Search Results (35)

Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, is a well-documented adverse outcome of anticancer treatments. While the neurotoxicity of doxorubicin (DOX) has been extensively studied, targeted therapies such as sunitinib (SUN) remain largely unexplored concerning this outcome. This study aimed to compare the neurotoxic effects of DOX and SUN in dopaminergic neuronal cells and to explore the involvement of oxidative stress and autophagy as potential mechanisms underlying their cytotoxicity. Human neuronal SH-SY5Y cells were differentiated into a dopaminergic phenotype and exposed to clinically relevant concentrations of DOX (0.1–10 µM) and SUN (1–10 µM) for 24 or 48 h. To investigate the involvement of oxidative stress in their cytotoxicity, redox modulators [N-acetylcysteine (NAC); dimethyl fumarate (DMF); sulforaphane (SFN); and cheirolin (CH)] were tested alongside DOX and SUN for their potential protective effects. The role of autophagy in SUN-induced toxicity was assessed using 3-methyladenine (3-MA; an early-stage inhibitor); chloroquine (CH; a late-stage inhibitor); and rapamycin (RAP; an autophagy inducer). Additionally, LC3-I and LC3-II expression levels were determined. Both DOX and SUN exhibited time- and concentration-dependent cytotoxicity and induced mitochondrial membrane depolarization. NAC conferred partial protection against SUN toxicity but enhanced DOX’s cytotoxicity at the lowest concentration tested. DMF and SFN had dual effects, depending on the drug’s concentration, while CH exhibited a consistent protective effect towards the cytotoxicity induced by both drugs. Regarding autophagy, 3-MA partially protected against SUN-induced toxicity, whereas CLQ and RAP exacerbated it. LC3-II levels were increased in some conditions, suggesting that SUN-induced toxicity involves autophagy. This study shows that SUN, though less studied in chemobrain, has a cytotoxic profile similar to DOX, which is a known contributor to chemobrain, in SH-SY5Y cells. These findings highlight the need for further research on neuroprotective strategies targeting oxidative stress and autophagy to reduce chemobrain in cancer patients and survivors. Full article

Chemotherapy-induced renal encephalopathy (RE) is a disease characterized by cognitive impairment of the brain caused by impaired kidney function for which there is no definitive treatment. Icariin (ICA), the main active component of Epimedium, has a good nervous system protection and anti-neuroinflammation effect, but its effect on the brain injury caused by renal insufficiency as a result of chemotherapy remains unclear. In this study, we demonstrated that 100 mg/kg ICA can not only successfully interface with serotonin and regulate hormone levels but also ameliorates kidney damage and cognitive impairment in cyclophosphamide (CTX)-induced RE mouse models and inhibits inflammation, oxidation, and apoptosis by regulating NF-κB, keap1-Nrf2, and apoptosis pathways. In order to further study the protective effect of ICA on RE, we used CTX-induced HT22 and HEK293 cell injury models, and the ICA intervention showed that ICA could prevent apoptosis by regulating the expression of the apoptosis-related proteins caspase-3, Bcl-2, Bax and BDNF. Overall, our study provides a basis for further investigation of the therapeutic potential of ICA in the treatment of neurodegenerative diseases in the context of renal dysfunction, and further studies are needed at a later stage to fully elucidate the underlying molecular mechanisms. Full article

The genotoxic drug doxorubicin (Dox) remains one of the most powerful chemotherapeutic options available for a wide range of cancers including breast, ovarian, and other cancers. However, emerging evidence links Dox treatment with chemotherapy-induced cognitive impairment, a condition that is popularly referred to as Dox-induced neurotoxicity or “chemobrain”, which limits the use of the drug. There are no specific treatments for Dox-induced neurotoxicity, only interventions to mitigate the neurotoxic effects of the drug. Accumulating evidence indicates that DNA damage, oxidative stress, dysregulation of autophagy and neurogenesis, inflammation, and apoptosis play central roles in Dox-induced neurotoxicity. Additionally, germline mutations in the tumour suppressor genes breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) increase the risk of breast, ovarian, and related cancers. BRCA1 and BRCA2 are distinct proteins that play crucial, unique roles in homologous recombination-mediated double-stranded break repair. Furthermore, BRCA1 and 2 mitigate oxidative stress in both neural cells and brain microvascular endothelial cells, which suggests that they have a critical role as regulators of pathways central to the development of Dox-induced neurotoxicity. Despite research on the effects of Dox on cognitive function, there is a gap in knowledge about the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity. In this review, we discuss existing findings about the role of different mechanisms and the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity, along with future perspectives. Full article

The human papillomavirus type 16 (HPV 16) is a high-risk human papillomavirus strain commonly associated with oropharyngeal cancers, including lymph node involvement. The treatment for HPV 16-related tonsil cancer, commonly involving surgery, radiation, and chemotherapy, presents significant challenges. Complications such as oral mucositis, xerostomia, dysphagia, dysgeusia, hypogeusia, impaired gustatory function, and significant weight loss frequently arise, leading to reduced nutritional intake, impaired healing, and recovery progression. These challenges underscore the need for supportive interventions to enhance rehabilitation and the post-recovery period, improve treatment tolerance, and maintain quality of life. Objective: This single-subject study examines a 67-year-old male patient diagnosed with a T1N3b (small primary tumor with advanced lump node involvement) associated with HPV 16 positivity, indicating a virus-associated oncogenesis. Methods: The patient underwent radiation therapy and chemotherapy, leading to treatment-associated side effects. After having dietary drinks for daily nourishment, the patient routinely incorporated oral bio extra virgin olive oil (BEVOO) to cope with indicated challenges. Results: Body composition and metabolic parameters showed treatment-induced declines, followed by substantial but not complete recovery during follow-up examination. Visual Analog Scale (VAS) scores reflected gradual improvements in dysphagia, xerostomia, mucositis, and subtle but ongoing enhancement of the dysgeusia, gustatory perception, and oral palatability. The BEVOO supplementation and mindfulness were associated with positive recovery trends. Additional variables could have impacted the outcomes, preceding and throughout treatment, including the patient’s cognitive and somatic health, environmental conditions, dietary habits, individual attitudes toward recovery, physical activity, and patient way of life. Conclusions: These results emphasize the need for additional research employing a comprehensive, multi-factorial framework that accounts for the complex interplay of physiological, psycho-social, and environmental contributors. More extensive, more diverse studies are essential to confirm these observations and substantiate the role of BEVOO as a supportive intervention in cancer recovery. Full article

Cognitive impairment and anxiety are common side effects of chemotherapy, particularly with the use of doxorubicin (DOX), known as “chemobrain”. This study aimed to examine the dose-dependent effects of DOX on cognitive decline, anxiety, and locomotor activity in healthy female Wistar rats. The rats were divided into groups receiving low (2 mg/kg), intermediate (4 mg/kg), and high (5 mg/kg) doses of DOX for four weeks, alongside a control group. Behavioral tests, including open field, elevated plus maze, and Y-maze tests, assessed anxiety, locomotion, and cognitive performance, while brain tissue analysis evaluated neuroinflammation using markers such as GFAP and Iba-1. The results showed that all doses of DOX induced anxiety-like behavior, reduced locomotion, and caused neuroinflammation in the hippocampus, with more severe effects at higher doses. Notably, high-dose DOX also caused short-term memory deficits. These findings highlight the dose-dependent nature of DOX’s impact on behavior and cognition, suggesting that DOX plays a key role in the development of cognitive symptoms during chemotherapy. Further research is needed to understand the mechanisms behind these effects and to explore potential interventions. Full article

Background: Cancer-related cognitive impairment (CRCI) represents one of the most common and debilitating effects in patients surviving after cancer treatments. Neurocognitive deficits are important causes of disability and burden in cancer survivors. The true magnitude of CRCI is difficult to define due to significant heterogeneity of literature data. At present, there is no agreement on the gold standard for detection and grading of CRCI in clinical trials, and there is a lack of clear knowledge of its pathophysiology. Objectives: In this review, we aim to discuss some perspectives for future research to pursue in order to cover the gaps in knowledge in the CRCI field. Methods: We focused our literature research on the following relevant issues: neuroradiological correlates of CRCI; objective neuropsychological evaluation and subjective complaint assessment and their correlation with objective measures; timing of assessment; and possible treatments. Results: The correct methodology for evaluating cognitive deficits induced by anti-tumor treatments still requires a definition based on quality scientific evidence, and literature data are currently scarce. Conclusions: This review highlights the need for further research to understand the causes and consequences of cancer-related cognitive impairment using standardized and sensitive measures of cognitive functions and the long-term effects of chemotherapy on cognitive functions and to develop effective interventions. Full article

Background: Post-treatment side effects of chemotherapy can include cognitive deficits commonly known as Chemo-brain. The treatment of patients with Doxorubicin (DOX), one of the most widely used chemotherapeutic drugs in the treatment of cancer, can induce depression, anxiety, and impaired cognitive function. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that has been identified as a possible therapeutic agent against many neurodegenerative disorders, including traumatic brain injury, spinal cord injury, Tau-protein-induced neurodegeneration, and neuropathic pain. Therefore, this study aimed to assess whether oral CBD administration could reduce DOX-induced anxiety and depression-like behaviors and alter the expression of mRNA associated with neuroinflammation. Methods: Female Long Evans Hooded rats received intraperitoneal injections of DOX (6 mg/kg) or the vehicle (0.9% saline) once a week for four weeks, followed by oral administration of CBD (10 mg/kg) three times a week for the same period. Results: CBD was significantly protective against DOX-induced anxiety and depression-like behaviors, as measured by several behavioral tests. Furthermore, CBD improved DOX-induced alterations in the gene expression of biomarkers of neuroinflammation in the hippocampus and prefrontal cortex. Conclusions: This provides insights into future studies on possible mechanisms by which DOX-induced cognitive dysfunction could be alleviated by CBD. Full article

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter^® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies. Full article

Chemotherapy-induced cognitive impairment or “chemobrain” is a prevalent long-term complication of chemotherapy and one of the more devastating. Most of the studies performed so far to identify the cognitive dysfunctions induced by antineoplastic chemotherapies have been focused on treatment with anthracyclines, frequently administered to breast cancer patients, a population that, after treatment, shows a high possibility of long survival and, consequently, of chemobrain development. In the last few years, different possible strategies have been explored to prevent or reduce chemobrain induced by the anthracycline doxorubicin (DOX), known to promote oxidative stress and inflammation, which have been strongly implicated in the development of this brain dysfunction. Here, we have critically analyzed the results of the preclinical studies from the last few years that have evaluated the potential of phenolic compounds (PheCs), a large class of natural products able to exert powerful antioxidant and anti-inflammatory activities, in inhibiting DOX-induced chemobrain. Several PheCs belonging to different classes have been shown to be able to revert DOX-induced brain morphological damages and deficits associated with learning, memory, and exploratory behavior. We have analyzed the biological and molecular mechanisms implicated and suggested possible future perspectives in this research area. Full article

This study aims to estimate the prevalence and to identify the determinants of cancer-related neuropathic pain (CRNP), chemotherapy-induced peripheral neuropathy (CIPN) and cognitive decline among patients with breast cancer over five years after diagnosis. Women with an incident breast cancer (n = 462) and proposed for surgery were recruited at the Portuguese Institute of Oncology-Porto in 2012 and underwent systematic neurological examinations and evaluations with the Montreal Cognitive Assessment (MoCA) before treatment and after one, three, and five years. Multivariate logistic regression was used to assess the determinants of CRNP and CIPN, and multivariate linear regression for the variation in MoCA scores. Prevalence of CRNP and CIPN decreased from the first to the fifth year after diagnosis (CRNP: from 21.1% to 16.2%, p = 0.018; CIPN: from 22.0% to 16.0% among those undergoing chemotherapy, p = 0.007). Cognitive impairment was observed in at least one assessment in 17.7% of the women. Statistically significant associations were observed between: cancer stage III and both CRNP and CIPN; triple negative breast cancer, chemotherapy, axillary node dissection, older age, higher education, and being single and CRNP; taxanes and fruit and vegetable consumption and CIPN. Anxiety, depression and poor sleep quality at baseline were associated with decreases in MoCA values from pre- to post-treatment and with CRNP. Follow-up protocols should consider the persistence of CRNP, CIPN, and cognitive impairment for several years following diagnosis. Full article

Background: In addition to pharmacological prevention, chemotherapy-induced nausea and vomiting (CINV) can be mitigated through patient education; written supporting materials can be beneficial. Methods: This is a randomized, controlled trial which randomly assigned patients undergoing first chemotherapy cycle to receive oral information regarding CINV prevention and management (control arm) or oral information plus an informative booklet (experimental arm). Overall, 384 cancer patients fulfilling the following inclusion criteria were enrolled: age ≥18 years; life expectancy ≥6 months; no cognitive impairment; written informed consent. After the first cycle, CINV occurrence and its impact on daily activities were assessed using the Functional Living Index Emesis (FLIE). Results: Severe nausea was self-reported by 3.0% and 10.8% of patients in the experimental and control group, respectively (difference: 7.8%; 95% confidence interval: 2.3% to 13.1%). Moderate/high impact of nausea on daily activities was lower in patients also receiving the booklet than in the control group (4.2% and 10.1%, respectively; difference: 5.9%; 95% confidence interval: 0.3% to 11.5%). Vomiting was not statistically different between study arms. Conclusions: This integrated nursing approach was effective in aiding cancer patients in CINV self-management. Although the beneficial effect was moderate, this intervention demands minimal resources in terms of costs and time. Full article

Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca²⁺ signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain. Full article

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress. Full article

Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: −9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: −29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67⁺ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67⁺ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit. Full article

Chemotherapy-induced neurotoxicity is a well-known complication of several very effective systemic anticancer treatments, mainly presenting as cognitive impairment (“chemo-brain”) and peripheral neuropathy. The social and economic effects of long-lasting chemotherapy-induced neurotoxicity on patients’ lifestyles and their relationships are under-investigated, and their impact is, therefore, largely unknown. In this study, we used a web-based questionnaire to record the self-reported perception of chemotherapy-induced neurotoxicity on cancer patients’ health status, but also on several different aspects of their daily life. From the study results, it emerged that the impact of chemotherapy-induced neurotoxicity on personal, social, and working activities is very high. A similar effect was also observed when the psychological impact is assessed. Moreover, there is evidence suggesting that the management of CIPN is suboptimal; this is partially due to a lack of effective drugs, but also of appropriate advice from healthcare providers. In conclusion, this study provides evidence for the relevance of the impact on the explored aspects of the daily life of cancer patients and spotlights the need for a larger and more structured investigation on these long-term side effects of anticancer chemotherapy. Full article