• cisplatin;
  • mirtazapine;
  • neurotoxicity;
  • oxidative stress;
  • protective


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References


Cisplatin chemotherapy is associated with neurotoxicity, and oxidative stress might play an important role in the pathogenesis. Mirtazapine may be a preventative agent via its less-known antioxidant properties. The aim of this study was to examine the potential chemoprotective effects of mirtazapine against cisplatin-induced oxidative stress and DNA damage.


Twenty-four rats were divided equally into four groups: control; cisplatin (10 mg/kg i.p.); cisplatin plus mirtazapine (10–30 mg/kg, respectively i.p and p.o.); and mirtazapine (30 mg/kg p.o.). The rats were killed at the end of the 14th day of treatment. Brain tissue was examined with regard to antioxidant/oxidant biochemical parameters.


Although glutathione (tGSH) and nitric oxide (NO) end product mean scores were found to be statistically higher in the control group when compared with the cisplatin group (72.44% and 61.99% percentage change [PC], respectively), malondialdehyde (MDA), myeloperoxidase (MPO), and 8-hydroxyguanine (8-OH-GUA) mean scores were statistically lower in the control group in comparison with the cisplatin group (−55.48%, −67.99%, and −48.81% PC, respectively; P < 0.01). Finally, tGSH and NO end product levels were restored to normal (85.90% and 55.30% PC, respectively), and MDA, MPO, and 8-OH-GUA were significantly reduced by treatment with mirtazapine (−60.50%, −78.59%, and −38.10% PC, respectively; P < 0.01).


Mirtazapine has chemoprotective effects against cisplatin-induced oxidative stress and DNA damage in the rat brain, which may be attributed to its antioxidant capabilities. It would be useful to investigate whether cisplatin at the desired doses can be given concurrently with mirtazapine.

CISPLATIN IS ONE OF the most widely used and most effective cytotoxic agents in the treatment of a variety of malignancies, including lung, colorectal, ovarian, breast, head/neck, bladder, and testicular cancers in both children and adults.[1, 2] Similarly to other anti-cancer therapeutics, cisplatin treatment is associated with significant toxicities consisting of myelotoxicity, nephrotoxicity, neurotoxicity, and ototoxicity.[3] Nephro- and neurotoxicity, however, are the major side-effects of cisplatin treatment that hinder its use in the clinic. Neurotoxicity occurs in a dose-dependent manner, is cumulative, and arises in approximately 50% of patients receiving cisplatin.[4, 5] Cisplatin-mediated neurotoxicity is therefore a significant limitation to effective anti-cancer treatment because it may lead to dose reduction or even treatment withdrawal.[6] Therefore, effective strategies to reduce the severity of nerve damage following chemotherapy are intensively being searched for.

The chemotherapeutic mechanism of cisplatin is through DNA binding, inducing DNA damage that leads to apoptosis.[7] The classical target of cisplatin neurotoxicity has also been well established (i.e. dorsal root ganglia neurons). In addition, excitotoxic glutamate release, neuronal expression of copper transporter 1, interference with normal cell metabolism, formation of platinum-DNA-protein cross-links, polymorphisms in the DNA repair genes and, finally, activation of the Rho GTPases have all been found to be associated with cisplatin-induced neurotoxicity.[2, 8-12] Another possible, although less well-documented, common site of action of this compound is represented by mitochondria. Lately, evidence that mitochondrial dysfunction can be induced, probably through binding to mitochondrial DNA by cisplatin, has been reported.[13] Mitochondrial dysfunction here increases the oxidative stress, and oxidative stress plays an important role in the pathogenesis of cisplatin neurotoxicity.[14, 15] Moreover, several antioxidant treatments have been used successfully in order to prevent cisplatin-mediated neurotoxicity.[16-18] Some protective agents, however, may interfere with the anti-tumoral effects of cisplatin. New treatment strategies that do not interfere with the anti-neoplastic effects of cisplatin to limit cisplatin neurotoxicity are therefore always necessary.

In contrast, mirtazapine, as a noradrenergic and specific serotonergic antidepressant, may be a promising agent for the avoidance of cisplatin-induced neurotoxicity. Mirtazapine is used to treat major depressive disorder effectively in clinical psychiatric practice.[19] Mirtazapine also has a less-known additional feature of repression of the production of enzymatic and non-enzymatic oxidation indicators while increasing the antioxidant parameters. Mirtazapine has recently been reported to protect gastric tissue from the gastrotoxic effect of indomethacin via its antioxidant properties.[20] Furthermore, we recently found that mirtazapine ameliorated cisplatin-induced nephrotoxicity in rats.[21] These findings suggest that mirtazapine could be a cytoprotective agent, but no systematic data on the defensive effect of mirtazapine with regard to the cisplatin neurotoxicity have been reported to date. In the present study, we examined the potential chemoprotective effects of mirtazapine against cisplatin-induced oxidative stress and DNA damage in rat brains by biochemical methods.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References


Whole biochemical assay compounds were purchased from Sigma (Munich, Germany) and Merck (Darmstadt, Germany). Additionally, mirtazapine was bought from Merck Sharp and Dohme (Istanbul, Turkey), and cisplatin was obtained from Orna (Istanbul, Turkey).


All experiments were performed with 24 adult male Wistar Albino rats, each weighing 210–230 g. They were obtained from Ataturk University Experimental Animal Laboratory of Medicinal and Experimental Application and Research Centre. Care of the rats was in accordance with the ILAR/NRC Guide for the Care and Use of Laboratory Animals (2010 edition), and all procedures were also approved by the Ataturk University Local Animal Care Committee. The Ethics Committee of the Ataturk University Medical Faculty approved the whole study protocol. Rats were housed in standard plastic cages on sawdust bedding in an air-conditioned room at 22 ± 1°C under controlled lighting (14 h light/10 h dark cycle). Standard rat chow and tap water were given ad libitum. The rats were divided equally into four groups: control, cisplatin, cisplatin plus mirtazapine, and mirtazapine. The groups were separated in different cages.

Pharmacological procedures

The cisplatin plus mirtazapine group and the mirtazapine group were first given 30 mg/kg mirtazapine in distilled water by gastric gavage while the animals in the control and the cisplatin groups received solely distilled water in equal volume by the same route.[20] One hour after this procedure, 10 mg/kg cisplatin, which was dissolved in isotonic saline solution, was injected i.p. every day for 14 days into the animals in the cisplatin and the cisplatin plus mirtazapine groups, while the animals in the control and the mirtazapine groups were given only isotonic saline solution in equal volume on the same schedule.[22] All animals were killed by high-dose anesthesia (50 mg/kg thiopental sodium) at the end of the 14 days; their brains were removed quickly and analyzed for biochemistry as soon as possible.

The present study was carried out with a high dose of cisplatin (10 mg/kg body weight, i.p.) corresponding to the dose of cisplatin currently being used in clinical practice. The corresponding dose in human being (60 kg) is 30 mg/m2.[23] The onset of toxicity, however, is delayed in humans until a cumulative dose >300 mg/m2 has been given.[5] Therefore, we extended the treatment duration to guarantee induction of oxidative stress and, consequently, neurotoxicity. We also worked under exactly the same conditions (i.e. chemicals, animals, pharmacological procedures, biochemical procedures, laboratories, and staff) as in our previous nephrotoxicity study.[21]

Biochemical procedures


The amount of glutathione (tGSH) in the total homogenate was measured according to the method of Sedlak and Lindsay with some modifications.[24]

Nitric oxide end products

NO end product levels were measured using the Griess reaction[25, 26] with further biochemical techniques. The details of the procedure were described in one of our recent studies.[27]


The concentrations of lipid peroxidation were determined by estimating malondialdehyde (MDA) using the thiobarbituric acid test.[28]


Myeloperoxidase (MPO) activity was measured according to the method of Bradley et al.[29]


Brain tissue was drawn and DNA isolated using the modified method of Shigenaga et al.[30] Approximately 50 mg of DNA was hydrolyzed with 0.5 mL of formic acid (60%, v/v) for 45 min at 150°C.[31] The amount of 8-hydroxyguanine (8-OH-GUA) and GUA was measured using a high-performance liquid chromatography system equipped with an electrochemical detector (HP Agilent 1100 module series, ECD HP 1049A), as described previously.[31, 32] GUA and 8-OH-GUA (25 pmol) were used as standards. 8-OH-GUA level is expressed as the number of 8-OH-GUA molecules/105 GUA molecules.[33] 8-OH-GUA is a marker of oxidative DNA damage here.

Statistical analysis

Statistical evaluation was performed using SPSS (Chicago, IL, USA) v18.0 for Windows. The data were analyzed using analysis of variance (ANOVA) followed by post-hoc Bonferroni tests when comparing the four groups. Statistical significance was set at P < 0.01.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

On ANOVA it was found that levels of tGSH, NO end products, MDA, MPO, and 8-OH-GUA significantly differed across groups (Table 1). Findings obtained with the Bonferroni multiple comparison tests were as follows. tGSH was lower in the cisplatin group than the control group, the cisplatin plus mirtazapine group, and the mirtazapine group (72.44%, 85.90%, and 90.06% percentage changes [PC], respectively). Similarly, the level of NO end products were higher in the control group, the cisplatin plus mirtazapine group, and the mirtazapine group (61.99%, 55.30%, and 62.77% PC, respectively). MDA level was higher in the cisplatin group than the control group, the cisplatin plus mirtazapine group, and the mirtazapine group (−55.48%, −60.50%, and −56.37% PC, respectively). MPO level was higher in the cisplatin group than the control group, the cisplatin plus mirtazapine group, and the mirtazapine group (−67.99%, −78.59%, and −79.69% PC, respectively). In order from high to low MPO level, the groups were: cisplatin, control group, and cisplatin plus mirtazapine. MPO level did not differ within the cisplatin plus mirtazapine group and the mirtazapine-alone group. Finally, 8-OH-GUA level was higher in the cisplatin group than the control group, the cisplatin plus mirtazapine group, and the mirtazapine group (−48.81%, −38.10%, and −49.40% PC, respectively). The level of 8-OH-GUA in both the control and mirtazapine groups was lower than in the cisplatin group and the cisplatin plus mirtazapine group. The combination cisplatin–mirtazapine group had significantly lower 8-OH-GUA than the cisplatin group.

Table 1. Biochemical parameters (one-way ANOVA) vs group
 Control (A)Cisplatin (B)Cisplatin plus mirtazapine (C)Mirtazapine (D)   
MeanSDMeanSDMeanSDMeanSDF(3, 20)PPost-hoca
  1. a

    Bonferroni multiple comparison test. 8-OH-GUA, 8-hydroxyguanine; MDA, malondialdehyde; MPO, myeloperoxidase; NO, nitric oxide; tGSH, glutathione.

tGSH5.380.283.120.345.800.615.931.1557.9280.000A = C = D > B
NO end products10.400.496.420.199.970.5610.450.42117.7090.000A = C = D > B
MDA2.480.265.570.312.200.292.430.22208.7890.000B > A = C = D
MPO1.450.194.530.330.970.210.920.17334.8490.000B > A > C = D
8-OH-GUA0.860.071.680. > C > A = D


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The continued clinical use of cisplatin is limited by the onset of severe neurotoxicity.[34] Cisplatin-induced neurotoxicity is associated with histological damages and behavioral alterations.[35-38] Neurotoxicity has been observed in approximately 50% of patients treated with cisplatin.[5] A great effort has been made to resolve this issue with regard to optimal dose and duration, especially in recent years. For this purpose, various methods have been investigated to prevent the neurotoxic side-effects of cisplatin. Among the compounds with potential neurotrophic action, several antioxidants have shown a great range of neuroprotective effects both in vitro and in vivo.[16-18] Although the exact mechanism of cisplatin-induced neurotoxicity is still not completely understood, however, there is general agreement that it depends on the induction of apoptosis in neuronal cells.[39] Presumably, irreversible cell damage and apoptosis might result mainly from oxidative stress.[40] Therefore, trials of antioxidant supplements in cisplatin-induced neurotoxicity have been carried out.

The previous success of antioxidants in this area, however, also supports a central role of oxidative stress in the pathogenesis of cisplatin-mediated neurotoxicity indirectly. In line with this inference, we found that although the tGSH and NO end product mean scores were significantly decreased, MDA and MPO mean scores were statistically higher in the cisplatin group when compared with the control group. tGSH here plays an important role in a number of critical cellular processes, including providing the major line of defense for the protection of cells from oxidative and other forms of stress. tGSH can scavenge free radicals, reduce peroxides and be conjugated with electrophilic compounds. It thereby provides cells with multiple defenses against both reactive oxygen species (ROS) and their toxic by-products.[41] It has also been demonstrated that cisplatin induces cell death, which is characterized by reduced tGSH level, which is suggestive of accelerated oxidative processes not only in the brain, but also in other tissues previously.[15, 21, 42-45] When cisplatin enters cells, adduct formation between cisplatin and tGSH can occur, and tGSH may decrease as a consequence.[46]

In the last decade, among signal molecules interest has grown in NO in the central nervous system (CNS) due to NO involvement in the maintenance and regulation of normal neuronal processes, including those related to the toxic conditions. NO has also been suggested to play an important role in cisplatin-induced cytotoxicity. Similarly, cisplatin has been shown to cause a decrease of NO activity in various tissues, as well as in the brain.[47-49] In the mammalian CNS, the NO-producing enzyme, that is, neuronal nitric oxide synthase (nNOS), is Ca2+/calmodulin dependent. Previously, a direct interaction between hydrolyzed forms of cisplatin and the calcium-binding sites of the calmodulin molecule in the stomach of the rat has been demonstrated: this interaction, indirectly, inhibited nNOS activity in the pyloric sphincter.[50] We may deduce that a similar mechanism may also compromise the nNOS activity of the brain in cisplatin-treated rats, resulting in a decrease in the level of NO end products. In line with this inference, Kim et al. showed that the expression of nNOS decreased in the renal inner medulla following treatment of cisplatin.[51] The selective downregulation of nNOS here may play a role in decreased medullary blood flow and secondary tissue injury. In addition, l-arginine, the precursor of NO in the body, attenuates cisplatin-induced nephrotoxicity, and a competitive inhibitor of NOS, NG-nitro-l-arginine methyl ester hydrochloride (l-NAME), exacerbates cisplatin-induced nephrotoxicity.[52, 53] In contrast, l-NAME and 7-nitroindazole, a nNOS inhibitor, have also been shown to significantly suppress oxaliplatin-induced pain behavior in rats.[54] But another possible, although probably less pronounced, explanation is that the expression and/or activity of brain inducible nitric oxide synthase (iNOS) compared with kidney iNOS did not reach the expected level even under these oxidative stress conditions induced by cisplatin treatment. Therefore, both beneficial and toxic effects of NO have been suggested in cisplatin-induced cytotoxicities, and the exact role of NO in these experimental models remains controversial. Further studies are needed in order to confirm the present findings.

MDA is one of the end products of lipid peroxidation and an indicator of ROS production. Therefore, an increase in MDA tissue level indicates an increase in free oxygen radicals.[55] The most important and damaging cellular effect of free radicals is lipid peroxidation. MDA in its turn causes more advanced cellular injury. Cisplatin treatment can cause marked organ damage, characterized by a significant increase in tissue MDA level compared to normal control.[21, 56-60] In summary, elevation of MDA in different tissues seems to be a result of the direct peroxidative effect of cisplatin use.

Similarly, cisplatin injections caused significant elevation in tissue MPO activities compared to control values.[21, 61-63] MPO is found in phagocytic cells. As an enzyme, MPO catalyses the production of the highly chlorinating and oxidizing agent hypochlorous acid from chloride and peroxide, which reacts with the low-density lipoprotein apoprotein moiety, leading to the derivatization of its aminoacid residues. Therefore, excess production of MPO and other reactive radicals causes oxidative damage. Additionally, it is also used as an indication of tissue neutrophil accumulation.[64] In all these contexts, alteration of MPO activity might be associated with increased neurotoxicity.

To our knowledge, we have shown that brain tissue 8-OH-GUA level was increased in the rat cisplatin group in comparison to the rat control group for the first time in the literature. ROS are known to induce several types of oxidative DNA damage, including 8-OH-GUA.[65] Notably, aforementioned recent studies indicated that cisplatin acted as a pro-oxidant. Therefore, we can speculate that 8-OH-GUA accumulation in the brain tissue reflects an imbalance between DNA damage and repair. In short, the disturbance of DNA repair enhances the accumulation of 8-OH-GUA. The overproduction of 8-OH-GUA is also thought to be responsible for apoptosis.[66] In summary, cisplatin exerts its neurotoxic effects via oxidative stress predominantly. All of the previous antioxidant therapies, however, have not been able to achieve good results in the fight against cisplatin neurotoxicity.

Three main features of the possible defending antioxidant agents came into prominence during these studies. First, because the anti-tumoral properties of cisplatin originate mainly from its binding to DNA, which causes significant distortion of the helical structure and results in the inhibition of DNA replication and transcription, some of the protective molecules that disrupt this special relationship might also reduce the anticancer qualities of cisplatin.[67] For instance, Fischer et al. showed that cisplatin binds rapidly to dimethyl sulfoxide (DMSO) to form a DMSO adduct.[68] The resulting compound has a reduced ability to bind to double-stranded DNA both in vitro and in cells. This compound has reduced toxicity for both cancer cells and neurons in vitro. Additionally, cisplatin also induces apoptosis via activation of caspase 3.[69-72] Caspase 3 can be activated by caspase 9, which is activated by the release of cytochrome c from the mitochondria.[73, 74] Thiol-based antioxidants such as sodium thiosulfate block these apoptotic pathways induced by cisplatin and decrease anti-tumor efficacy while protecting against neurotoxicity.[75] Second, although the platinum drugs have poor penetration through the blood–brain barrier, levels of cisplatin have been shown to be sufficient to cause toxicity in the brain. For example, although CNS toxicity associated with cisplatin chemotherapy is characterized by acute encephalopathy, stroke-like episodes, acute blindness, and seizures in humans, it has been shown that use of systemic cisplatin in mice is associated with increased cell death and decreased cell division in the subventricular zone, in the dentate gyrus of the hippocampus, and in the corpus callosum of the CNS.[2, 76, 77] For this reason, the antioxidant compounds should cross blood–brain barrier so that the drug can be given peripherally in the treatment of neurotoxicity. Third, of course, protective antioxidant molecules are expected not to be toxic. For instance, Church et al. found that although high doses of amifostine provided the beneficial effect of protecting against cisplatin-induced ototoxicity, it had the harmful side-effect of neurotoxicity.[78] Thus, new treatment alternatives that do not interfere with the anti-neoplastic effects of cisplatin; are not stopped by the blood–brain barrier; and have not their own toxic side-effects to limit cisplatin-mediated neurotoxicity are always needed.

For this purpose, we have preferred to use mirtazapine for its possible protective effects against oxidant stress due to cisplatin treatment in the present study. The results showed that brain antioxidant defense systems, such as tGSH and NO end products that are depleted by cisplatin therapy, were restored to normal by treatment with mirtazapine. Cisplatin-induced lipid peroxidation, that is, MDA level, was also found to be markedly reduced by treatment with mirtazapine. Furthermore, mirtazapine decreased leukocyte/macrophage infiltration in rat brain tissue considerably (i.e. activity of MPO). And finally, mirtazapine ameliorated DNA damage (significant decline in 8-OH-GUA level), indicating that damage was probably mediated by the oxidative stress. Bilici et al. recently investigated the anti-ulcer effects of mirtazapine and determined its relationship with antioxidant mechanisms.[20] In agreement with the present findings, they found that although mirtazapine treatment significantly increased tGSH in the stomach tissue compared to the control, the gastric MDA and MPO levels significantly decreased with mirtazapine therapy in comparison with distilled water. We investigated a possible role of oxidative stress in the pathogenesis of cisplatin-induced nephrotoxicity and tested the potential protective effects of mirtazapine against this harmful side-effect in rat kidneys by biochemical and histological methods.[21] While tGSH level was restored to normal, MDA and MPO levels were again significantly reduced by treatment with mirtazapine. In this context, activation of enzymatic and non-enzymatic antioxidant mechanisms and inhibition of some toxic oxidant mechanisms might also have a role in the defense of mirtazapine against cisplatin neurotoxicity. The latter fact, however, does not mean that the neuroprotective effect of mirtazapine is due to a single mechanism of action. Mirtazapine also blocks 5-hydroxytriptamine2/3 (5-HT2/3) receptors specifically and blockade of these receptors may contribute to the protective properties of mirtazapine, because some of the substance-induced neurotoxicities are mediated via 5-HTergic transmission involving 5-HT2/3 receptors.[56, 79-81] Interestingly, the MPO mean score of the cisplatin plus mirtazapine group was statistically lower than the control group. The MPO-reducing effect of mirtazapine might be explained by its potent antioxidant properties, as shown in previous studies.[20, 82] We also found a significant difference between the control group and the cisplatin plus mirtazapine group for 8-OH-GUA. Therefore, the 8-OH-GUA mean score of the control group was higher than the cisplatin plus mirtazapine group. Surely, mirtazapine could not prevent the entire DNA damage via its antioxidant and 5-HT2/3 receptor antagonistic qualities, because the anti-neoplastic mechanism of cisplatin is through DNA binding, inducing DNA damage, and mirtazapine does not have a special effect on this relationship.[7] Also, mirtazapine also reduces nausea, anorexia, sleep disturbance, as well as depression in cancer patients.[83-86] All these positive effects might provide a new indication for mirtazapine, and it might become one of the first-choice drugs in depressive patients receiving cisplatin chemotherapy.

In summary, the present results suggest that although oxidative stress plays a central role in the pathogenesis of cisplatin-mediated neurotoxicity, mirtazapine has protective effects against this severe situation, which may be attributed to its antioxidant and 5-HT2/3 receptor antagonistic potentials. Mirtazapine might also be a cytoprotective agent and therefore it would be useful to investigate whether cisplatin at the desired doses can be given concurrently with mirtazapine in the absence of other considerations. We were unable, however, to compare the present findings with others because no other experimental study in the literature has yet investigated the protective effects of mirtazapine on cisplatin-induced neurotoxicity in rat brain. Demonstration of the possible histological and/or behavioral benefits of reducing oxidative stress with mirtazapine is advisable in the future. In contrast, large-scale prospective studies that examine the association between cisplatin neurotoxicity and the protective effects of mirtazapine are also needed in order to confirm the present findings in humans.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We report no conflict of interest and thank Research Assistant Murat Boysan, and Associate Professor Hamit Acemoglu for support with statistical analysis.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Cerri S, Piccolini VM, Santin G et al. The developmental neurotoxicity study of platinum compounds. Effects of cisplatin versus a novel Pt(II) complex on rat cerebellum. Neurotoxicol. Teratol. 2011; 33: 273281.
  • 2
    McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol. Cancer Ther. 2009; 8: 1016.
  • 3
    Joseph D, Dubashi B, Karthikeyan B, Jain A. Arterial occlusion precipitated by cisplatin based chemotherapy. Curr. Oncol. 2010; 17: 7172.
  • 4
    Lee KW, Jeong JY, Lim BJ et al. Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. Toxicology 2009; 257: 137143.
  • 5
    Amptoulach S, Tsavaris N. Neurotoxicity caused by the treatment with platinum analogues. Chemother. Res. Pract. 2011; 2011: 15.
  • 6
    Nowis D, Legat M, Bil J et al. Erythropoietin reduces cisplatin-induced neurotoxicity without impairment of cytotoxic effects against tumor cells. Int. J. Oncol. 2007; 31: 15471552.
  • 7
    Podratz JL, Staff NP, Froemel D et al. Drosophila melanogaster: A new model to study cisplatin-induced neurotoxicity. Neurobiol. Dis. 2011; 43: 330337.
  • 8
    Carozzi VA, Chiorazzi A, Canta A et al. Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. Neurotox. Res. 2010; 17: 380391.
  • 9
    Liu JJ, Jamieson SM, Subramaniam J et al. Neuronal expression of copper transporter 1 in rat dorsal root ganglia: Association with platinum neurotoxicity. Cancer Chemother. Pharmacol. 2009; 64: 847856.
  • 10
    Bernocchi G, Bottone MG, Piccolini VM et al. Developing central nervous system and vulnerability to platinum compounds. Chemother. Res. Pract. 2011; 2011: 114.
  • 11
    Vilmar A, Santoni-Rugiu E, Sørensen JB. ERCC1, toxicity and quality of life in advanced NSCLC patients randomized in a large multicentre phase III trial. Eur. J. Cancer 2010; 46: 15541562.
  • 12
    James SE, Dunham M, Carrion-Jones M, Murashov A, Lu Q. Rho kinase inhibitor Y-27632 facilitates recovery from experimental peripheral neuropathy induced by anti-cancer drug cisplatin. Neurotoxicology 2010; 31: 188194.
  • 13
    Carozzi V, Chiorazzi A, Canta A et al. Effect of the chronic combined administration of cisplatin and paclitaxel in a rat model of peripheral neurotoxicity. Eur. J. Cancer 2009; 45: 656665.
  • 14
    Hino K, Nishikawa M, Sato E, Inoue M. L-carnitine inhibits hypoglycemia-induced brain damage in the rat. Brain Res. 2005; 1053: 7787.
  • 15
    Altun ZS, Gunes D, Aktas S, Erbayraktar Z, Olgun N. Protective effects of acetyl-L-carnitine on cisplatin cytotoxicity and oxidative stress in neuroblastoma. Neurochem. Res. 2010; 35: 437443.
  • 16
    Gunes D, Kirkim G, Kolatan E et al. Evaluation of the effect of acetyl L-carnitine on experimental cisplatin ototoxicity and neurotoxicity. Chemotherapy 2011; 57: 186194.
  • 17
    Maggioni D, Nicolini G, Chiorazzi A, Meregalli C, Cavaletti G, Tredici G. Different effects of erythropoietin in cisplatin- and docetaxel-induced neurotoxicity: An in vitro study. J. Neurosci. Res. 2010; 88: 31713179.
  • 18
    Tuncer S, Dalkilic N, Akif Dunbar M, Keles B. Comparative effects of alpha lipoic acid and melatonin on cisplatin-induced neurotoxicity. Int. J. Neurosci. 2010; 120: 655663.
  • 19
    Gulec M, Selvi Y, Boysan M, Aydin A, Besiroglu L, Agargun MY. Ongoing or re-emerging subjective insomnia symptoms after full/partial remission or recovery of major depressive disorder mainly with the selective serotonin reuptake inhibitors and risk of relapse or recurrence: A 52-week follow-up study. J. Affect. Disord. 2011; 134: 257265.
  • 20
    Bilici M, Ozturk C, Dursun H et al. Protective effect of mirtazapine on indomethacin-induced ulcer in rats and its relationship with oxidant and antioxidant parameters. Dig. Dis. Sci. 2009; 54: 18681875.
  • 21
    Sener MT, Sener E, Tok A et al. Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine. Pharmacol. Rep. 2012; 64: 594602.
  • 22
    Gaona-Gaona L, Molina-Jijon E, Tapia E et al. Protective effect of sulforaphane pretreatment against cisplatin-induced liver and mitochondrial oxidant damage in rats. Toxicology 2011; 286: 2027.
  • 23
    Ajith TA, Nivitha V, Usha S. Zingiber officinale Roscoe alone and in combination with alpha-tocopherol protect the kidney against cisplatin-induced acute renal failure. Food Chem. Toxicol. 2007; 45: 921927.
  • 24
    Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal. Biochem. 1968; 25: 192205.
  • 25
    Bories PN, Bories C. Nitrate determination in biological fluids by an enzymatic one-step assay with nitrate reductase. Clin. Chem. 1995; 41: 904907.
  • 26
    Moshage H, Kok B, Huizenga JR, Jansen PL. Nitrite and nitrate determinations in plasma: A critical evaluation. Clin. Chem. 1995; 41: 892896.
  • 27
    Polat B, Suleyman H, Alp HH. Adaptation of rat gastric tissue against indomethacin toxicity. Chem. Biol. Interact. 2010; 186: 8289.
  • 28
    Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 1979; 95: 351358.
  • 29
    Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. J. Invest. Dermatol. 1982; 78: 206209.
  • 30
    Shigenaga MK, Aboujaoude EN, Chen Q, Ames BN. Assays of oxidative DNA damage biomarkers 8-oxo-2'-deoxyguanosine and 8-oxoguanine in nuclear DNA and biological fluids by high-performance liquid chromatography with electrochemical detection. Methods Enzymol. 1994; 234: 1633.
  • 31
    Kaur H, Halliwell B. Measurement of oxidized and methylated DNA bases by HPLC with electrochemical detection. Biochem. J. 1996; 318 (Pt 1): 2123.
  • 32
    Floyd RA, Watson JJ, Wong PK, Altmiller DH, Rickard RC. Hydroxyl free radical adduct of deoxyguanosine: Sensitive detection and mechanisms of formation. Free Radic. Res. Commun. 1986; 1: 163172.
  • 33
    Asami S, Hirano T, Yamaguchi R, Tomioka Y, Itoh H, Kasai H. Increase of a type of oxidative DNA damage, 8-hydroxyguanine, and its repair activity in human leukocytes by cigarette smoking. Cancer Res. 1996; 56: 25462549.
  • 34
    Cavaliere R, Schiff D. Neurologic toxicities of cancer therapies. Curr. Neurol. Neurosci. Rep. 2006; 6: 218226.
  • 35
    Al Moundhri MS, Al-Salam S, Al Mahrouqee A, Beegam S, Ali BH. The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: Some behavioral, biochemical, and histopathological studies. J. Med. Toxicol. 2012. doi: 10.1007/s13181-012-0239-x.
  • 36
    Arrieta Ó, Hernández-Pedro N, Fernández-González-Aragón MC et al. Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer. Neurology 2011; 77: 987995.
  • 37
    Canta A, Chiorazzi A, Carozzi V et al. In vivo comparative study of the cytotoxicity of a liposomal formulation of cisplatin (lipoplatin™). Cancer Chemother. Pharmacol. 2011; 68: 10011008.
  • 38
    Carozzi VA, Canta A, Oggioni N et al. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. Exp. Neurol. 2010; 226: 301309.
  • 39
    Scuteri A, Galimberti A, Maggioni D et al. Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology 2009; 30: 312319.
  • 40
    Kim HJ, Lee JH, Kim SJ et al. Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity. J. Neurosci. 2010; 30: 39333946.
  • 41
    Maher P. The effects of stress and aging on glutathione metabolism. Ageing Res. Rev. 2005; 4: 288314.
  • 42
    Martins NM, Santos NA, Curti C, Bianchi ML, Santos AC. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J. Appl. Toxicol. 2008; 28: 337344.
  • 43
    Rjiba-Touati K, Ayed-Boussema I, Belarbia A, Achour A, Bacha H. Recombinant human erythropoietin prevents cisplatin-induced genotoxicity in rat liver and heart tissues via an antioxidant process. Drug Chem. Toxicol. 2012; 35: 134140.
  • 44
    Sohn SI, Rim HK, Kim YH et al. The ameliorative effect of 23-hydroxytormentic acid isolated from Rubus coreanus on cisplatin-induced nephrotoxicity in rats. Biol. Pharm. Bull. 2011; 34: 15081513.
  • 45
    Ilbey YO, Ozbek E, Cekmen M, Simsek A, Otunctemur A, Somay A. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: Mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum. Reprod. 2009; 24: 17171725.
  • 46
    Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp. Toxicol. Pathol. 2009; 61: 223242.
  • 47
    Azambuja AA, Lunardelli A, Nunes FB et al. Effect of fructose-1,6-bisphosphate on the nephrotoxicity induced by cisplatin in rats. Inflammation 2011; 34: 6771.
  • 48
    Mansour HH, Hafez HF, Fahmy NM. Silymarin modulates cisplatin-induced oxidative stress and hepatotoxicity in rats. J. Biochem. Mol. Biol. 2006; 39: 656661.
  • 49
    Pisu MB, Guioli S, Conforti E, Bernocchi G. Signal molecules and receptors in the differential development of cerebellum lobules. Acute effects of cisplatin on nitric oxide and glutamate systems in Purkinje cell population. Brain Res. Dev. Brain Res. 2003; 145: 229240.
  • 50
    Jarve RK, Aggarwal SK. Cisplatin-induced inhibition of the calcium-calmodulin complex, neuronal nitric oxide synthase activation and their role in stomach distention. Cancer Chemother. Pharmacol. 1997; 39: 341348.
  • 51
    Kim CS, Choi JS, Park JW et al. Altered regulation of nitric oxide and natriuretic peptide system in cisplatin-induced nephropathy. Regul. Pept. 2012; 174: 6570.
  • 52
    Saleh S, El-Demerdash E. Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide. Basic Clin. Pharmacol. Toxicol. 2005; 97: 9197.
  • 53
    Pourahmad J, Hosseini MJ, Eskandari MR, Shekarabi SM, Daraei B. Mitochondrial/lysosomal toxic cross-talk plays a key role in cisplatin nephrotoxicity. Xenobiotica 2010; 40: 763771.
  • 54
    Mihara Y, Egashira N, Sada H et al. Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Mol. Pain 2011; 7: 8.
  • 55
    Pan H, Mukhopadhyay P, Rajesh M et al. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J. Pharmacol. Exp. Ther. 2009; 328: 708714.
  • 56
    Ilbey YO, Ozbek E, Simsek A, Otunctemur A, Cekmen M, Somay A. Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil. Steril. 2009; 92: 11241132.
  • 57
    El-Awady el SE, Moustafa YM, Abo-Elmatty DM, Radwan A. Cisplatin-induced cardiotoxicity: mechanisms and cardioprotective strategies. Eur. J. Pharmacol. 2011; 650: 335341.
  • 58
    Karadeniz A, Simsek N, Karakus E et al. Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin. Oxid. Med. Cell. Longev. 2011; 2011: 110.
  • 59
    Sahu BD, Rentam KK, Putcha UK, Kuncha M, Vegi GM, Sistla R. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. Food Chem. Toxicol. 2011; 49: 30903097.
  • 60
    Song TY, Chen CL, Liao JW, Ou HC, Tsai MS. Ergothioneine protects against neuronal injury induced by cisplatin both in vitro and in vivo. Food Chem. Toxicol. 2010; 48: 34923499.
  • 61
    Muthuraman A, Singla SK, Peters A. Exploring the potential of flunarizine for cisplatin-induced painful uremic neuropathy in rats. Int. Neurourol. J. 2011; 15: 127134.
  • 62
    Ozkol H, Musa D, Tuluce Y, Koyuncu I. Ameliorative influence of Urtica dioica L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma. Drug Chem. Toxicol. 2012; 35: 251257.
  • 63
    Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Perez-Barriocanal F, Morales AI, Lopez-Novoa JM. Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity. Nephrol. Dial. Transplant. 2011; 26: 34843495.
  • 64
    Iseri S, Ercan F, Gedik N, Yuksel M, Alican I. Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology 2007; 230: 256264.
  • 65
    Kizek R, Adam V, Hrabeta J et al. Anthracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances. Pharmacol. Ther. 2012; 133: 2639.
  • 66
    Hirano T, Kawai K, Ootsuyama Y, Orimo H, Kasai H. Detection of a mouse OGG1 fragment during caspase-dependent apoptosis: Oxidative DNA damage and apoptosis. Cancer Sci. 2004; 95: 634638.
  • 67
    Kostova I. Platinum complexes as anticancer agents. Recent Pat. Anticancer Drug Discov. 2006; 1: 122.
  • 68
    Fischer SJ, Benson LM, Fauq A, Naylor S, Windebank AJ. Cisplatin and dimethyl sulfoxide react to form an adducted compound with reduced cytotoxicity and neurotoxicity. Neurotoxicology 2008; 29: 444452.
  • 69
    Bulat N, Widmann C. Caspase substrates and neurodegenerative diseases. Brain Res. Bull. 2009; 80: 251267.
  • 70
    Ludwig T, Oberleithner H. Platinum complex toxicity in cultured renal epithelia. Cell. Physiol. Biochem. 2004; 14: 431440.
  • 71
    Siddik ZH. Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22: 72657279.
  • 72
    Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J. Pharmacol. Exp. Ther. 2005; 312: 424431.
  • 73
    Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J. Biol. Chem. 2000; 275: 73377342.
  • 74
    Zhan Y, van de Water B, Wang YP, Stevens JL. The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells. Oncogene 1999; 18: 65056512.
  • 75
    Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J. Pharmacol. Exp. Ther. 2005; 314: 10521058.
  • 76
    Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 2006; 5: 22.
  • 77
    Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother. Pharmacol. 2009; 63: 761767.
  • 78
    Church MW, Blakley BW, Burgio DL, Gupta AK. WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes neurotoxicity in hamsters: Dose-dependent effects. J. Assoc. Res. Otolaryngol. 2004; 5: 227237.
  • 79
    Ago Y, Nakamura S, Baba A, Matsuda T. Neuropsychotoxicity of abused drugs: Effects of serotonin receptor ligands on methamphetamine- and cocaine-induced behavioral sensitization in mice. J. Pharmacol. Sci. 2008; 106: 1521.
  • 80
    Maurya AN, Deshpande SB. Involvement of 5-hydroxytryptaminergic transmission for the Mesobuthus tamulus venom-induced depression of spinal reflexes in neonatal rat in vitro. Neurosci. Lett. 2010; 482: 3539.
  • 81
    Yamamura S, Abe M, Nakagawa M, Ochi S, Ueno S, Okada M. Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions. Neuropharmacology 2011; 60: 550560.
  • 82
    Tok A, Sener E, Albayrak A et al. Effect of mirtazapine on oxidative stress created in rat kidneys by ischemia-reperfusion. Ren. Fail. 2012; 34: 103110.
  • 83
    Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N. Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: Superiority over imipramine. Support. Care Cancer 2008; 16: 12911298.
  • 84
    Ersoy MA, Noyan AM, Elbi H. An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Clin. Drug Investig. 2008; 28: 113120.
  • 85
    Kim SW, Shin IS, Kim JM et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin. Neurosci. 2008; 62: 7583.
  • 86
    Riechelmann RP, Burman D, Tannock IF, Rodin G, Zimmermann C. Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Am. J. Hosp. Palliat. Care 2010; 27: 106110.