Cisplatin-induced Neurotoxicity Research Articles

The Ameliorative Effects of Naringin on Cisplatin-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

The Ameliorative Effects of Naringin on Cisplatin-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Exercise alleviates cisplatin-induced toxicity in the hippocampus of mice by inhibiting neuroinflammation and improving synaptic plasticity.

Chemotherapy-induced cognitive impairment is recognized as the most typical symptom in patients with cancer that occurs during and following the chemotherapy treatment. Recently many studies focused on pharmaceutical strategies to control the chemotherapy side effects, however it is far from satisfactory. There may be a need for more effective treatment options. The aim of this study was to investigate the protective effect of exercise on cisplatin-induced neurotoxicity. Eightweek- old C57BL6 mice were separated into three group: normal control (CON, n = 8); cisplatin injection control (Cis-CON, n = 8); cisplatin with aerobic exercise (Cis-EXE, n = 8). Cisplatin was administered intraperitoneally at a dose of 3.5 mg/kg/day. The Cis-EXE group exercise by treadmill running (14-16 m/min for 45 min daily, 3 times/ week) for 12 weeks. Compared to the CON group, the cisplatin injection groups showed significant decrease in body weight and food intake, indicating successful induction of cisplatin toxicity. The Cis-CON group showed significantly increased levels of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α in the hippocampus, while the Cis-EXE group was significantly decreased in the expression of IL- 6, IL-1β, and TNF-α. In addition, compared to the CON group, the levels of synapserelated proteins including synapsin-1 and -2 were significantly reduced in the Cis- CON group, and there was a significant difference between the Cis-CON and Cis-EXE groups. Antioxidant and apoptosis factors were significantly improved in the Cis-EXE group compared with the Cis-CON group. This study suggest that exercise could be meaningful approach to prevent or improve cisplatin-induced cognitive impairment.

Protective effect of Galantamine on attenuating Cisplatin-induced Neurotoxicity: An In-vitro and In-vivo approach

Galantamine is a drug of choice for the treatment of Alzheimer's disease and possesses antioxidant, anti-inflammatory and cholinomimetic as non-FDA-approved indications. This study designed to explore the impact of Galantamine to attenuate cisplatin-induced neurotoxicity and oxidative stress. Experimental animals were segregated into five groups viz-a-viz group I as normal control, II as cisplatin control, and III-V as galantamine at varying doses, low (2.5mg/kg), medium (5mg/kg) and higher (10mg/kg). All the samples were orally administered, daily for 14 days. Cisplatin was injected intraperitoneally on day 8 to all groups except normal control. Assessment of neurotoxicity was done by measurement of a balance of antioxidant (GSH, SOD) and pro-oxidant (MDA), histopathological investigations. Dose-dependent significant (p<0.05) reduction in neurotoxicityhas been found by galantamine with reduction (p<0.01) in oxidant stress markers. Pronouncedreduction in apoptosis and elevation of disturbed hematological, and biochemical alterations were also observed with significance of p<0.001 in galantamine groups. We have observed that galantaminedose-dependentlyattenuates neurotoxicity, and oxidative stress, reversed the histopathological alterations and inhibits activated pro-inflammatory mediators (TNF-α). The research work provides drug repurposing of galantamine and providespreliminary ground for the treatment and management of cisplatin-induced neurotoxicity towards the clinical domain.

NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA

Abstract Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.

Synergetic impact of combined navoximod with cisplatin mitigates chemo-immune resistance via blockading IDO1+ CAFs-secreted Kyn/AhR/IL-6 and pol ζ-prevented CIN in human oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most prevalent aggressive form of HNSC and treated with platinum-based chemotherapy as initial therapy. However, the development of acquired resistance and neurotoxicity to platinum agents poses a significant challenge to treat locally advanced OSCC. Notably, IDO1+ CAFs could promote immunosuppressive TME for OSCC progression. Therefore, we developed a potent IDO1 inhibitor navoximod to overcome chemo-immune resistance via an antitumor immune effect synergized with cisplatin in SCC-9 co-cultured IDO1+/IDO1− CAFs and SCC-7/IDO1+ CAFs-inoculated mice. The in vitro biological assays on IDO1+ CAFs co-cultured OSCC cancer cells supported that combined navoximod with cisplatin could mitigate chemo-immune resistance through blockading IDO1+ CAFs-secreted kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-IL-6 via suppressing p-STAT3/NF-κB signals and ceasing AhR-induced loss of pol ζ-caused chromosomal instability (CIN). Moreover, the combination elicited antitumor immunity via reducing IDO1+ CAFs-secreted Kyn/AhR and conferring pol ζ in SCC-7/IDO1+ CAFs-inoculated BALB/c mice. Meanwhile, the combination could block cisplatin-induced neurotoxicity and not interfere with chemotherapy. Taken together, the study investigated the promising therapeutic potential of combined navoximod with cisplatin to mitigate tumoral immune resistance via alleviating IDO1+ CAFs-secreted immune-suppression and CIN-caused cisplatin resistance, providing a paradigm for combined chemo-immunotherapy to prolong survival in patients with OSCC.

Integrated in vivo and in silico evaluation of sweet basil oil as a protective agent against cisplatin-induced neurotoxicity in mice

BackgroundCisplatin is a wide-ranging antineoplastic drug. Neurotoxicity is one of cisplatin’s side effects that restrict its usage. This study aimed to investigate the possible protective properties of sweet basil oil against cisplatin-induced neurotoxicity in mice. A docking study was carried out to elucidate the fundamental mechanism of sweet basil oil’s ameliorative influence. Thirty male mice were allocated into three groups as follows: control group, cisplatin group (2.3 mg/kg), and sweet basil oil group (25 µl/kg basil oil + cisplatin 2.3 mg/kg). Cisplatin was given for five successive days, followed by five days of rest, for two cycles, while sweet basil oil was orally administered for 21 successive days.ResultsOur results revealed that sweet basil oil’s antioxidant activity ameliorated the oxidative stress induced by cisplatin in mice’s brains via lowering MDA levels and increasing CAT activity and Nrf2 levels. Also, the anti-apoptotic activity of sweet basil oil was obvious via lowering the gene expression levels of Bid and caspase-3 but did not affect the serum level of P38 MAPK. Changes in acetylcholinesterase activity, serotonin and dopamine levels induced by cisplatin were significantly alleviated by sweet basil oil.ConclusionSweet basil oil can be used as a food supplement to guard against cisplatin-induced neurotoxicity.Graphical abstract

Sea urchin (Diadema savignyi) extract as a novel protective agent against cisplatin induced neurotoxicity in rats

Neurotoxicity is a severe side effect of platinum compounds used for cancer chemotherapy such as Cisplatin. This neurotoxicity leads to severe cognitive and nervous dysfunction, therefore, limiting the dose of Cisplatin and compromising the treatment protocol.The present study investigates the neuroprotective effect of Sea Urchins which is a marine animal known for its rich bioactive compounds. Male Sprague Dawley rats received Cisplatin (2 mg/kg body weight) for 4 weeks, two times per week, followed by Sea Urchin extracts (50 and 100 mg/kg body weight) twice weekly for 4 weeks.Results show that rats treated with Urchin’s extracts showed a significant improvement in the thermal (heat and cold) sensitivity compared to untreated rats. Liver enzymes Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) and Urea levels were also significantly decreased back to normal following treatment with sea urchin extracts. Brain tissue oxidative stress marker Nitric oxide (NO) and lipid peroxidation marker Malondialdehyde (MDA) increased significantly in the cisplatin-treated rats while the reduced glutathione levels (GSH) and catalase activity (CAT) showed a significant decrease. Treatment with sea Urchin extracts reversed these changes.Histological and immunohistochemical examination of the cerebral cortex reveled degenerative changes such as karyopyknosis and shrunken necrotic ghost like neurons in the cisplatin treated groups. There was also strong positive Glial fibrillary acidic protein (GFAP) reactivity and a negative B-cell leukemia/lymphoma 2 protein (Bcl2) reaction in most apparent neurons, indicating strong apoptotic changes. Treatment with Urchin extracts reversed these changes. Quantification of cerebral cortex neurons also revealed the strong effect of the extracts. Cisplatin treated groups showed 3708 cells/ mm3 compared to 8091 cells/mm3 in the normal rats. Extract treatment increased the neuronal numbers to almost normal levels. Quantification of the Immuno-histochemical expression of GFAP showed an increase by 10-folds after cisplatin administration. A remarkable decline from the cisplatin group was seen in the extract treated groups.In Conclusion, Sea Urchins extracts possess a strong neuroprotective activity and could provide a novel therapeutic method to prevent Cisplatin-induced neurotoxicity.

Effects of chemical and green nano-zinc oxide on histological changes, oxidative stress, and apoptosis in rat kidney associated with cisplatin

Cisplatin (CP) is used to treat various tumors. A main restriction of cisplatin is nephrotoxicity. This study aimed to evaluate the protective effects of ZnONPs on cisplatin-induced oxidative stress and rat kidney tissue damage. Eighty adult male Wistar rats (250g-270g) were divided into ten groups: Control (CON), Sham (SH), Bulk ZnO (BZnO), Chemical ZnONPs (ChZnONPs), Green ZnONPs (GrZnONPs), Cisplatin (CP), Cisplatin+BulkZnO (CP+BZnO), Cisplatin+Green ZnONPs (CP+GrZnONPs), Cisplatin+Chemical ZnONPs (CP+ChZnONPs), Cisplatin+Explant (CP+EX). CP was i.p administered 5mg/kg/week and BZnO, ChZnONPs and GrZnONPs were i.p administered at a dose of 5mg/kg/day. After 30 days of the treatment, the expression of apoptosis/anti apoptosis related genes oxidant/antioxidant factors and histological changes in the were studied. The CP-treated group showed a decrease in body weight, while the Co-administration of ZGNPs to CP-treated rats showed a significant increase compared to the CP group. The results showed that the increased mRNA level of bax, MDA and the decreased mRNA level of bcl2, SOD and CAT activities in kidney of CP group were improved when animals were treated with ZnO NPs. Our results showed that GrZnONPs, ChZnONPs and BZnO had the potential to protect against oxidative stress and cisplatin-induced neurotoxicity that this protective effect was more evident in GrZnONPs.

Nicotinamide Mononucleotide Prevents Cisplatin-Induced Mitochondrial Defects in Cortical Neurons Derived from Human Induced Pluripotent Stem Cells.

Chemotherapy-induced cognitive impairment (CICI) is a neurotoxic side effect of chemotherapy that has yet to have an effective treatment. Using cisplatin, a platinum-based chemotherapy together with excitatory cortical neurons derived from human induced pluripotent cells (iPSCs) to model of CICI, our recent study demonstrated that dysregulation of brain NAD+ metabolism contributes to cisplatin-induced impairments in neurogenesis and cognitive function, which was prevented by administration of the NAD+ precursor, nicotinamide mononucleotide (NMN). However, it remains unclear how cisplatin causes neurogenic dysfunction and the mechanism by which NMN prevents cisplatin-induced cognitive impairment. Given that mitochondrial dysfunction is thought to play a prominent role in age-related neurodegenerative disease and chemotherapy-induced neurotoxicity, we sought to explore if NMN prevents chemotherapy-related neurotoxicity by attenuating cisplatin-induced mitochondrial damage. We demonstrate that cisplatin induces neuronal DNA damage, increases generation of mitochondrial reactive oxygen species (ROS) and decreases ATP production, all of which are indicative of oxidative DNA damage and mitochondrial functional defects. Ultrastructural analysis revealed that cisplatin caused loss of cristae membrane integrity and matrix swelling in human cortical neurons. Notably, pretreatment with NMN prevents cisplatin-induced defects in mitochondria of human cortical neurons. Our results suggest that increased mitochondrial oxidative stress and functional defects play key roles in cisplatin-induced neurotoxicity. Thus, NMN may be an effective therapeutic strategy to prevent cisplatin-induced deleterious effects on mitochondria, making this organelle a key factor in amelioration of cisplatin-induced cognitive impairments.

Effects of protocatechuic acid against cisplatin-induced neurotoxicity in rat brains: an experimental study

Aims/Objectives: Cisplatin (CIS) is widely used in the treatment of various malignant tumors. The aim of study is to determine the potential protective effects of protocatechuic acid (PCA) on the brain in neurotoxicity induced by CIS in rats.Materials and methods: Forty rats were divided into four groups: 1-Control group: 2- PCA group: PCA was administered orally at a dose of 100 mg/kg/day for 5 weeks. 3-CIS group: 5 mg/kg/week of CIS was administered intraperiteonally 4-PCA + CIS group: The rats were given PCA orally daily for 5 weeks and CIS of 5 mg/kg/week. The brain tissues were used for histopathological examinations and for total antioxidant capacity (TAC), total oxidative state (TOS), oxidative stress index (OSI), tumornecrosis factor-alpha (T NF-α), interleukin 6 (IL-6) Interleukin 1 beta (IL-1β), acetylcholinesterase (AChE), glutamate, gamma aminobutyric acid (GABA), dopamine analyzes in ELISA. WBC, RBC, hemoglobin and hematocrit levels were measured.Results: PCA + CIS group compared to CIS group TOS, OSI, T NF-α, IL-6, IL-1β, AChE, glutamate, WBC levels decreased significantly, while TAC and GABA levels increased statistically significant. With this study, P CA corrected the deterioration in the oxidant / antioxidant status, suppressed neuro-inflammation, decreased AChE activity, partially normalized neurotransmitters, and decreased the increased WBC count. Necrosis seen in the CIS group in histopathological examinations was never seen in the PCA + CIS group.Conclusions: PCA may provide therapeutic benefit when used in conjunction with CIS.

Berberis lyceum root bark extract attenuates anticancer drugs induced neurotoxicityand cardiotoxicity in rats.

Traditionally, Berberis lyceum was extensively used for the treatment of several human diseases. This study was undertaken to determine in vivo effects of Berberis lyceum root bark against doxorubicin-induced cardiotoxicity and cisplatin-induced neurotoxicity in Sprague Dawley rats. A single dose of doxorubicin (20 mg/ kg i. p) and cisplatin (4mg/kg i.p) was used to induce cardiotoxicity and neurotoxicity, respectively. Berberis lyceum methanolic extract was given orally (200 and 400 mg/ kg) to toxicity-induced rats. The cardiac biomarkers i.e. serum aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, creatine kinase and creatine kinase MB were analyzed in blood collected from cardiotoxic rats. The tissue oxidative stress markers included protein, glutathione s-transferase specific activity, catalase activity, total glutathione, and malondialdehyde levels were measured in cardiac and brain homogenate of the respective groups. Berberis lyceum methanolic extract has the potential to reduce the doxorubicin-induced cardiotoxicity and cisplatin-induced neurotoxicity significantly (*p<0.05) by reducing the serum markers and oxidative stress parameters. Histopathological analysis exhibited a marked improvement in the morphology of cardiac and brain tissues. It is concluded that methanolic extract of Berberis lyceum root bark has the potential to protect and reverse anticancer drugs induced cardiotoxicity and neurotoxicity.

Protective effect of short-term thymoquinone administration on the central nervous system in cisplatin-induced neurotoxicity.

This study was performed to investigate the potential beneficial effects of thymoquinone (TQ) on brain tissue based on biochemical and histopathological analyses in cisplatin (CIS) treated rats with central nervous system (CNS) neurotoxicity. The rats were randomly divided into 4 groups with 8 rats in each group (n:8). Group 1: (Control), saline was administered for 3 days at a volume of 0.5 ml per day intraperitoneal (i.p.). Group 2: (CIS Group), one dose of CIS was administered (7 mg/kg i.p.). Group 3: (TQ Group), TQ was given at a dose of 5 mg/kg per day for 3 days (i.p.). Group 4: (CIS+TQ Group), one dose of 7 mg/kg was initiated half an hour before administration of CIS and one dose of 5 mg/kg per day was administered TQ i.p. for 3 days. Malondialdehyde levels were found to be statistically significantly higher in the CIS group compared to the control group. Degenerative changes observed in the CIS+TQ group were found to be milder than in the CIS group. In the CIS+TQ group, a statistically significant decrease in the severity of caspase-3 immunoreactivity was found when compared to the CIS group. It was found that the severity of neurofilament immunoreactivity monitored in neuronal extensions was similar in all groups. In the CIS+TQ group, the severity of tau protein's immunoreactivity was similar to that of the CIS-group. According to the results obtained in our study, beneficial effects were obtained in reducing neurotoxicity with short-term TQ application in rats treated with CIS treatment.

Roasted cashew (Anacardium occidentale L.) nut-enhanced diet forestalls cisplatin-initiated brain harm in rats

The incessant dose constraining symptom of the chemotherapeutic agent, cisplatin is neurotoxicity. This examination tried to explore the neuroprotective impact of roasted cashew nut-enhanced diet against brain deficits related with treatment with cisplatin. Rats were separated in to six groups: Control, CIS (cisplatin [7 mg/kg body weight, i.p]), CIS +10% CN (cisplatin plus 10% roasted cashew nut), CIS +20% CN (cisplatin plus 20% roasted cashew nut), 10% CN (10% roasted cashew nut) and 20% CN (20% roasted cashew nut) for 28 days. Key enzymes associated with brain function, including cholinesterases (AChE and BChE), monoaminergic enzyme (MAO), arginase, and adenosine deaminase (ADA), were investigated after the treatment. The following oxidative stress indicators were also measured in the rat brain: glutathione-S-transferase (GST), glutathione peroxidase (GPx), total antioxidant capacity (TAC), total thiol (T-SH), non-protein thiol (NPSH), thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS), nitric oxide (NO), superoxide dismutase (SOD). Our outcomes demonstrated that roasted cashew nut enhanced diet showed inhibitory impact on activities of AChE, BChE, ADA, MAO and arginase in cisplatin-induced rats. The roasted cashew nut supplemented diet also boosted redox equilibrium and displayed protection against cispaltin-induced oxidative damage to rats' brains by an increase in SOD, CAT, GST and GPx activities, TAC, T-SH, NPSH and NO levels as well as a considerable drop in ROS and RBARS levels. Roasted cashew nut enhanced diet additionally forestalled neuronal degeneration in rat brain. Thus, roasted cashew nuts could be used as a nutraceutical or functional food to treat cisplatin-induced neurotoxicity. Practical applicationsThe results show that increasing roasted cashew nut consumption can significantly improve antioxidant status, reduce lipid peroxidation, and suppress cholinesterase, adenosine deaminase, monoamine oxidase, and arginase activities in the brain under cisplatin-induced circumstances.

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin.

Platinum-based chemotherapeutic treatment of cancer patients is associated with debilitating adverse effects. Several adverse effects have been well investigated, and can be managed satisfactorily, but chemotherapy-induced peripheral neuropathy (CIPN) remains poorly treated. Our primary aim in this study was to investigate the neuroprotective effect of the immunomodulatory drug rapamycin in the mitigation of cisplatin-induced neurotoxicity. Pain assays were performed in vivo to determine whether rapamycin would prevent or significantly decrease cisplatin-induced neurotoxicity in adult male Balb/c mice. Neuropathic pain induced by both chronic and acute exposure to cisplatin was measured by hot plate assay, cold plate assay, tail-flick test, and plantar test. Rapamycin co-treatment resulted in significant reduction in cisplatin-induced nociceptive-like symptoms. To understand the underlying mechanisms behind rapamycin-mediated neuroprotection, we investigated its effect on certain inflammatory mediators implicated in the propagation of chemotherapy-induced neurotoxicity. Interestingly, cisplatin was found to significantly increase peripheral IL-17A expression and CD8- T cells, which were remarkably reversed by the pre-treatment of mice with rapamycin. In addition, rapamycin reduced the cisplatin-induced neuronal apoptosis marked by decreased neuronal caspase-3 activity. The rapamycin neuroprotective effect was also associated with reversal of the changes in protein expression of p21Cip1, p53, and PUMA. Collectively, rapamycin alleviated some features of cisplatin-induced neurotoxicity in mice and can be further investigated for the treatment of cisplatin-induced peripheral neuropathy.

Antioxidant Supplementation with N-Acetylcysteine as a Protection Against Cisplatin-Induced Motor Impairment in Rats

Abstract The aim of this study was to estimate a potential beneficial influence of N-acetylcysteine (NAC) in the treatment of cisplatin-induced motor impairment. We included 32 male Wistar albino rats, divided into 4 equal groups: control (received saline on the 1st and 5th day), cisplatin – CIS (received saline on the 1st and cisplatin 7.5 mg/kg i.p. on the 5th day), NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p.), and CIS+NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p. and cisplatin 7.5 mg/kg i.p. on the 5th day) group. Motor performance was estimated by rotarod, grip wire, open field (OF), elevated plus maze (EPM) and beamwalking (BW) tests on the 10th day. Cisplatin administration resulted in decreased motor performance in all tests, except for BW test, compared to the control group. NAC supplementation on its own had no significant effect on motor performance parameters. However, simultaneous administration of NAC along with cisplatin reversed negative impact of cisplatin in rotarod, OF and EPM tests, with no significant effect on the results obtained in grip wire test. The results of this study confirmed numerous motoric manifestations of cisplatin-induced neurotoxicity in rats. However, the decline in most of the estimated parameters was successfully prevented by antioxidant supplementation with NAC.

Role of inflammation and oxidative stress in chemotherapy-induced neurotoxicity.

Chemotherapeutic agents may adversely affect the nervous system, including the neural precursor cells as well as the white matter. Although the mechanisms are not completely understood, several hypotheses connecting inflammation and oxidative stress with neurotoxicity are now emerging. The proposed mechanisms differ depending on the class of drug. For example, toxicity due to cisplatin occurs due to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which alters hippocampal long-term potentiation. Free radical injury is also involved in the cisplatin-mediated neurotoxicity as dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been seen which protects against the free radical injury by regulating glutathione S-transferases and hemeoxygenase-1 (HO-1). Thus, correcting the imbalance between NF-κB and Nrf2/HO-1 pathways may alleviate cisplatin-induced neurotoxicity. With newer agents like bortezomib, peripheral neuropathy occurs due to up-regulation of TNF-α and IL-6 in the sensory neurons. Superoxide dismutase dysregulation is also involved in bortezomib-induced neuropathy. This article reviews the available literature on inflammation and oxidative stress in neurotoxicity caused by various classes of chemotherapeutic agents. It covers the conventional medicines like platinum compounds, vinca alkaloids, and methotrexate, as well as the newer therapeutic agents like immunomodulators and immune checkpoint inhibitors. A better understanding of the pathophysiology will lead to further advancement in strategies for management of chemotherapy-induced neurotoxicity.

Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2/ARE Pathway in Cisplatin-Induced Cognitive Impairment.

Cisplatin is a cytotoxic chemotherapeutic drug that leads to DNA damage and is used in the treatment of various types of tumors. However, cisplatin has several serious adverse effects, such as deterioration in cognitive ability. The aim of our work was to study neuroprotectors capable of preventing cisplatin-induced neurotoxicity. Methylene blue (MB) and AzurB (AzB) are able to neutralize the neurotoxicity caused by cisplatin by protecting nerve cells as a result of the activation of the Ntf2 signaling pathway. We have shown that cisplatin impairs learning in the Morris water maze. This is due to an increase in the amount of mtDNA damage, a decrease in the expression of most antioxidant genes, the main determinant of the induction of which is the Nrf2/ARE signaling pathway, and genes involved in mitophagy regulation in the cortex. The expression of genes involved in long-term potentiation was suppressed in the hippocampus of cisplatin-injected mice. MB in most cases prevented cisplatin-induced impairment of learning and decrease of gene expression in the cortex. AzB prevented the cisplatin-induced decrease of genes in the hippocampus. Also, cisplatin induced disbalance in the gut microbiome, decreased levels of Actinotalea and Prevotella, and increased levels of Streptococcus and Veillonella. MB and AzB also prevented cisplatin-induced changes in the bacterial composition of the gut microbiome.

Melatonin is effective in attenuating cisplatin-induced neurotoxicity.

Cisplatin (Cis) is a chemotherapeutic agent that has many side effects. Neurotoxicity is one of the most important of these side effects. Oxidative stress and neuroinflammation are the best-known mechanisms in the pathogenesis of neurotoxicity development. In this study, we aimed to determine whether melatonin (Mel), with antioxidant and anti-inflammatory effects, is effective in preventing Cis-induced neurotoxicity. Forty-eight male Sprague-Dawley rats were divided into six groups (n = 8) as follows: control (0.9% NaCl), vehicle (5% ethanol), Cis (6 mg/kg), Cis (6 mg/kg) + vehicle (5% ethanol), Mel (20 mg/kg), and Cis (6 mg/kg) + Mel (20 mg/kg) groups. Cis was administered as a single dose on the 3rd day of the experiment while Mel was given for 5 days. All administrations were performed via intraperitoneal injection. After injections, T-maze, rotarod, and hot plate tests were performed to evaluate cognitive, motor, and sensory functions, respectively. Following sacrification oxidative stress markers, cholinergic function, and proinflammatory cytokines were studied from brain homogenates. Cis impaired cognitive function and motor performance in the Cis and Cis+Vehicle groups. The drug also increased oxidative stress in the brain. Mel significantly improved brain oxidant/antioxidant status and also decreased the overproduction of proinflammatory cytokines (superoxide dismutase activities in Cis+Vehicle and Cis+Mel groups: 104.55 ± 9.50 µU/mg protein vs. 150.13 ± 4.70 µU/mg protein, respectively, p < 0.05; tumor necrosis factor-α levels in Cis and Cis+Mel groups: 40 pg/ml vs. 20 pg/ml, respectively, p < 0.05). It seems that Mel can improve Cis neurotoxicity. For a more firm conclusion, further studies using Mel at different doses with larger groups should be performed.

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.

ABSTRACTCisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we used C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. First, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse XFe96 Analyzer, we observed a detrimental effect of cisplatin and glucose on mitochondrial respiration. Second, because catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. Using a Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects against the dose-dependent neurotoxicity caused by cisplatin.

The Investigation of Ameliorating Effect of Methylene Blue on Cisplatin-Induced Neurotoxicity in Female Rats

Objective: Cisplatin is indispensable in many solid tumors, and peripheral neurotoxicity is an essential dose-limiting side effect. The study aims to investigate the ameliorating effect of methylene blue, which has anti-oxidant properties, in rats with neurotoxicity due to cisplatin treatment. Materials and methods: Twenty-four adult female rats were included in the study and divided into 3 groups. The first group (n=8), the control group, did not receive any treatment. The second (n=8) and the third (n=8) group received 2.5 mg/kg/day of cisplatin and 1 ml/kg/day of 0.9% NaCl (saline) twice a week for 4 weeks. Also, the third group received 20 mg/kg/day of methylene blue every day for 4 weeks. Blood samples were collected from rats for malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor- α (TNF-α), and interleukin-6 (IL-6) levels, and electromyography (EMG) and motor function were evaluated. Results: In non-treated cisplatin injected rats, a significant increase in the lipid peroxidation product MDA and pro-inflammatory cytokines compared to the control group (p<0.001). Electromyography measurements also resulted in a significant decrease in cisplatin injected rats’ compound muscle action potential (CMAP) amplitude and prolongation in CMAP latency compared to the control group (p<0.05). A statistically significant decrease in MDA, TNF-α, and IL-6 levels and a statistically significant increase in GSH levels and CMAP amplitude was observed in the methylene blue-treated group compared to the group injected with cisplatin alone. Conclusions: We concluded that methylene blue has ameliorating effects against cisplatin-induced neurotoxicity (CIN) by enhancing anti-oxidative capacity, energy metabolism and suppressing inflammatory parameters and oxidative stress.