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Cancer treatment is associated with long lasting cognitive impairment in cancer survivors. This cognitive impairment is often termed cancer related cognitive impairment (CRCI). Cancer survivors treated for tumors outside the central nervous system are increasingly diagnosed with CRCI. The development of strategies to mitigate the negative effects of cancer treatment on the brain are crucial. Although neuroimaging research has proposed several candidate mechanisms, the pathogenic underpinnings of CRCI remain uncertain. As such, preventative and treatment strategies have not been identified. To fill these gaps, animal models play a vital role in isolating underlying contributing mechanisms that promote CRCI and in testing new therapeutic approaches.

Background: Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction. Objective: In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI. Materials and methods: The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25 mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40 mg/kg; p.o.) for up to 3 weeks followed by behavioral, biochemical, molecular and histopathological analysis. Results: Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1β) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment. Conclusion: This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI. [ABSTRACT FROM AUTHOR]

Background: Chemobrain is widespread in breast cancer patients receiving chemotherapy. However, the exact mechanism, especially the associated signalling pathway, is not currently clear. This study was to evaluate the behavioural changes in breast cancer mice after chemotherapy and to further explore the role of Wnt3a/glycogen synthase kinase (GSK3β)/β-catenin signalling in chemobrain. Methods: MMTV-PyMT(+) breast cancer mice were injected intraperitoneally with doxorubicin (4 mg/kg) once a week for three weeks to establish a chemobrain model. The Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and memory ability. Electron microscopy was used to observe the structural changes in the hippocampal CA1 region. The brain tissue of breast cancer mice after chemotherapy was taken out for mRNA-seq detection. Then, the expression levels and phosphorylation of key proteins in the Wnt3a/GSK3 β/β-catenin signalling pathway were evaluated through Western blotting (WB) and immunofluorescence. Results: Doxorubicin-induced spatial and short-term memory impairment was observed in breast cancer mice, and obvious neuronal damage could be seen in the hippocampal CA1 region. Immunofluorescence staining for GSK3β was increased. Wnt signalling pathway is highly enriched from mRNA-seq analysis, with GSK3β genes at important nodes. The relative protein levels of p-PI3K, p-AKT, p-GSK3 β, Wnt3a and TCF-1 were decreased significantly, while the p-β-catenin level was increased. After injection of the GSK3β inhibitor sb216763 (1 ng/0.5 µl/side), hippocampal neuronal injury was alleviated to some extent, and the changes in the expression of proteins upstream and downstream of this signalling pathway were reversed. Conclusion: Wnt3a/GSK3 β/β-catenin signalling is likely involved in doxorubicin-induced memory impairment. This result provides basic evidence for the further study of chemobrain in breast cancer. [ABSTRACT FROM AUTHOR]

Today, we critically need alternative therapeutic options for chemotherapy-induced cognitive impairment (CICI), often known as chemo brain. Mitochondrial dysfunction and oxidative stress are two of the primary processes that contribute to the development of chemobrain. Therefore, the purpose of this study was to investigate how CoQ10 and berberine shield neurons from chemotherapy-induced damage in in-vitro studies and memory loss in vivo studies. For the in-vitro investigation, we employed SH-SY5Y cell lines, and for the in-vivo study, we used female Swiss albino mice divided into seven different groups. Data from in-vitro studies revealed that treatment with coenzyme Q10 (CoQ10) and berberine improved chemotherapy-induced toxicity by reducing mitochondrial and total cellular ROS, as well as apoptosis-elicited markers (caspase 3 and 9). CoQ10 and berberine therapy inhibited the nuclear translocation of NF-κB and, consequently, the subsequent expressions of NLRP3 and IL-1β, implying the prevention of inflammasome formation. Furthermore, CoQ10 and berberine therapy boosted Nrf2 levels. This is a regulator for cellular resistance to oxidants. The in vivo results showed that treatment with CoQ10 (40 mg/kg) and berberine (200 mg/kg) improved the behavioral alterations induced by CAF (40/4/25 mg/kg) in both the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Furthermore, biochemical and molecular evidence revealed the antioxidant, mitochondrial restorative, and anti-inflammatory potential of CoQ10 (40 mg/kg) and berberine (200 mg/kg) against CAF (40/4/25 mg/kg) subjected mice. In addition, the histological analysis using H&E staining and transmission electron microscopy (for mitochondrial morphology) showed that mice treated with the cocktails had an increased number of healthy neurons with intact mitochondria and a reduced presence of autophagic vacuoles in the hippocampal region of the brain. These findings back up our theory about this novel cocktail method for CAF-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Objective To study the effects of chemotherapy on cognitive function in breast cancer patients, and to investigate the relationship of MemTrax test of memory and related functions to the FACT-Cog functional self-assessment for the evaluation and management of chemobrain. Methods In this prospective cohort study, clinical information of pathologically confirmed female breast cancer patients who decided to receive chemotherapy were collected in a questionnaire which was developed for this study and provided as a supplementary file. The FACT-Cog self-assessment and MemTrax test were administered before and after the chemotherapy treatments. Patients with chemobrain were identified using published criteria based on FACT-Cog scores, and MemTrax scores from chemobrain patients were analyzed. Results Fifty-six patients participated in this study, of which 41 participants completed 4 or more cycles of chemotherapy and were included in the final analyses here. Using the reported high end of minimal clinical differences (10.6 points) of FACT-Cog before and after chemotherapy, 18 patients suffered from chemobrain in this study. In these 18 chemobrain patients, no cognitive impairments were detected by MemTrax, which paradoxically demonstrated an improvement in the normal cognitive range. Conclusion The cognitive impairment induced by chemotherapy in breast cancer patients is detectable by the FACT-Cog in a Chinese cohort but is not detected by the MemTrax memory test. The fact that the more objective MemTrax could not detect the impairment could alleviate patients’ concerns which in turn would be beneficial for patients’ mental health.

Objective: To study the effects of chemotherapy on cognitive function in breast cancer patients, and to investigate the relationship of MemTrax test of memory and related functions to the FACT-Cog functional self-assessment for the evaluation and management of chemobrain. Methods: In this prospective cohort study, clinical information of pathologically confirmed female breast cancer patients who decided to receive chemotherapy were collected in a questionnaire which was developed for this study and provided as a supplementary file. The FACT-Cog self-assessment and MemTrax test were administered before and after the chemotherapy treatments. Patients with chemobrain were identified using published criteria based on FACT-Cog scores, and MemTrax scores from chemobrain patients were analyzed. Results: Fifty-six patients participated in this study, of which 41 participants completed 4 or more cycles of chemotherapy and were included in the final analyses here. Using the reported high end of minimal clinical differences (10.6 points) of FACT-Cog before and after chemotherapy, 18 patients suffered from chemobrain in this study. In these 18 chemobrain patients, no cognitive impairments were detected by MemTrax, which paradoxically demonstrated an improvement in the normal cognitive range. Conclusion: The cognitive impairment induced by chemotherapy in breast cancer patients is detectable by the FACT-Cog in a Chinese cohort but is not detected by the MemTrax memory test. The fact that the more objective MemTrax could not detect the impairment could alleviate patients' concerns which in turn would be beneficial for patients' mental health. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Implications for cancer survivors Chemotherapy is one of the common treatments in cancer management. However, chemotherapy‐induced cognitive impairment (CICI) is one notable side effect that can greatly impact a patient's quality of life. Literature on CICI in gastrointestinal (GI) cancers are few and inconsistent. This review aims to identify the methodological differences in such studies.A systematic search was performed in four electronic databases. All peer‐reviewed primary literature published in English that evaluated cognitive‐related functioning scores related to chemotherapy in GI cancer patients were included. Information about each study such as CICI findings, study limitations, methodology, and sample characteristics was extracted and synthesized.A total of 19 studies were included. Evidence of CICI was found in 50.0% (8 of 16) and 62.5% (5 of 8) studies that used objective and subjective measures, respectively. Methodological differences such as groups used for comparison, instruments used, and assessment from the length of time since chemotherapy were highlighted between studies that did and did not find evidence of CICI.This review suggests that the mixed findings can be attributed to the heterogeneous methodologies adopted in the evaluation of CICI in this field.Further studies are necessary to establish the presence and chronicity of CICI, and in which groups of patients to facilitate targeted interventions and treatments. [ABSTRACT FROM AUTHOR]

Background: Cancer-related cognitive dysfunction (CRCD) is a major functional disorder in patients with cancer. This central nervous dysfunction is found in up to 60% of patients after tumour therapy, often significantly limits the quality of life, and significantly impedes participation in working life. For this reason, diagnosis and treatment of CRCD are of central importance. This narrative review is intended to provide an overview and support for practical clinical care with regard to diagnostics and therapeutic options. Summary: In Germany, CRCD has received insufficient attention in clinical practice due to the lack of guidelines for diagnosis and therapy. The pathophysiology is complex and cannot be explained by chemotherapeutic treatment alone. In addition to the tumour disease as such and the tumour therapy, psychological factors such as anxiety and depression as well as sleep disorders also play a significant role. Today, it is known that in addition to age, molecular genetic changes also have an effect on cognitive function. Morphologically, CRCD can be located in the frontal cortex and hippocampus. In addition to easy-to-use screening instruments such as the visual analogue scale, validated questionnaires such as the Questionnaire of Subjectively Experienced Deficits in Attention (FEDA) developed in Germany are also available. These allow the suspected diagnosis to be substantiated and the patient to be referred to further neurological, neuropsychological, or psycho-oncological diagnostics. Within the framework of further neuropsychological diagnostics, the International Cognition and Cancer Task Force (ICCTF) recommends testing learning, memory, processing speed, and executive functions. From the authors' point of view, a step-by-step diagnosis is recommended in order to avoid overdiagnosis. In clinical practice, graduation according to the "Common Terminology Criteria for Adversity Events" (CTCAE Version 5.0) is suitable for assessing the degree of severity. Cognitive training should be behaviourally oriented and include regular practice of cognitive skills to restore attention, psychomotor speed, memory, and executive functions. The best evidence is currently found for web-based training programmes that can be used by the patient at home. There is also evidence for mindfulness training and physical exercises. In particular, the combination of these three therapeutic elements currently seems to be the optimal treatment strategy for CRCD. Key Messages: Cognitive dysfunction should be given much more attention in the clinical care of cancer patients. Diagnostic tools for this purpose and evidence-based therapeutic interventions are available. In the future, networks should be created that allow for better care of patients with CRCD. [ABSTRACT FROM AUTHOR]

Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin®, ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI.

Background and Purpose: Adverse neurological effects after cancer therapy are common, but biomarkers to diagnose, monitor, or risk stratify patients are still not validated or used clinically. An accessible imaging method, such as fluorodeoxyglucose positron emission tomography (FDG PET) of the brain, could meet this gap and serve as a biomarker for functional brain changes. We utilized FDG PET to evaluate which brain regions are most susceptible to altered glucose metabolism after chemoradiation in patients with head and neck cancer (HNCa). Methods: Real‐world FDG PET images were acquired as standard of care before and after chemoradiation for HNCa in 68 patients. Linear mixed‐effects voxelwise models assessed changes after chemoradiation in cerebral glucose metabolism quantified with standardized uptake value ratio (SUVR), covarying for follow‐up time and patient demographics. Results: Voxelwise analysis revealed two large clusters of decreased glucose metabolism in the medial frontal and polar temporal cortices following chemoradiation, with decreases of approximately 5% SUVR after therapy. Conclusions: These findings provide evidence that standard chemoradiation for HNCa can lead to decreased neuronal glucose metabolism, contributing to literature emphasizing the vulnerability of the frontal and anterior temporal lobes, especially in HNCa, where these areas may be particularly vulnerable to indirect radiation‐induced injury. FDG PET shows promise as a sensitive biomarker for assessing these changes. [ABSTRACT FROM AUTHOR]

Purpose: In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E (Vit. E). Methods: Adult male rats were injected with four doses of 2 mg/kg/week DOX, or 2 mg/kg PAC every other day intraperitoneally. Vit. E was co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. Results: There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances (TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus, which was overcome by the co-administration of Vit. E. Conclusion: There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which cognitive deficits stand out. The present study aimed to assess the neurologic adverse outcome pathways of two clinically relevant cumulative doses of DOX. Adult male CD-1 mice received biweekly intraperitoneal administrations for 3 weeks until reaching cumulative doses of 9 mg/kg (DOX9) or 18 mg/kg (DOX18). Animals were euthanized one week after the last administration, and biomarkers of oxidative stress and brain metabolism were evaluated in the whole brain. Coronal sections of fixed brains were used for specific determinations of the prefrontal cortex (PFC) and hippocampal formation (HF). In the whole brain, DOX18 tended to disrupt the antioxidant defences, affecting glutathione levels and manganese superoxide dismutase expression. Considering the regional analysis, DOX18 increased the volume of all brain areas evaluated, while GFAP-immunoreactive astrocytes decreased in the dentate gyrus (DG) and increased in the CA3 region of HF, both in a dose-dependent manner. Concerning the apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group. Only in the latter group did Bcl-2 levels also decrease. While p53 only increased in the CA3 region of the DOX9 group, AIF increased in the PFC and DG of DOX18. Finally, phosphorylation of Tau decreased with the highest DOX dose in DG and CA3, while TNF-α levels increased in CA1 of DOX18. Our results indicate new pathways not yet described that could be responsible for the cognitive impairments observed in treated patients.

Background: The evidence links chemotherapy to cognitive impairment in breast cancer patients. This study assessed the link between subjective chemotherapy-related cognitive impairment and neuroinflammation in breast cancer patients. Methods: In a correlational study, 113 patients aged 21 to 60 years on chemotherapy regimens completed the Functional Assessment of Cancer Therapy-Cognition Test (FACT-Cog) as a measure of subjective cognitive functioning at three time points (baseline- T0, third cycle- T1, and sixth cycle- T2). The levels of inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-alpha (TNF-α)) were measured using an assay method and compared with the subjective cognitive impairment. Results: Midway through chemotherapy, higher levels of TNF-α were inversely linked with self-perceived cognitive performance, while higher levels of IL-1β were positively associated (p = 0.030). However, at the end of chemotherapy, only IL-8 (p = 0.50) was associated with higher self-perceived cognitive problems. Conclusions: The specific roles that various cytokines and their interactions may play in neuroinflammation or neuroprotection require further investigation.

• Fibre-rich diet mitigates 5-FU-induced increases to astrocyte abundance. • Protective microbial profiles associate with decreased neuroinflammatory markers. • Increased propionic acid levels associate with decreased neuroinflammatory markers. • Propionic acid links diet-induced changes to gut microbiota and CNS after 5-FU. The gastrointestinal microbiota has received increasing recognition as a key mediator of neurological conditions with neuroinflammatory features, through its production of the bioactive metabolites, short-chain fatty acids (SCFAs). Although neuroinflammation is a hallmark shared by the neuropsychological complications of chemotherapy (including cognitive impairment, fatigue and depression), the use of microbial-based therapeutics has not previously been studied in this setting. Therefore, we aimed to investigate the effect of a high fibre diet known to modulate the microbiota, and its associated metabolome, on neuroinflammation caused by the common chemotherapeutic agent 5-fluorouracil (5-FU). Twenty-four female C57Bl/6 mice were treated with 5-FU (400 mg/kg, intraperitoneal, i.p.) or vehicle control, with or without a high fibre diet (constituting amylose starch; 4.7 % crude fibre content), given one week prior to 5-FU and until study completion (16 days after 5-FU). Faecal pellets were collected longitudinally for 16S rRNA gene sequencing and terminal SCFA concentrations of the caecal contents were quantified using gas chromatography-mass spectrometry (GC–MS). Neuroinflammation was determined by immunofluorescent analysis of astrocyte density (GFAP). The high fibre diet significantly altered gut microbiota composition, increasing the abundance of Bacteroidaceae and Akkermansiaceae (p < 0.0001 and p = 0.0179) whilst increasing the production of propionate (p = 0.0097). In the context of 5-FU, the diet reduced GFAP expression in the CA1 region of the hippocampus (p < 0.0001) as well as the midbrain (p = 0.0216). Astrocyte density negatively correlated with propionate concentrations and the abundance of Bacteroidaceae and Akkermansiaceae , suggesting a relationship between neuroinflammatory and gastrointestinal markers in this model. This study provides the first evidence of the neuroprotective effects of fibre via dietary intake in alleviating the neuroimmune changes seen in response to systemically administered 5-FU, indicating that the microbiota-gut-brain axis is a targetable mediator to reduce the neurotoxic effects of chemotherapy treatment. [ABSTRACT FROM AUTHOR]

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. Highlights: An inflammatory burst could be the background for chemobrain in blood cancer. In acute phases, blood sera of patients contain massive levels of proinflammatory cytokines.In blood cancer, direct cytokine neurotoxicity, and neuroinflammation occur in concert with cytokine‐mediated disruption of the blood–brain barrier.A blood cancer drug exerts multifaceted effects on chemobrain: ∘Methotrexate combines brain structure damage with persisting chemotherapy‐induced neuroinflammation.∘Doxorubicin fulfills the concept of chemotherapy‐induced neuroinflammation with peripheral origin. [ABSTRACT FROM AUTHOR]

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI. [ABSTRACT FROM AUTHOR]

Purpose: starting from a lack of precise and coherent data in literature, aim of this work is to retrospectively study the influence of chemotherapy with Temozolomide (TMZ) on a wide series of neuropsychological functions in a population of adult high-grade glioma patients. Methods: an extensive neuropsychological battery was administered pre-operatively (T0) and after 6 (T1) and 12 months (T2) from surgery. After full recovery from surgery, TMZ was delivered concomitant to radiotherapy and, subsequently, adjuvantly for 5-day cycles per month. Parametric and non-parametric analyses were conducted to verify the influence of several aspects of chemotherapy on the adjusted scores of each cognitive test at the two post-operative follow-ups. Results: Sixty-one patients were included at T0; patients with a lower adjuvant TMZ dosage reported a better performance at the visual attention test at T1, and at the deductive reasoning test at T2. Undergoing more than 8 cycles of adjuvant therapy was slightly associated with a better performance at the long-term verbal memory tasks at T2. No other associations were found with the other cognitive tests and autonomy scales administered. Conclusions: TMZ proved to be a secure treatment with no negative side effects on cognition and on level of daily autonomy, even at the highest dosage used. This is a positive finding which enables clinicians to reassure patients about the absence of significant negative effects of TMZ on their daily life functioning. In this view, eventual cognitive changes during treatment might not be attributed to chemotherapy but to other events such as tumour relapse. [ABSTRACT FROM AUTHOR]

Simple Summary: Many people who have completed cancer treatment experience a 'fog' that affects their ability to remember, concentrate, process information, and make decisions. This is known as cancer-related cognitive impairment. There are no purpose-built tools currently available that health professionals can use to understand the needs of cancer survivors who experience cancer related cognitive impairment. To inform the development of such tools, we conducted interviews with (a) cancer survivors with cancer-related cognitive impairment and (b) oncology health professionals to understand the challenges and associated needs of people with cancer-related cognitive impairment. We found five themes describe cancer survivors' challenges and needs relating to cancer-related cognitive impairment: (1) executing regular activities, (2) relational difficulties, (3) occupational functioning, (4) psychological distress, and (5) social functioning, as well as an additional informational needs domain. This research can be used to inform the development of a purpose-built needs assessment for cancer-related cognitive impairment. Many cancer survivors experience cognitive impairments that impact memory, concentration, speed of information processing, and decision making. These impairments, collectively known as cancer-related cognitive impairments (CRCIs), are a key domain of unmet needs and can significantly impact a cancer survivor's identity and quality of life. However, there are no purpose-built, multi-domain, needs assessment tools specifically for CRCI. The development of such tools requires an in-depth understanding of cancer survivors' CRCI-specific challenges and associated needs. This study explored the challenges and associated needs of cancer survivors with persistent CRCI. An in-depth qualitative design using semi-structured interviews with (a) cancer survivors with perceived CRCI (n = 32) and (b) oncology health professionals (n = 19) was utilised. A reflexive thematic analysis of the interviews resulted in five overarching themes: (1) executing regular activities, (2) relational difficulties, (3) occupational functioning, (4) psychological distress, and (5) social functioning, as well as an additional informational needs domain. Ultimately, CRCI was found to directly produce a range of challenges that negatively, and persistently, impact cancer survivors' quality of life. Cancer survivors were also found to have a range of needs associated with these challenges. This research should be used to inform future challenges and needs assessment tools as well as treatment and supportive care priority areas directly relating to CRCI. [ABSTRACT FROM AUTHOR]

Cancer treatment is associated with long lasting cognitive impairment in cancer survivors. This cognitive impairment is often termed cancer related cognitive impairment (CRCI). Cancer survivors treated for tumors outside the central nervous system are increasingly diagnosed with CRCI. The development of strategies to mitigate the negative effects of cancer treatment on the brain are crucial. Although neuroimaging research has proposed several candidate mechanisms, the pathogenic underpinnings of CRCI remain uncertain. As such, preventative and treatment strategies have not been identified. To fill these gaps, animal models play a vital role in isolating underlying contributing mechanisms that promote CRCI and in testing new therapeutic approaches.

Background/aim: Doxorubicin (DOX) is a highly effective chemotherapy medicine commonly used to treat breast cancer; yet, despite its clinical efficacy, it usually causes chemobrain. As a result, we investigated the neuroprotective effects of Diosmin (DIOS) on DOX-induced chemobrain in male rat brains. Animals and methods: In the experimental protocol, Rats were divided into 4 groups: group I received solvent and saline for 56 days, group II received Dios and a concomitant dose of saline for 56 days, group III received DOX intraperitoneally on 7th, 14th, 21st, 28th, 35th, 42nd, 49th and 56th days, and Group IV received DIOS (40 mg/kg P.O.) for 56 days and DOX was administered one hour after DIOS oral administration. The novel-object recognition memory test (NORT) was used to assess non-spatial memory function. Following that, brain neurochemical status were assessed. Results: DIOS increased cognitive performance in DOX-treated rats by enhancing exploration of unfamiliar objects. DIOS protects the brain from DOX-mediated alterations in oxidative status, as well as brain metabolic enzyme indicators. It also decreased MMP-6, IL-6, IL-β1, TNF-α and COX-2 expression, reduced apoptotic markers levels, boosted mTOR protein levels, lowered beclin-1, restored brain metabolic enzyme activities, increased neurotransmitter as well as cathepsin levels, and avoided the rise in α-synuclein and PON1 enzyme activity. Conclusion: In conclusion, DIOS protects rats' brains against DOX-induced chemobrain via oxidative stress inhibition, autophagy modulation, and down-regulation of inflammatory and apoptotic markers.

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI.

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.

Purpose: To examine children’s experiences of chemotherapy-induced cognitive impairment––colloquially “chemobrain”––and the impact on children’s social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors’ lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child’s own voice and/or parent proxy report through an exploration of the qualitative research literature. Methods: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0–18 years) during and/or following chemotherapy treatment and explored children’s experiences of chemobrain. Results: Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children’s experiences primarily related to changes in their academic and social functioning. Conclusion: This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cognitive impairment in cancer patients is known as "chemobrain". Doxorubicin and Cyclophosphamide are two chemotherapeutic agents used in combination to treat solid tumors. L-carnitine was reported for its anti-oxidant and anti-inflammatory activities. The goal of the present study was to elucidate the neuroprotective effect of L-carnitine against chemobrain induced by Doxorubicin and Cyclophosphamide in rats. Rats were divided into five groups: Control group; Doxorubicin (4mg/kg, IV) and Cyclophosphamide (40mg/kg, IV)-treated group; two L-carnitine-treated groups (150 and 300mg/kg, ip) with Doxorubicin and Cyclophosphamide; and L-carnitine alone-treated group (300mg/kg). Doxorubicin and Cyclophosphamide induced histopathological changes in rats' hippocampi and prefrontal cortices, as well as reduced memory as evidenced by behavioural testing. L-carnitine treatment showed opposite effects. In addition, chemotherapy treatment enhanced oxidative stress via reducing catalase and glutathione levels, and inducing lipid peroxidation. By contrast, L-carnitine treatment showed powerful antioxidant effects reversing chemotherapy-induced oxidative damage. Moreover, chemotherapy combination induced inflammation via their effect on nuclear factor kappa B (p65), interleukin-1β, and tumor necrosis factor-α. However, L-carnitine treatment corrected such inflammatory responses. Furthermore, Doxorubicin and Cyclophosphamide reduced synaptic plasticity via hindering expression of brain-derived neurotrophic factor, phosphorylated cyclase response element binding protein, synaptophysin, and postsynaptic density protein 95 whereas protein expression of such synaptic plasticity biomarkers was enhanced by L-carnitine treatment. Finally, acetylcholinesterase activity was found to be enhanced by chemotherapy treatment affecting rats' memory while L-carnitine treatment reduced acetylcholinesterase activity. L-carnitine also showed hepatoprotective and renal protective effects suggesting liver/brain and kidney/brain axes as possible mechanisms for its neuroprotective effects. [ABSTRACT FROM AUTHOR]

Treatment in oncology may lead to several adverse side effects, including those affecting the nervous system. These side effects may reduce the quality of life of patients, both during and after treatment, and may necessitate changes in the treatment regimen or reduction of drug doses, thus reducing the effectiveness of therapy. The knowledge of therapy-induced side effects is essential for their early recognition and differentiation from symptoms resulting from the progression of neoplastic disease, metabolic disorders, or infections, requiring prompt initiation of causal treatment. This article presents the current state of knowledge regarding central and peripheral neurotoxicity of treatment in oncology. Adverse effects described after chemo- and radiotherapy are better known but still limit the potential possibilities of the applied treatment. Neurotoxicities of targeted therapy and immunotherapy, which are of increasing importance in the era of personalization of treatment, are presented. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague–Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV–visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adjuvant chemotherapy for breast cancer is undeniably effective in increasing survival rates but many breast cancer survivors (BCS) exhibit side effects including nausea, fatigue, stress, and neurocognitive deficits, known as "chemobrain." This pilot study explored how neurotherapy, or EEG biofeedback, a non-pharmacological approach, improved neurocognitive, behavioral, and neurophysiological deficits associated with BCS who underwent chemotherapy. Subjects underwent 18 sessions of EEG biofeedback training, in which audio and visual feedback occurred with successful shifting of EEG patterns. Quantitative EEG and assessment tests demonstrated neurophysiological, cognitive, and behavioral deficits in all nine subjects prior to training. EEG biofeedback resulted in significant improvements in neurophysiological, neurocognitive, and psychological functions in all nine subjects after training. We propose that this intervention and related forms of EEG biofeedback have the potential to significantly alleviate common side effects of chemotherapy in BCS and therefore merits additional research attention. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide despite efforts in early diagnosis of the disease and advances in treatment. The use of drugs that exert toxic effects on tumor cells or chemotherapy is one of the most widely used treatments against cancer. However, its low toxic selectivity affects both healthy cells and cancer cells. It has been reported that chemotherapeutic drugs may generate neurotoxicity that induces deleterious effects of chemotherapy in the central nervous system. In this sense, patients report decreased cognitive abilities, such as memory, learning, and some executive functions after chemotherapy. This chemotherapy-induced cognitive impairment (CICI) develops during treatment and persists even after chemotherapy. Here we present a review of the literature on the main neurobiological mechanisms involved in CICI using a Boolean formula following the steps of the PRISMA guidelines that were used to perform statements searches in various databases. The main mechanisms described in the literature to explain CRCI include direct and indirect mechanisms that induce neurotoxicity by chemotherapeutic agents. Therefore, this review provides a general understanding of the neurobiological mechanisms of CICI and the possible therapeutic targets to prevent it..

Highlights • Cisplatin accelerates formation of tau deposits in entorhinal cortex and hippocampus of older female and male mice. • Nasal administration of MSC after cisplatin prevents formation of tau deposits in the brain. • Tau deposits are associated with astrocyte activation but not with activation of microglia. • Most of the tau deposits in cisplatin-treated mice develop in neurons. • Nasal administration of MSC reverses cognitive deficits in older mice treated with cisplatin.

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

Abstract Background The objective of this report is to share the clinicopathological features of chemotherapy-induced toxic leukoencephalopathy, which is a rare and under-recognized disease, clinically characterized by rapidly progressive cognitive loss that often leads to sudden death. Case presentation A 64-year-old woman and a 63-year-old man, who had both suffered from a rapid deterioration of consciousness, were autopsied under the clinical impressions of either the central nervous system graft versus host disease (CNS-GVHD), infectious encephalitis, or autoimmune encephalitis. Both patients had been treated with multiple chemotherapy regimens, including adriamycin, cytarabine arabinoside, daunorubicin, fludarabine, azacitidine, and allogeneic peripheral blood stem cell transplantation to treat hematological malignancies (acute myelogenous leukemia and myelodysplastic syndrome). Neuropathological findings at autopsy revealed rarefaction and vacuolar changes of the white matter with axonal spheroids, reactive gliosis, and foamy macrophage infiltration, predominantly in the visual pathways of the occipital and temporal lobes. Damaged axons exhibited immunoreactivity to beta-amyloid, consistent with axonopathy. However, there was no lymphocyte infiltration that suggested CNS-GVHD or any type of encephalitis. Conclusion The neuropathology found in the presented cases had the characteristic features of toxic leukoencephalopathy (chemobrain). Our cases showed that toxic leukoencephalopathy can also be caused by chemotherapy drugs other than methotrexate.

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 reduce cognitive impairment can be helpful to patients. Nurses can make better assessments and individualized care plans by educating patients about the signs and symptoms of CICI. [ABSTRACT FROM AUTHOR]

The study's primary goal was to enhance medicinal potential of piperine (PIP)-loaded zeolitic imidazolate frameworks-8 (PIP@ZIF-8) against doxorubicin (DOX)-induced cognitive impairments in zebrafish. Herein, PIP@ZIF-8 was synthesized via easy, economical and reproducible ultrasonication method followed by spray drying technology. ZIF-8's structural integrity has been confirmed by PXRD, and even after PIP was encapsulated, the structure of ZIF-8 remained unchanged. Pure ZIF-8 and PIP@ZIF-8 were subjected to TEM analysis, which revealed hexagonal morphology with a nanosize range. FTIR and UV–Visible spectroscopy studies confirmed the drug loading of ZIF-8. Studies on in vitro release revealed 71.48 ± 7.21% and 34.56 ± 5.35% PIP release from PIP@ZIF-8 and unformulated PIP, respectively in pH 7.4. The highest antioxidant scavenging results were obtained with vitamin C (73.77 ± 6.7%) at an intensity of 200 μg/ml, though it was 65.09 ± 2.5% and 57.99 ± 3.1% for PIP@ZIF-8 and PIP, respectively. In vivo studies on zebrafish showed that DOX administration remarkably impaired cognitive activity in T-Maze, and downregulated spatial memory and locomotor activity in the open field test. In addition, DOX administration caused a downregulation in GSH and SOD levels and increase in LPO, AChE and TNF-α levels compared to the vehicle group along with changes in brain histopathology. Further, PIP@ZIF-8 reversed the DOX-induced cognitive impairments by its antioxidant and neuroprotective properties. It can be concluded that PIP@ZIF-8 has a promising therapeutic potential against the chemotherapy-induced cognitive impairments in zebrafish. [Display omitted] • Novel piperine (PIP) loaded zeolitic imidazolate (ZIF-8) metal organic frameworks nanoparticles (PIP@ZIF-8) were prepared using ultrasonication method and dried by spray dryer. • PIP@ZIF-8 nanoparticles were characterized by FTIR, DSC, PXRD, DSC, FE-SEM, EDS and TEM techniques and result showed successful loading of the PIP into the pores of ZIF-8. Physicochemical characterization studies revealed the successful loading of PIP and formation of MOFs. • In vitro release studies demonstrated sustained release over 48 h at pH 7.4. • In vitro antioxidant activitydemonstrated dose dependent antioxidant activity. • Behavioural, biochemical, pro-inflammatory cytokine (TNF-α) and histopathological analysis studies displayed improved neuroprotection activity in chemobrain experimental zebrafish model [ABSTRACT FROM AUTHOR]

Many cancer survivors experience cognitive impairments that impact memory, concentration, speed of information processing, and decision making. These impairments, collectively known as cancer-related cognitive impairments (CRCIs), are a key domain of unmet needs and can significantly impact a cancer survivor’s identity and quality of life. However, there are no purpose-built, multi-domain, needs assessment tools specifically for CRCI. The development of such tools requires an in-depth understanding of cancer survivors’ CRCI-specific challenges and associated needs. This study explored the challenges and associated needs of cancer survivors with persistent CRCI. An in-depth qualitative design using semi-structured interviews with (a) cancer survivors with perceived CRCI (n = 32) and (b) oncology health professionals (n = 19) was utilised. A reflexive thematic analysis of the interviews resulted in five overarching themes: (1) executing regular activities, (2) relational difficulties, (3) occupational functioning, (4) psychological distress, and (5) social functioning, as well as an additional informational needs domain. Ultimately, CRCI was found to directly produce a range of challenges that negatively, and persistently, impact cancer survivors’ quality of life. Cancer survivors were also found to have a range of needs associated with these challenges. This research should be used to inform future challenges and needs assessment tools as well as treatment and supportive care priority areas directly relating to CRCI.

Objectives The aim of the article is to study the changes in the level of cognitive and affective functioning in patients with multiple myeloma undergoing chemotherapy. Material and methods Montreal Cognitive Assessment scale (MoCA) - screening method - was used to determine the general cognitive state of patients. The general level of depression and its characteristic symptoms were determined with the use of Depression Measurement Questionnaire. Results Gathering first initial results of author’s own research – increasing the research sample could indicate an improved cognitive functioning in patients with multiple myeloma during chemotherapeutic treatment. Moreover, the research demonstrates a decrease in depression symptoms, i.e., self-blame and anxiety states, during chemotherapy. Conclusions The study requires further research owing to a small group of research participants (n=21), the presence of research data at the level of statistical tendency, and a need for a comparison with a group of healthy people (without a cancer diagnosis).

Background: There is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus. Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin. Results: We show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production. Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes. Conclusion: In summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life. Highlights: • Cisplatin accelerates formation of tau deposits in entorhinal cortex and hippocampus of older female and male mice. • Nasal administration of MSC after cisplatin prevents formation of tau deposits in the brain. • Tau deposits are associated with astrocyte activation but not with activation of microglia. • Most of the tau deposits in cisplatin-treated mice develop in neurons. • Nasal administration of MSC reverses cognitive deficits in older mice treated with cisplatin. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer survivors can experience neurological complications after exposure to anticancer therapy. Chemotherapy-induced peripheral neurotoxicity (CIPN), mainly consisting of sensory loss and neuropathic pain in hands and feet, is most commonly encountered. Cognitive impairment, although less frequent, is also a severe adverse event, significantly diminishing patients' quality of life. The introduction of immunotherapy has resulted in durable remissions in several types of solid tumor malignancies, although severe neurological immune-related adverse events involving both the central and peripheral nervous system can occur in up to 10% of patients. We herein describe what it is currently known on the topic, and provide directions for future neuroprotection and symptomatic treatment studies. Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy is known to cause cognitive defects in patients. Our study investigated the effect of piracetam (PIRA; 200 or 400 mg/kg) against doxorubicin (DOX)-induced cognitive deficits in a rat model. The cognitive parameters were analyzed using elevated plus-maze, novel object recognition, and Y-maze tests. Acetylcholinesterase (AChE), neuroinflammatory mediators (cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α)), apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl2 associated X protein (Bax), cysteine aspartate specific protease-3 (caspase-3)), oxidative parameters (malondialdehyde (MDA), catalase (CAT), and glutathione (GSH)) were also determined in the brain. PIRA administration offered significant protection against DOX-induced cognitive deficits in all maze tests and restored cholinergic functions via a significant reduction in AChE levels. Additionally, PIRA suppressed DOX-induced neuroinflammatory mediators (COX-2, PGE2, NF-κB, and TNF-α), pro-apoptotic proteins (Bax and caspase-3), and oxidative stress (MDA). Besides, it facilitated antioxidant (CAT and GSH) levels. Hence, our study highlighted that the neuroprotective activity of PIRA against DOX-induced cognitive deficits can be linked to reductions of AChE levels, neuro-inflammatory mediators, pro-apoptotic proteins, and oxidative stress. [ABSTRACT FROM AUTHOR]

Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases, and chemotherapy-related brain changes (known as "chemobrain") in NSCLC patients were found in previous studies. However, the effects of platinum-based chemotherapy on brain structural networks are still unclear. Structural magnetic resonance imaging (sMRI) data were collected from 32 NSCLC patients following platinum-based chemotherapy, 36 NSCLC patients without chemotherapy, and 39 healthy controls. Clinical physiological indicators of patients were collected. Then, morphological similarity networks were constructed using MRI data, and topological properties were calculated using graph theory method. Differences between three groups were investigated using one-way ANOVA and two-sample t-test, and relations between topological properties and clinical physiological indicators were calculated. We found that degree and nodal efficiency in temporal-parietal networks were significantly reduced in NSCLC patients following platinum-based chemotherapy compared to healthy controls/patients without chemotherapy (F-test, p < 0.001; post hoc t-test, p < 0.01, Bonferroni corrected). These changes (p < 0.05) were positively correlated with clinical measures, including thrombocytes, granulocytes and hemoglobin, and were negatively correlated with measures of triglycerides and cholesterol levels. Network properties including clustering coefficient (F(2,104) = 41.435, p < 0.001), number of K-edges (F(2,104) = 40.304, p < 0.001), density of K-edges (F(2,104) = 40.304, p < 0.001), global efficiency (F(2,104) = 42.585, p < 0.001) and small-world (F(2,104) = 37.132, p < 0.001) were also significantly reduced (post hoc t-test, p < 0.01, Bonferroni corrected). These results indicate that platinum-based chemotherapy might cause cerebrovascular damage and clinical indicators' changes, which then cause the properties of morphological similarity networks' changes in the temporal and parietal lobes. This study may help us better understand the "chemobrain" in NSCLC patients. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cognitive impairment (CICI) comprises different neurological problems, including difficulty in learning new things, concentrating and making decisions that affect daily life activities. Clinical reports indicate that around 70% of cancer patients receiving chemotherapy suffer from cognitive impairment. The purpose of the present study is to examine the effects of widely used anticancer medication (Carmustine) on cognitive function using mice model and investigation of the neuroprotective effects of Cerebrolysin (CBN). Cerebrolysin (CBN) is a mixture of several neurotrophic factors and active peptides with anti-inflammatory, antioxidant, and neuroprotective actions. Our study aimed to establish a mice model of Carmustine (BCNU)-induced cognitive deficits and determine the protective effects of CBN. BCNU (10 mg/kg, i.v.) was administered to mice for 28 days, and behavioral parameters were measured on a weekly basis. CBN (44 and 88 mg/kg, i.p.) was administered daily from day 1 to 28 to BCNU treatment mice. All animals were sacrificed on day 29 and brain hippocampus tissues were used for biochemical, neuroinflammatory, neurotransmitters analysis. BCNU administration animals showed impaired cognition and memory, confirmed from behavioral analysis. Further, BCNU increased oxidative stress, inflammatory cytokines release and altered neurotransmitters concentration as compared to the control group (p < 0.01). However, mice treated with CBN (44 and 88 mg/kg, i.p.) significantly and dose-dependently improved cognitive functions, reduced oxidative stress markers, inflammatory cytokines and restored neurotransmitters concentration as compared to BCNU administered mice (p < 0.05). The finding of current study suggested that CBN could be the promising compound to reverse cognitive impairment associated with use of chemotherapy. [ABSTRACT FROM AUTHOR]

Tabebuia impetiginosa (Bignoniaceae) was traditionally used for memory enhancement and central nervous system (CNS) stimulation. Aim of the study : This study aims to create a metabolic profile of the ethyl acetate fraction of T. impetiginosa (TEF) and investigate for the first time its neuroprotective potential on cyclophosphamide (CP)-induced chemobrain, validating its traditional use. Metabolite profiling of TEF was performed using Liquid Chromatography coupled with Quadrupole Time of Flight-Mass/Mass Spectrometry (LC-qTOF-MS/MS). For the in vivo study, CP (200 mg/kg, i.p.) was administered to induce cognitive impairment in rats; TEF (30 mg/kg, p.o.) was administered throughout the 14 days of the experiment to assess its role in mitigating CP-induced neuronal deficits. Behavioral tests including locomotor, Y-maze, and passive avoidance tests were conducted. Additionally, biochemical markers such as reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and caspase-3 immunoexpression were assessed in the hippocampus area. Forty-four phytoconstituents were tentatively identified in TEF, mainly iridoids and organic acids. TEF showed significant memory enhancement as evidenced by the increase in step-through latency in the passive avoidance test by 1.5 folds and the increase in sequence alternation percentage (SAP) in the Y-maze test by 67.3%, as compared to CP-group. Moreover, it showed pronounced antioxidant and anti-inflammatory potentials evidenced by the significant elevation in reduced glutathione (GSH) levels by 80% and a pronounced decline in MDA and TNF-α levels by 24% and 45%, respectively relative to the CP group. TEF treatment restored normal hippocampal histological features and attenuated apoptotic caspase-3 expression by 70% compared to the CP group. TEF can act as a promising natural scaffold in managing the chemobrain induced by CP in cancer patients. [Display omitted] • Metabolic profiling of its ethyl acetate fraction (TEF) was done by LC/MS/MS. • Forty-four compounds were identified in TEF mainly iridoids and organic acids. • TEF exhibited pronounced antioxidant and anti-inflammatory potentials. • It also showed promising neuroprotective effect in in vivo chemobrain model. [ABSTRACT FROM AUTHOR]

Amantadine (AMA) is a useful drug in neuronal disorders, but few studies have been performed to access its toxicological profile. Conversely, doxorubicin (Dox) is a well-known antineoplastic drug that has shown neurotoxic effects leading to cognitive impairment. The aims of this study are to evaluate the cytotoxic, genotoxic, and mutagenic effects of AMA, as well as its possible protective actions against deleterious effects of Dox. The Salmonella/microsome assay was performed to assess mutagenicity while cytotoxicity and genotoxicity were evaluated in SH-SY5Y cells using MTT and comet assays. Possible modulating effects of AMA on the cytotoxicity, genotoxicity, and mutagenicity induced by Dox were evaluated through cotreatment procedures. Amantadine did not induce mutations in the Salmonella/microsome assay and decreased Dox-induced mutagenicity in the TA98 strain. AMA reduced cell viability and induced DNA damage in SH-SY5Y cells. In cotreatment with Dox, AMA attenuated the cytotoxicity of Dox and showed an antigenotoxic effect. In conclusion, AMA does not induce gene mutations, although it has shown a genotoxic effect. Furthermore, AMA decreases frameshift mutations induced by Dox as well as the cytotoxic and genotoxic effects of Dox in SH-SY5Y cells, suggesting that AMA can interfere with Dox mutagenic activity and attenuate its neurotoxic effects. • Amantadine increases strand break DNA in SH-SY5Y cells. • Frameshift mutations induced by doxorubicin are inhibited for amantadine. • The combination amantadine plus doxorubicin increases the cell viability of SH-SY5Y cells. • Amantadine decreases the genotoxicity of doxorubicin in SH-SY5Y cells. [ABSTRACT FROM AUTHOR]