10 mg/kgMiceCold, mechanical, and electrical current hypersensitivities, and thermal hypoesthesia.Increases in blood flow and skin temperature[72]
Ibudilast7.5 mg/kgRatsMechanical allodyniaN/A[73]
Endothelin receptorBosentan100 mg/kgMiceMechanical and thermal hypersensitivityAntagonism of endothelin ETA and ETB receptors[74]
Cannabinoid receptorCannabidiol1.25–10 mg/kgMiceMechanical allodyniaN/A[75]
Sigma-1 receptorE-5286220–80 mg/kgRatsCold allodyniaSigma-1 receptor antagonist[76]
SA45033 mg/kgRatsMechanical allodyniaSigma-1 receptor agonist[77]
Opioid receptorFentanyl0.017–0.03 mg/kgRatsMechanical and cold allodyniaN/A[78]
LOR17 (κ-opioid receptor agonist)1–20 mg/kgRatsCold allodyniaκ-opioid receptor agonist[79]
Morphine1–3 mg/kgRatsMechanical and cold allodyniaN/A[78]
Oxycodone0.3–0.56 mg/kgRatsMechanical and cold allodyniaN/A[78]
Tramadol20 mg/kgMiceCold allodyniaN/A[46]
Tramadol30 mg/kgRatsCold allodyniaN/A[80]
MonoaminesAmitriptyline2.5–10 mg/kgMiceCold allodyniaN/A[81]
Bee venom0.1 mg/kgMiceMechanical allodynia and IENF densityActivation of the noradrenergic system, via α2-adrenegic receptors[82]
Bee venom acupuncture0.25–2.5 mg/kgMiceMechanical and cold allodyniaActivations of spinal opioidergic and 5-HT3 receptors[83]
Bee venom acupuncture0.25–1 mg/kgRatsCold allodyniaActivation of the noradrenergic system[84]
Bee Venom derived phospholipase A20.2 mg/kgMiceMechanical and cold allodyniaActivation of the noradrenergic system, via α2-adrenegic receptors[85]
Clomipramine2.5 mg/kgRatsCold allodyniaN/A[11]
Clonidine0.1 mg/kgMiceMechanical allodynia and spinal p-p38 MAPK expressionα2 adrenoceptor agonist[86]
Duloxetine30–60 mg/kgMiceMechanical and cold allodyniaActivating spinal α1-adrenergic receptor[87]
Duloxetine30 mg/kgRatsCold allodyniaN/A[80]
Duloxetine2.5 mg/kgMiceCold allodyniaN/A[88]
Fluoxetine20 mg/kgRatsMechanical and cold allodyniaBlockade serotonergic 5-HT2C receptor[89]
Melittin (major content of bee venom)0.5 mg/kgMiceMechanical and cold allodyniaActivating the spinal α1- and α2-adrenergic receptors.[90]
Morphine2–5 mg/kgMiceMechanical and cold allodyniaActivations of spinal opioidergic and 5-HT4 receptors[83]
NLX-1120.1–5 mg/kgMiceMechanical allodynia5-HT1A receptor agonist[91]
Pregabalin30 mg/kgRatsCold allodyniaN/A[80]
Scolopendra subspinipes0.5%/20 µL (acupoint treatment)MiceMechanical allodyniaActivation of spinal α2-adrenoceptor[92]
Tandospirone1–3 mg/kgMiceMechanical allodynia and mast cell migration5-HT1A receptor agonist[93]
Venlafaxine7.5 mg/kgRatsCold allodyniaN/A[11]
Vortioxetine1–10 mg/kgMiceMechanical and cold allodyniaIncreases in NA and 5HT in brain[94]
Xaliproden0.3–3 mg/kgMiceMechanical allodynia and mast cell migration5-HT1A receptor agonist[93]
Acetylcholine receptorCiticoline (cytidine-5’-diphosphate- choline; CDP-choline)1–2 µmol (i.c.v.)RatsMechanical allodyniaInvolvement of α7 nAChRs, and interaction between GABAergic and cholinergic system[95]
(R)-ICH330 mg/kgRatsMechanical and cold allodyniaα7 nAChR agonist[96]
PNU-28298730 mg/kgRatsMechanical and cold allodyniaα7 nAChR agonist[96]
αO-Conotoxin GeXIVA 1,232–128 mg/kgRatsMechanical and cold allodyniaAntagonism of the α9α10 nAChR[97]
α-conotoxin RgIA2–10 nmol (i.m.)RatsMechanical, cold allodynia, and morphological changes of DRGα9α10 nAChR antagonist[98]
OCT2Dasatinib15 mg/kgMiceMechanical allodyniaInhibition of platinum accumulation via OCT2[99]
OCTN1Ergothioneine15 mg/kgRatsMechanical allodyniaInhibition of OCTN1 and decrease in platinum accumulation in DRG neurons.[100]
Orexin receptorOrexin-A0.1–1 nmol (i.c.v.)MiceMechanical allodyniaOrexin type-1 receptor agonist[101]
Histamine receptorS 380930.3–3 mg/kgRatsCold allodyniaHistamine H3 receptor agonist[102]
PKC/MEK/ERKTrametinib0.5 mg/kgMiceMechanical and cold allodyniaInhibition of the MEK/ERK pathway[103]
Tamoxifen10–30 mg/kgMiceMechanical and cold allodyniaInhibition of PKC/ERK/c-Fos pathway in spinal cord[104]
PD032590110–30 mg/kgMiceMechanical and cold allodyniaInhibition of MEK1/2[104]
Ceramide-sphingosine 1-phosphateFTY7200.01 mg/kgRatsMechanical allodyniaModulation of ceramide-S1P R1[105]
OxalateCalcium gluconate0.5 mmol/kgMiceCold allodyniaN/A[46]
Calcium0.5 mmol/kgRatsCold allodyniaN/A[13]
Magnesium90 mg/kgRatsCold allodyniaN/A[11]
Magnesium0.5 mmol/kgRatsCold allodyniaN/A[13]
Thrombin activityThrombomodulin alfa0.1–1 mg/kgRatsMechanical allodyniaActivation of TAFI and protein C by modulating thrombin activity[106]
Warfarin1 mg/kgMice and ratsMechanical allodyniaUpregulation of HMGB1[107]
Dabigatran75 mg/kgMice and ratsMechanical allodyniaUpregulation of HMGB1[107]
Rivaroxaban10 mg/kgMice and ratsMechanical allodyniaUpregulation of HMGB1[107]
VEGFBevacizumab1–15 mg/kgRatsMechanical allodyniaAnti VEGF-A effect[108]
Others17α-hydroxyprogesterone caproate10 mg/kgRatsMechanical and cold allodyniaReduction of ATF-3, c-Fos, GFAP, Iba-1, IL-1β and TNFα in DRG and spinal cord[109]
Allopregnanolone4 mg/kgRatsMotor dysfunction and electrophysiological assesment of motor nervesN/A[110]
Alogliptin10 mg/kgRatsMechanical allodynia and sciatic nervedenegerationsNeuroprotective effects[111]
Aqueous Extract of Forsythia viridissima100 mg/kgMiceMechanical allodynia and decrease in IENF densityN/A[112]
Aqueous extract of Forsythiae suspensa fruits50–100 mg/kgMiceMechanical allodynia and decrease in IENF densityN/A[113]
Aqueous extract of Lithospermi Radix250 mg/kgMiceMechanical allodyniaAttenuation of spinal microglia and astrocyte[114]
Aripiprazole10 mg/kgMiceMechanical allodyniaN/A[115]
Astragali radix100–300 mg/kgRatsMechanical and thermal allodyniaReductions of morphometric and molecular alterations in peripheral nerve and DRG, and inactivation of microglia and astrocytes in spinal cord and brain[116]
Benztropine10 mg/kgMiceMecahnical, cold allodynia, and demyelination in sciatic nerveN/A[117]
Ceftriaxone200 mg/kgMiceMechanical allodyniaN/A[115]
Cinnamomi Cortex100–400 mg/kgRatsCold allodyniaAttenuation of spinal microglia and astrocyte, and downregulation of IL-1β and TNF-α[118]
Cryptotanshinone10–30 mg/kgMiceCold allodyniaN/A[119]
Curcumin10 mg/kgRatsNeurodegeneration in sciatic nerveDownregulation of neurotensin and platinum concentrations in sciatic nerve[120]
Elcatonin20 U/kgRatsMechanical and cold allodyniaN/A[54]
Exenatide0.1 mg/kgRatsMecahnical, cold allodynia, and demyelination in sciatic nerveNeuroprotective effects[121]
Fulvestrant5–10 mg/kgRatsMechanical allodynia and sciatic nervedenegerationsNeuroprotective effects[122]
Goshajinkigan300–1000 mg/kgMiceMechanical and cold allodyniaN/A[123]
Goshajinkigan300–1000 mg/kgRatsMechanical and cold allodyniaN/A[124]
Hirudin10 mg/kgMiceMechanical allodyniaDownregulation of p38, HIF-1α and MMP-9/2[125]
HM0110–30 mg/kgRatsNerveconductionvelocity of digital nerve, caudal nerve and IENF densityGhrelin agonist[126]
Melatonin3–10 mg/kgMiceMechanical and cold allodyniaAntioxidant effect, improvement of mitochondrial function, activation of autophagy pathway, and anti-apoptotic effect[127]
Metformin250 mg/kgRatsMecahnical, cold allodynia, decrease in IENF density, and increase in GFAP of spinal cordN/A[128]
Metformin250 mg/kgMiceMechanical allodyniaDecreases in ATF-3 and c-Fos expressions in spinal cord and DRG[129]
Neurotropin (a non-protein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus)100–200 U/kgRatsMechanical and cold allodyniaMonoaminergic descending pain inhibitory system via Gi protein-coupled receptors[130]
Neurotropin (a non-protein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus)200 U/kgRatsMechanical allodyniaNeuroprotective effects[131]
Ninjin’yoeito1000 mg/kgMiceMechanical and cold allodyniaN/A[132]
Palmitoylethanolamine30 mg/kgRatsMechanical and cold allodyniaNeuroprotective effects and glia-activation prevention[133]
Phenytoin5–10 mg/kgMiceCold allodyniaN/A[48]
Processed aconite root1000 mg/kgMiceMechanical and cold allodyniaN/A[134]
Retigabine5–10 mg/kgMiceCold allodyniaN/A[48]
Salmon calcitonin20 U/kgRatsMechanical and cold allodyniaN/A[135]
Salvia miltiorrhiza root extract (Danshen)300–600 mg/kgMiceCold allodyniaN/A[119]
Tanshinone IIA25 mg/kgRatsMecahnical, cold allodynia, and demyelination in sciatic nerveMitochondrial protection and autophagy promotion[136]
Tanshinone IIA10 mg/kgMiceCold allodyniaN/A[119]
Topiramate100 mg/kgRatsMechanical allodynia, dischange in nerve sensory conduction velocity, caudal nerve fibers density, and IENF densityN/A[137]
Water extract of Lepidium meyenii root10,000 mg/kgRatsMechanical allodyniaN/A[138]
Wen-luo-tongPaws and tails were soaked in 0.6 g/mL solution for 20 minRatsMechanical allodyniaReductions of histological dischange in DRG and glial activation in the spinal dorsal horn[139]
Abbreviations: 5-HT, serotonin; Akt, protein kinase B; ATF-3, activating transcription factor 3; ATP, adenosine triphosphate; CAT, catalase; CaMKII, calmodulin-dependent protein kinase II; DRG, dorsal root ganglia; ERK, extracellular signal-regulated kinase; ETA, endothelin A; ETB, endothelin B; GFAP, glial fibrillary acidic protein; GLT-1, glutamate transporter 1; GPx, glutathione peroxidase; HCN1, hyperpolarization-activated, cyclic nucleotide-gated cation channel 1; HCN2, hyperpolarization-activated, cyclic nucleotide-gated cation channel 2; HIF-1, hypoxia inducible factor 1; HMGB1, high mobility group box 1; Iba-1, ionized calcium binding adaptor protein 1; i.c.v., intracerebroventriculary; IENF, intra-epidermal nerve fibers; IL-1β, interleukin-1 beta; IL-6, interleukin-6; i.m., intramuscular; i.t., intrathecal; MAPK14, mitogen-activated protein kinase-14; MBP, myelin basic protein; MEK1/2, mitogen-activated protein kinase kinases 1 and 2; MMP9/2, matrix metalloproteinase-9 and -2; mTOR, mammalian target of rapamycin; nAChR, nicotinic acetylcholine receptor; NF-κB, nuclear factor kappa-B; NMDA, N-methyl-D-aspartate; OCT2, organic cation transporter 2; OCTN1, organic cation transporter novel type 1; PDE, phosphodiesterase; PI3K, phosphatidylinositol-3 kinase; PKC, protein kinase C; SOD, superoxide dismutase; S1P, sphingosine-1-phosphate; TAFI, thrombin-activatable fibrinolysis inhibitor; TNF-α, tumor necrosis factor-α; TREK-1, tandem pore domains in weak rectifying K+ channel (TWIK)-related K+ channel 1; TRPA1, transient receptor potential ankyrin 1; TRPM8, transient receptor potential melastatin 8; TRPV1, transient receptor potential vanilloid 1; VEGF, vascular endothelial growth factor.
Table 2. The therapeutic drugs for oxaliplati-induced peripheral neuropathy in clinical experiments.
Table 2. The therapeutic drugs for oxaliplati-induced peripheral neuropathy in clinical experiments.
Investigational DrugDoseChemotherapyStudy DesignPatient NumberSummaryReferences
Duloxetine60 mg/day
(30 mg/day for the first week)
Taxane or platinumRandomized, double-blind, placebo-controlled, cross-over231RRs (95% CI) of experiencing 30% and 50% pain reduction were 1.96 (1.15–3.35) and 2.43 (1.11–5.30), respectively.[148]
Calcium and magnesium Calcium gluconate, 1 g; magnesium sulfate, 1 g (pre- and post-oxaliplatin)OxaliplatinRandomized, double-blind, placebo-controlled102Significant improvements in incidence of ≥ Grade 2 neuropathy, oxaliplatin-specific scale, and acute muscle spasms[149]
Calcium gluconate, 1 g; magnesium sulfate, 1 g (pre- and post-oxaliplatin)OxaliplatinRandomized, double-blind, placebo-controlled139No significant differences in time to treatment discontinuation[150]
Calcium gluconate, 1 g; magnesium sulfate, 1 g (pre- and post-oxaliplatin, or pre-oxaliplatin)OxaliplatinRandomized, double-blind, placebo-controlled353No significant differences compared to placebo group[151]
Calcium gluconate, 1 g; magnesium sulfate, 1 g (pre- and post-oxaliplatin)OxaliplatinRandomized, double-blind, placebo-controlled, cross-over19No significant differences compared to placebo group[152]
N/AOxaliplatinMeta-analysis694No significant differences compared to control group
RRs (95% CI) of the incidence of ≥ Grade 2 neuropathy and ≥ Grade 1 chronic neuropathy were 0.81 (0.60–1.11) and 0.95 (0.69–1.32), respectively.
Goshajinkigan 7.5 g/dayOxaliplatinRandomized, controlled45Significant improvement in incidence of ≥ Grade 2 neuropathy compared control group[154]
7.5 g/dayOxaliplatinRandomized, double-blind, placebo-controlled93No significant differences compared to placebo group[155]
7.5 g/dayOxaliplatinRandomized, double-blind, placebo-controlled188Significant increase in incidence of ≥ Grade 2 neuropathy compared placebo group[156]
Alpha--lipoic acid1800 mg/dayCisplatin or oxaliplatinRandomized, double-blind, placebo-controlled243No significant differences compared to placebo group for FACT/GOG-Ntx scores, BPI scores, and patients’ functional outcomes.[157]
Vitamin E400 mg/dayOxaliplatinRandomized, controlled65No significant differences compared to control group[158]
N/APlatinum, taxane or othersMeta-analysis353No significant differences compared to control group
RR (95% CI) of incidence of neuropathy was 0.55 (0.29–1.05).
Glutathione1500 mg/m2OxaliplatinRandomized, double-blind, placebo-controlled52Significant improvements in incidence of ≥ Grade 2 neuropathy and neurophysiological findings compared placebo group[160]
Calmangafodipir2–10 µmol/kgOxaliplatinRandomized, controlled173Significant improvements in Leonard scale compared to control group[161]
Pregabalin150–600 mg/kgOxaliplatinRandomized, double-blind, placebo-controlled199No significant differences compared to placebo group in pain score[162]
Minocycline200 mg/dayOxaliplatinRandomized66No significant differences compared to control group[163]
Abbreviations: 95% CI, 95% confidence interval; FACT/GOG-NTx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; RR, relative risk.
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Kawashiri, T.; Mine, K.; Kobayashi, D.; Inoue, M.; Ushio, S.; Uchida, M.; Egashira, N.; Shimazoe, T. Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence. Int. J. Mol. Sci. 2021, 22, 1393.

AMA Style

Kawashiri T, Mine K, Kobayashi D, Inoue M, Ushio S, Uchida M, Egashira N, Shimazoe T. Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence. International Journal of Molecular Sciences. 2021; 22(3):1393.

Chicago/Turabian Style

Kawashiri, Takehiro, Keisuke Mine, Daisuke Kobayashi, Mizuki Inoue, Soichiro Ushio, Mayako Uchida, Nobuaki Egashira, and Takao Shimazoe. 2021. "Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence" International Journal of Molecular Sciences 22, no. 3: 1393.

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