Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model.

The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C-C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1ß, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.

Web-based cognitive rehabilitation intervention for cancer-related cognitive impairment following chemotherapy for aggressive lymphoma: protocol for a randomised pilot trial.

INTRODUCTION: Cancer-related cognitive impairment is common among people diagnosed with and treated for cancer. This can be a distressing and disabling side effect for impacted individuals. Interventions to mitigate cognitive dysfunction are available, but, to date, most have been trialled in samples that are largely or exclusively composed of people with solid tumours. Intervention strategies to support cognitive functioning are needed, but there is a paucity of research in this area. The main aim of this study is to test the feasibility and acceptability of methods and procedures intended for use in a definitive trial of a web-based cognitive rehabilitation programme, Responding to Cognitive Concerns (eReCog), in people who have received chemotherapy for aggressive lymphoma. METHODS AND ANALYSIS: The proposed study is a single-site, parallel-group, pilot randomised controlled trial, with one baseline and one follow-up (or postintervention) assessment. 38 people from the target population with low perceived cognitive function based on the Cognitive Change Screen will be recruited from a specialist cancer centre between July 2023 and June 2024. After baseline assessment, participants will be randomised one-to-one to receive usual care only (a factsheet about changes in memory and thinking for people with cancer) or eReCog plus usual care. The 4-week eReCog intervention consists of four online modules offering psychoeducation on cognitive impairment associated with cancer and its treatment, skills training for improving memory, and attention and relaxation training. Study outcomes will include the feasibility of recruitment and retention at follow-up assessment (primary outcomes), as well as adherence to, usability of and intrinsic motivation to engage with eReCog, and compliance with study measures. The potential efficacy of eReCog will also be evaluated. ETHICS AND DISSEMINATION: Ethical approval was granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee in Victoria, Australia (HREC/97384/PMCC). Study findings will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000705684.

Effects of different exercise interventions on chemotherapy-related cognitive impairment in patients with breast cancer: a study protocol for systematic review and network meta-analysis.

INTRODUCTION: Breast cancer stands as the most prevalent type of cancer affecting women globally, and chemotherapy plays a pivotal role in its treatment by diminishing tumour recurrence and enhancing the survival rates of patients. However, chemotherapy-related cognitive impairment (CRCI) often occurs in patients undergoing treatment. Although multiple clinical trials have indicated that exercise therapy can improve CRCI in patients with breast cancer, there are variations in the types of exercise interventions and their effectiveness. We aim to perform a pioneering network meta-analysis (NMA) to assess and prioritise the effectiveness of various exercise interventions in enhancing cognitive function in patients with breast cancer undergoing chemotherapy. METHODS AND ANALYSIS: We will search multiple databases, including PubMed, Web of Science, Cochrane, Embase, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Wanfang and Sinomed databases, from their inception to May 2023. The main outcome is the cognitive function changes in patients with breast cancer, including subjective and objective results. We will specifically include randomised controlled trials reported in English and Chinese languages, whose primary outcome consists of an assessment of the cognitive function of patients with breast cancer using standardised and validated assessment tools, encompassing both subjective and objective outcomes. The quality of all the trials included will be evaluated based on 'Version 2 of the Cochrane tool for assessing the risk of bias in randomized controlled trials (RoB2)'. We will conduct a Bayesian NMA to thoroughly evaluate and compare the effectiveness of different exercise interventions. We will use cumulative ranking probability plots to estimate the ranking of the best interventions for various exercises. Network plots and funnel plots will be employed to display the study sizes and participants of each exercise intervention, as well as potential publication biases. ETHICS AND DISSEMINATION: The study findings will be shared via peer-reviewed journals to ensure the highest quality and credibility of the research. As the reporting will not include any private patient data, there are no ethical considerations associated with this protocol. PROSPERO REGISTRATION NUMBER: CRD42023406597.

Ondansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway.

Cisplatin is an effective and commonly used chemotherapeutic drug; however, its use is accompanied by several adverse effects, including chemobrain. Ondansetron is a 5-HT3 antagonist, commonly used in prophylactic against chemotherapy-induced nausea and vomiting. Moreover, it has been identified as a novel neuroprotective agent in different animal models. However, its protective role against chemotherapy-induced chemobrain has not been investigated. The current study was the first study that explored the potential neuroprotective effect of ondansetron against cisplatin-induced chemobrain in rats. Cisplatin (5 mg/Kg) was injected intraperitoneally, once weekly, for 4 weeks with the daily administration of ondansetron (0.5 and 1 mg/Kg). Compared to the cisplatin-treated group, ondansetron administration showed a significant decrease in the latency time and a significant increase in ambulation, rearing, and grooming frequency in the open field test (OFT). Moreover, a significant improvement in the latency time in the rotarod and passive avoidance tests, following ondansetron administration. In addition, ondansetron treatment increased the percentage of alternation in the Y-maze test. Also, ondansetron showed a remarkable enhancement in the biochemical parameters in the hippocampus. It increased the acetylcholine (Ach) level and decreased the level of the acetylcholine esterase enzyme (AchE). Ondansetron significantly decreased interleukin-1ß (Il-1ß), tumor necrosis factor-alpha (TNF-α), toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3) inflammasome as well as caspase-1 and caspase-3 levels. Furthermore, ondansetron significantly decreased the levels of copper transporter-1(CTR1) expression in the hippocampus. Collectively, these findings suggest that ondansetron may exhibit a neuroprotective and therapeutic activity against cisplatin-induced chemobrain.

The Impact of Chemotherapy-Related Cognitive Impairment on Social Roles and Well-Being in Breast Cancer Survivors.

PURPOSE: To explore the impact of disruptions in information processing (DIPs) on social roles, well-being, and quality of life (QOL) in breast cancer survivors after chemotherapy. PARTICIPANTS & SETTING: Experiences of DIPs were explored in eight breast cancer survivors aged 53-70 years, 12-60 months post-treatment, referred from a National Cancer Institute-designated cancer center and a nonprofit breast cancer support organization from January 6 to August 31, 2020. METHODOLOGIC APPROACH: This study used a mixed-methods approach. Participants journaled and answered questionnaires sent via mail that asked them about changes in their cognition, QOL, and social roles. Qualitative data were thematically analyzed using constant comparative analysis, and questionnaire scores were compared with qualitative data. FINDINGS: Journals revealed problems with functioning in occupational roles and increased stress, anxiety, and frustration. Women with more DIPs tended to have lower role satisfaction and QOL. Greater role satisfaction was associated with higher QOL and social role participation. IMPLICATIONS FOR NURSING: Mitigating the effects of DIPs on social function may allow women to continue in important roles, which has the potential to affect QOL.

Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice.

Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or "chemobrain," which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics with neurodegenerative diseases, including chronic neuroinflammation, DNA damage, and synaptic loss. We investigated whether a noninvasive sensory stimulation treatment we term gamma entrainment using sensory stimuli (GENUS), which has been shown to alleviate aberrant immune and synaptic pathologies in mouse models of neurodegeneration, could also mitigate chemobrain phenotypes in mice administered a chemotherapeutic drug. When administered concurrently with the chemotherapeutic agent cisplatin, GENUS alleviated cisplatin-induced brain pathology, promoted oligodendrocyte survival, and improved cognitive function in a mouse model of chemobrain. These effects persisted for up to 105 days after GENUS treatment, suggesting the potential for long-lasting benefits. However, when administered to mice 90 days after chemotherapy, GENUS treatment only provided limited benefits, indicating that it was most effective when used to prevent the progression of chemobrain pathology. Furthermore, we demonstrated that the effects of GENUS in mice were not limited to cisplatin-induced chemobrain but also extended to methotrexate-induced chemobrain. Collectively, these findings suggest that GENUS may represent a versatile approach for treating chemobrain induced by different chemotherapy agents.

Chemotherapy-induced cognitive impairment in breast cancer survivors: A systematic review of studies from 2000 to 2021.

BACKGROUND: Studies have indicated that apart from enhancing patient survival, chemotherapy has adverse side effects on the psychological, social, and cognitive functions of breast cancer survivors. AIMS: This study was conducted to understand chemotherapy's impact on breast cancer survivors' cognitive functions. METHODS AND RESULTS: Our study is a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched English databases, including PubMed/MEDLINE, PsycINFO, and Web of Science, and Persian databases, such as Irandoc and Elmnet, using Persian keywords of cancer, breast cancer, chemotherapy, cognitive functions, executive functions, and neuropsychological functions. Two reviewers independently evaluated the full text of the articles according to predefined criteria. Among the 937 available studies, 26 were selected based on the inclusion and exclusion criteria, of which 17 (65%) were longitudinal and 9 (35%) were cross-sectional. The findings indicated a significant relationship between the use of chemotherapy and cognitive impairments, most notably attention, working and short-term memory, and executive functions. However, the studies differed in their findings regarding the long-term persistence of cancer-related cognitive impairment (CRCI), which could be due to the wide range of tools used, different methods to measure cognitive functions, and the difference in the sample size of the studies. CONCLUSION: Chemotherapy, affecting cortical and subcortical brain structures, causes a set of cognitive impairments that can lead to impairments in social responsibility acceptance, daily functioning, and quality of life of women. Therefore, rigorous and extensive research design is required to understand the causes and consequences of CRCI using standardized and sensitive measures of cognitive functions. Specifically, studies comparing the effects of different chemotherapy regimens on cognition and potential mechanisms and/or moderators of CRCI would be instrumental in designing more effective therapy regimens and evaluating the efficacy and cost-effectiveness of cognitive rehabilitation and supportive care programs.

Senolytic treatment alleviates doxorubicin-induced chemobrain.

Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment.

Prevalence and associated factors of chemotherapy-related cognitive impairment in older breast cancer survivors.

AIMS: To examine the prevalence and associated factors of chemotherapy-related cognitive impairment (CRCI) in older breast cancer survivors (BCS). DESIGN: Systematic review. DATA SOURCES: We searched EMBASE, PubMed, PsychInfo, CINAHL, Cochrance Library, Web of Science, CNKI and SinoMed, without language restrictions, for studies published from the establishment of the database to September 2022. REVIEW METHODS: Two researchers independently examined the full texts, data extraction and quality assessment, and any discrepancies were resolved through discussion with a third reviewer. Quality of evidence was assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality Scale. RESULTS: The seven included studies showed that the estimated prevalence of CRCI in older BCS ranged from 18.6% to 27% on objective neuropsychological tests and from 7.6% to 49% on subjective cognitive assessments. The areas most affected were attention, memory, executive functioning and processing speed. CRCI was associated with 10 factors in six categories, including sociodemographic (e.g. age, education level), physiological (e.g. sleep disorders, fatigue and comorbidities), psychological (e.g. anxiety, depression), treatment modalities (e.g. chemotherapy cycles, chemotherapy regimens), genetic (e.g. APOE2, APOE4) and lifestyle factor (e.g. physical inactivity). CONCLUSION: CRCI is multifactorial and has a relatively high prevalence. However, the results of subjective and objective cognitive examinations were inconsistent, possibly due to variations in tools used to evaluate different definitions of CRCI. Nevertheless, as there are few published studies of older BCS, this conclusion still require verification by well-designed studies in the future. IMPACT: We found that the prevalence of CRCI in older adults is relatively high and multifactorial, providing evidence for further health care for this population. NO PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public involvement.

Nrf2 Signaling Pathway: a Potential Therapeutic Target in Combating Oxidative Stress and Neurotoxicity in Chemotherapy-Induced Cognitive Impairment.

Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI.

Câncer materno: a compreensão da criança e suas representações / Maternal cancer: the child's understanding and its representations / Cáncer materno: comprensión del niño y sus representaciones

O câncer é uma doença crônico-degenerativa, que tem como uma de suas principais características a capacidade de invadir tecidos e órgãos do corpo, favorecendo o crescimento desordenado de células. É uma doença que impacta fortemente a pessoa enferma e todos à sua volta, incluindo sua família e seus amigos. A partir desse cenário, este trabalho visou compreender a visão da criança e o impacto emocional sofrido diante do diagnóstico de câncer da mãe. Buscou-se avaliar, a partir de ferramentas lúdicas e do desenho-estória, o entendimento da criança em relação ao processo de adoecimento materno, tomando como base o referencial psicanalítico para reconhecer como ela lidou com a situação. Participaram desta pesquisa uma mulher de 39 anos com diagnóstico de câncer em remissão e seu filho de 9 anos. Os resultados demonstraram que o adoecimento materno causou impactos emocionais significativos e assustadores para o infante, gerando fantasias irreais relacionadas ao câncer e a si próprio. Dessa forma, considera-se de fundamental importância o cuidado estendido aos familiares do indivíduo doente, a fim de que se tenha um olhar a todos que sofrem diante desse contexto.(AU)

Cancer is a chronic-degenerative disease that has as one of its main characteristics the ability to invade tissues and organs of the body, favoring the disordered cell growth. It is a disease that strongly impacts the sick person and everyone around them, including their family and friends. Based on this scenario, this work aimed to understand the child's view and the emotional impact suffered in the face of the mother's cancer diagnosis. It sought to evaluate, with ludic tools and drawing history, the child's understanding about the mother's illness process, based on the psychoanalytic framework to recognize how they deal with the situation. A 39-year-old woman diagnosed with cancer, in remission, and her 9-year-old son participated in this research. The results showed that the maternal illness caused significant and frightening emotional impacts for the infant, creating unrealistic fantasies related to cancer and to himself. Thus, the care extended to the sick individual's family and to the relatives is considered of fundamental importance, to give a complete care for all those who suffer in this context.(AU)

El cáncer es una enfermedad crónico-degenerativa, que tiene como una de sus principales características la capacidad de invadir tejidos y órganos, favoreciendo un crecimiento desordenado de las células. Enfermedades como esta impactan fuertemente a la persona que está enferma y a todos los que la rodean, incluidos familiares y amigos. Considerando esta situación, este estudio tuvo como objetivo comprender la percepción de un niño y el impacto emocional que sufrió ante el diagnóstico del cáncer vivido por su madre. Se pretendió evaluar, utilizando herramientas lúdicas y de dibujo-cuento, la comprensión del niño al proceso de enfermedad materna, buscando reconocer cómo el niño manejó este proceso a partir del referencial teórico psicoanalítico. En esta investigación participaron una mujer de 39 años diagnosticada de cáncer en remisión y su hijo de 9 años. Los resultados mostraron que los impactos emocionales de la enfermedad materna fueron significativos y aterradores para el infante, generando fantasías irreales relacionadas con el cáncer y él mismo. De esta forma, el cuidado extendido a la familia del individuo que está enfrentando esta enfermedad es importante para promover una atención integral a quienes la padecen en este contexto.(AU)

Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions.

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.

More than a small adult brain: Lessons from chemotherapy-induced cognitive impairment for modelling paediatric brain disorders.

Childhood is recognised as a period of immense physical and emotional development, and this, in part, is driven by underlying neurophysiological transformations. These neurodevelopmental processes are unique to the paediatric brain and are facilitated by augmented rates of neuroplasticity and expanded neural stem cell populations within neurogenic niches. However, given the immaturity of the developing central nervous system, innate protective mechanisms such as neuroimmune and antioxidant responses are functionally naïve which results in periods of heightened sensitivity to neurotoxic insult. This is highly relevant in the context of paediatric cancer, and in particular, the neurocognitive symptoms associated with treatment, such as surgery, radio- and chemotherapy. The vulnerability of the developing brain may increase susceptibility to damage and persistent symptomology, aligning with reports of more severe neurocognitive dysfunction in children compared to adults. It is therefore surprising, given this intensified neurocognitive burden, that most of the pre-clinical, mechanistic research focuses exclusively on adult populations and extrapolates findings to paediatric cohorts. Given this dearth of age-specific research, throughout this review we will draw comparisons with neurodevelopmental disorders which share comparable pathways to cancer treatment related side-effects. Furthermore, we will examine the unique nuances of the paediatric brain along with the somatic systems which influence neurological function. In doing so, we will highlight the importance of developing in vitro and in vivo paediatric disease models to produce age-specific discovery and clinically translatable research.

A Drosophila model relevant to chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model relevant to CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurologic deficits were observed with all tested chemotherapies, with doxorubicin and in particular cisplatin also resulting in memory deficits. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model relevant to CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI (and chemotherapy-induced neurotoxicity more generally) and pharmacologic screens to identify disease-modifying therapies.

Phytochemical profiling and neuroprotective activity of Callistemon subulatus leaves against cyclophosphamide-induced chemobrain.

Cyclophosphamide (CPA) is a chemotherapeutic drug used for various types of cancers. However, patients receiving CPA for long periods suffer cognitive impairment associated with difficulties in learning, decreased concentration, and impaired memory. Chemotherapy-induced cognitive impairment, known as chemobrain, has been attributed to enhanced oxidative stress and inflammatory response. The current study aimed to identify the phytoconstituents of Callistemon subulatus extract (CSE) using HPLC-ESI/MS-MS analysis and evaluate its neuroprotective activity against CPA-induced chemobrain in rats. Fourteen compounds were identified following HPLC analysis including, five phlorglucinols, four flavonol glycosides, a triterpene, and a phenolic acid. Forty rats were divided into five groups treated for ten days as follows; group I (control group), group II received CPA (200 mg/kg, i.p.) on the 7th day, groups III and IV received CSE (200 and 400 mg/kg respectively, orally) for ten days and CPA (200 mg/kg, i.p.) on the 7th day, and group V received only CSE (400 mg/kg, orally) for ten days. The administration of CSE effectively ameliorated the deleterious effects of CPA on spatial and short-term memories, as evidenced by behavioral tests, Y-maze and passive avoidance. Such findings were further confirmed by histological examination. In addition, CSE counteracted the effect of CPA on hippocampal acetylcholinesterase (AChE) activity enhancing the level of acetylcholine. Owing to the CSE antioxidant properties, it hindered the CPA-induced redox imbalance, which is represented by decreased catalase and reduced glutathione levels, as well as enhanced lipid peroxidation. Therefore, CSE may be a promising natural candidate for protection against CPA-induced chemobrain in cancer patients.

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study.

Long-term cognitive dysfunction, or "chemobrain", has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.

Chemobrain: An accelerated aging process linking adenosine A2A receptor signaling in cancer survivors.

Chemotherapy has a significant positive impact in cancer treatment outcomes, reducing recurrence and mortality. However, many cancer surviving children and adults suffer from aberrant chemotherapy neurotoxic effects on learning, memory, attention, executive functioning, and processing speed. This chemotherapy-induced cognitive impairment (CICI) is referred to as "chemobrain" or "chemofog". While the underlying mechanisms mediating CICI are still unclear, there is strong evidence that chemotherapy accelerates the biological aging process, manifesting as effects which include telomere shortening, epigenetic dysregulation, oxidative stress, mitochondrial defects, impaired neurogenesis, and neuroinflammation, all of which are known to contribute to increased anxiety and neurocognitive decline. Despite the increased prevalence of CICI, there exists a lack of mechanistic understanding by which chemotherapy detrimentally affects cognition in cancer survivors. Moreover, there are no approved therapeutic interventions for this condition. To address this gap in knowledge, this review attempts to identify how adenosine signaling, particularly through the adenosine A2A receptor, can be an essential tool to attenuate accelerated aging phenotypes. Importantly, the adenosine A2A receptor uniquely stands at the crossroads of cancer treatment and improved cognition, given that it is widely known to control tumor induced immunosuppression in the tumor microenvironment, while also posited to be an essential regulator of cognition in neurodegenerative disease. Consequently, we propose that the adenosine A2A receptor may provide a multifaceted therapeutic strategy to enhance anticancer activity, while combating chemotherapy induced cognitive deficits, both which are essential to provide novel therapeutic interventions against accelerated aging in cancer survivors.

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice.

Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca2+) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor-α and transforming growth factor-ß signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure-associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies.

Chemotherapy-Induced Cognitive Impairment.

Terms such as "chemobrain" or "chemofog" may be familiar to many patients with cancer. Specific chemotherapy agents are known to cause chemotherapy-induced cognitive impairment (CICI). Interventions to prevent or redu.