Trimetazidine protects against doxorubicin-induced chemobrain in rats: Insights into energy imbalance and neuroinflammation.

Background: Chemotherapy-related hepatotoxicity may weaken the patient so much that the desired course of treatment is not achieved. Therefore, it is better to combine antioxidant therapy with doxorubicin (DOX). Vitamin E (Vit E) or trimetazidine (TMZ) were administered as antioxidants in this study. Objectives: In this study, the reparative effects of Vit E and TMZ administration on DOX-induced hepatotoxicity were investigated. Methods: Animals included 25 male BALB/c mice divided into five groups (n = 5). The groups included sham: No administration; DOX: An accumulative dose of 25 mg/kg/i.p. in the days 12, 13 and 14 of experiment; Vit E: Twice administration of 200 IU/kg PO for 10 days followed by DOX therapy; TMZ: Ten mg/kg/day for 10 days followed by DOX therapy; and Vit E-TMZ: Administration of Vit E and TMZ for 10 days followed by DOX therapy. On day 15, blood and liver tissue samples were collected after euthanasia. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels were measured to assess the severity of liver lesions. Half of the liver tissue was examined for histopathology. The other half for the liver was examined for total antioxidant capacity (TAC) and malondialdehyde measurements, as well as for examining the expression of TNFα (inflammation) and Bax (apoptosis) genes. Histopathological scoring for necrosis, vacuolar degeneration, and inflammation was from 0 to 3 based on the severity of the lesions. Results: The DOX group had the most liver tissue problems. In some areas, necrosis, vacuolation, and inflammation were seen. Liver-related enzymes such as GGT, ALT and AST were increased in DOX compared the others (P < 0.0001). The liver TAC level was only significant between the DOX group and the Vit E-TMZ group (P < 0.01). The liver MDA levels were highest in the DOX group and were significant with sham (P < 0.0001), Vit E (P < 0.05) and the other (P < 0.01) groups. In addition, TNF-α and Bax genes expression appeared much higher in the DOX group and were significant with sham (P < 0.0001) the other groups than normal. Regarding the other groups, it should be noted that in the Vit E or TMZ group, the amount of liver damage, liver-related enzymes, and TNFα and Bax expression increased compared to the DOX group but was not lower than the sham group. On the other hand, the Vit E-TMZ group showed the best results in terms of the significance of reducing damage, inflammation levels, and apoptosis. Conclusions: The simultaneous use of Vit E and TMZ reduces microscopic DOX induced liver lesions. This combination had effective reducing effects on the inflammatory factor TNF-alpha and the number of apoptotic cells after DOX administration.

Few studies have reported a prophylactic effect of the anti-ischemic trimetazidine (TRI) against cardiac toxicity caused by adriamycin (ADR). However, the mechanism of action of TRI remained incomplete. The cardioprotective mechanism(s) of TRI against ADR-induced cardiotoxicity was investigated in this study. Cardiotoxicity was induced in three groups of Wistar rats by injecting a single dose of ADR (10 mg/kg, i.p.). TRI was administered in two doses regimen, low (L) (2.5 mg/kg, i.p.) and high (H) (10 mg/kg, i.p.). The results of the study showed that both TRI L and H doses improved cardiac enzymes and pathology, while only the TRI H dose improved the electrocardiogram. Both TRI L and H doses decreased malondialdehyde and increased reduced glutathione and superoxide dismutase. Only TRI H dose increased glutathione peroxidase and catalase. Both TRI L and H doses decreased interleukin-1 beta and tumor necrosis factor-alpha (TNF-α). Both TRI L and H doses downregulated TNF-α, BAX, and vascular endothelial growth factor cardiac protein expression. The data obtained in this study provided evidence that TRI opposed ADR-induced cardiotoxicity. The mechanism could be due to improved antioxidant levels as well as inhibition of inflammation and programmed cell death.

In the present article, we report on the semi-quantitative proteome analysis and related changes in protein expression of the MCF-7 breast cancer cell line following treatment with doxorubicin, using the precursor acquisition independent from ion count (PAcIFIC) mass spectrometry method. PAcIFIC represents a cost-effective and easy-to-use proteomics approach, enabling for deep proteome sequencing with minimal sample handling. The acquired proteomic data sets were searched for regulated Reactome pathways and Gene Ontology annotation terms using a new algorithm (SetRank). Using this approach, we identified pathways with significant changes (≤0.05), such as chromatin organization, DNA binding, embryo development, condensed chromosome, sequence-specific DNA binding, response to oxidative stress and response to toxin, as well as others. These sets of pathways are already well-described as being susceptible to chemotherapeutic drugs. Additionally, we found pathways related to neuron development, such as central nervous system neuron differentiation, neuron projection membrane and SNAP receptor activity. These later pathways might indicate biological mechanisms on the molecular level causing the known side-effect of doxorubicin chemotherapy, characterized as cognitive impairment, also called 'chemo brain'. Mass spectrometry data are available via ProteomeXchange with identifier PXD002998.

Based on the murine model, this study explored the efficacy of Fangxia-Dihuang Decoction (FXDH) in interfering with cognitive impairment induced by doxorubicin (DOX) after chemotherapy for breast cancer. Build 4T1 breast cancer xenograft tumor model in Balb/c mice, intraperitoneal injection of DOX (5mg/kg) once a week, build the model of DOX induced chemotherapy related cognitive impairment (CRCI), and the administration lasted for three weeks. From the first week, while DOX was given, FXDH was given high, medium and low doses by gavage every day. Conduct Y-maze and Novel object recognition (NOR) tests, detect inflammatory factors and oxidative stress-related indicators in serum and hippocampus, observe neuroinflammation and neurodegenerative changes through immunofluorescence and Nissl staining. Observation of heart and liver injury through blood routine and cardiac Hematoxylin-Eosin(HE)Staining. Administration of FXDH significantly improved cognitive impairment in mice. FXDH reduced the levels of pro-inflammatory cytokines IL-6, IL-12p70, and TNF-α (P<0.05), and increased the levels of anti-inflammatory cytokines IL-10 and IL-4 (P<0.05). FXDH increased the levels of GSH, GSH-PX, SOD, and CAT in serum and hippocampus (P<0.05), and decreased the level of MDA (P<0.05). The results of Nissl staining and immunofluorescence staining showed that FXDH improved the neurodegenerative lesions caused by DOX and the neuroinflammatory response in the hippocampus (P<0.05). The intermediate dose group of FXDH showed better efficacy. The results of blood routine and cardiac HE staining showed that compared with the 4T1 group, the serum ALT, AST, CK, LDH, and CKMB in DOX group mice were significantly increased (P<0.05). After FXDH administration, all indicators in mice were decreased, but there was no statistical difference. FXDH improved the disordered arrangement of myocardial cells, uneven cytoplasmic staining, and loose and disordered arrangement of myocardial fibers caused by DOX. In the animal model, FXDH has the effect of anti-cognitive impairment after chemotherapy for breast cancer, and can improve the DOX induced learning, memory and cognitive impairment in mice. FXDH can reverse DOX induced neuroinflammation by improving the neurodegenerative changes caused by DOX, reducing pro-inflammatory cytokine levels in mouse serum and hippocampus, increasing anti-inflammatory cytokine levels, and reducing oxidative stress response.

Background: Cognitive complaints (“chemo brain”) are reported frequently after breast cancer treatment but little is known about its incidence and causes. Before we can intervene we need to be able to diagnose it properly. Mini Mental state examination (MMSE) can detect advanced Alzheimer's but won't help in detecting mild cognitive disturbances. We used Montreal Cognitive Assessment for Telephone (MoCA-T) and full scale Montreal Cognitive Assessment for Telephone (MoCA) to diagnose mild cognitive impairments in patients having normal MMSE. Methods: 20 breast cancer survivors aged 50 years or older completed MoCA-T and MoCA, a year after they completed their treatment for breast cancer, describing the impact of their treatment regimen on their short term memory and ability to think and concentrate. On Day 5, they underwent a standardized laboratory protocol that assessed both behavioral and electroencephalographic (EEG) indicators of memory consolidation. Results: Patient characteristics: 20 postmenopausal breast cancer survivors aged 50 or above participated in the study a year after they completed their therapy. We are reporting preliminary results of 10 patients. Patients had stage I-III disease (stage I – One patient, Stage II – five patients, and stage III- four patients). All of them received various chemo regimens e.g. Cytoxan, methotrexate, 5-FU (CMF), Taxol, Trastuzumab (TH), Adriamycin (AC), taxotere, carboplatin (TCH). 8/10 patients received adjuvant radiation. 1/10 patient underwent reconstruction later. 7/10 patients received hormonal therapy with aromatase inhibitors. Results of MoCA –T and MoCA: MoCA-T, tests attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. Possible scores range from 0-22 and scores &amp;lt;18 indicate mild cognitive impairment. The MoCA has possible scores from 0-30 and a score &amp;gt;26 is normal but &amp;lt;19 is indicative of cognitive impairment. 5/10 patients had abnormal MoCA and 3/10 patients had impaired MoCA-T signifying that almost 50%patients develop mild cognitive impairment after breast cancer treatment. During memory consolidation, EEG contained less theta and frequent bursts of alpha waves which is commonly seen in patients with neuropathic pain and insomnia. MoCA-T and MoCA results for the patientsPatient no.MoCA-TMoCAPtient 00817*23*Patient 0102126Patient 0111923*Patient 01216*27Patient 0132027Patient 01517*21*Patient 0161824*Patient 0172025*Patient 0191926Patient 0202129*presents affected patient Conclusions: The study signifies that mild cognitive impairment from breast cancer treatment (or “chemo brain”) was frequently reported and MoCA-T and MoCA tests were able to show even mild cognitive impairment in these patients. We are compiling our full data for EEG but the early results show that the patients had less theta but had frequent bursts of alpha waves, a pattern seen commonly in patients with insomnia and neuropathic pain. They retain fewer items and take more time responding to items as compared to normal people. We need more studies to diagnose and treat mild cognitive impairment (“chemo brain”) in breast survivors as most of these patients are still working and can be a valuable part of the community. Citation Format: Razaq WA, Tanaka T, Carlson B, Wenger M, Friedman J, Benbrook D, Craft M. Diagnosing cognitive impairment (“chemo brain”) in breast cancer survivors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-20-09.

Many survivors of childhood cancer experience significant side effects leading to inferior quality of life like chemotherapy-induced cognitive impairment (CICI). A growing body of literature implies that the gut-brain axis modulates neurological and inflammatory physiology. Cancer therapy may alter the gut microbiome in ways that modify the risk of CICI. We utilized a commonly used pediatric cancer chemotherapy drug, doxorubicin (DOXO), in our juvenile rat model, including both male and female rats. At 5 weeks of age, Long Evans rats were treated with weekly intraperitoneal DOXO (2mg/kg/dose for 4 weeks). Compared to PBS-treated rats, DOXO treatment caused impairment of visual memory among female rats and spatial memory among male rats, when tested 3-4 weeks after DOXO exposure. In both sexes, DOXO-induced cognitive deficits do not persist among the surviving animals. Microbiome analyses were conducted in fecal samples collected 48hours following the final DOXO injection. Compared to PBS-treated rats, female DOXO-treated rats had significant differences in beta diversity. Significant changes in the abundances of specific species, genera, and phyla were observed. These experimental results set the stage for further investigations of how chemotherapy-induced changes in gut microbiome might contribute to CICI, and point toward therapeutic interventions.

Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro–/– female mice with doxorubicin (DOX) because Ptpro–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment.

Cognitive impairment (impairment of memory, attention, or concentration) is documented in 17-75% of patients with various malignancies treated with chemotherapeutic agents that worsen quality of life. CRCI affects patients of all ages. The impairment of cognitive function in connection with chemotherapy is usually mild, but an event. relationship with dementia remains to be confirmed. Chemotherapy in combination with radiotherapy in Hodgkin lymphoma can cure 80-90% of patients. This review summarizes the most frequently observed changes in cognitive function in patients suffering from CRCI. The article further describes the possible pathophysiological mechanisms behind these changes and the risk factors that can increase the likelihood of cognitive functional impairment after chemotherapy of malignant tumors. Special attention is given to how this relates to Hodgkins lymphoma. We also discuss the neuroprotective factors involved in chemotherapy-related cognitive impairment and its treatment options. Changes occur mainly in the ability to learn and remember, in the speed of reactions, and in attention and executive functions. Although CRCI pathophysiological mechanisms are complex and not yet fully understood, the involvement of neurotoxicity, such as that induced by treatment, anemia, higher levels of oxidative stress and inflammatory responses, genetic factors, and reduced brain connectivity is discussed. CRCI is further modified by comorbidities and patient age. Pharmacological and nonpharmacological treatment options for CRCI are outlined.Key words: Hodgkin lymphoma - chemotherapy - cognitive impairment - risk factors The project was supported by the grant of the Agency for the Czech Republic Health Research of the Ministry of Health of the Czech Republic 16-29857A and by the project Sustainability for the National Institute of Mental Health No. LO1611 with a financial support of the Ministry of Education, Youth and Sports of the Czech Republic in the frame of the National Sustainability Programme I. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 29. 9. 2016Accepted: 12. 2. 2017.

Trying to unravel the mysteries of chemobrain

To review the etiology and assessment of chemotherapy-related cognitive impairment (CRCI). To explore current treatment and prevention strategies for CRCI and propose future research goals in the field of gynecologic oncology. Computerized searches in PubMed of cognitive impairment in cancer between 2000 and 2012 were conducted. The inclusion criteria were randomized control trials evaluating treatment of CRCI and search terms 'cognitive function, cognitive impairment, cognitive decline, chemobrain, chemofog, and cancer'. To date, numerous modalities have been utilized for assessing CRCI in patients undergoing therapy. It has been proposed to move towards web-based assessment modalities as a possible standard. Few studies have aimed to elucidate possible treatment and prevention options for CRCI; even less in the field of gynecologic oncology. Only seven of these studies were subjected to randomized control trials. Only one of these studies looked at treatment in patients with gynecologic cancers. The etiology of CRCI is multi-factorial. Following from this, there is no consensus on the best way to assess CRCI although objective measures are more reliable. One must extrapolate data from the non-gynecologic cancer literature, even venturing to non-cancer literature, to explore the treatment and prevention of CRCI. The methods found in these areas of research have not yet been applied to CRCI in gynecologic oncology.

Relationships Between Chemotherapy-Related Cognitive Impairment, Self-Care Ability, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Study

Generation of ten human induced pluripotent stem cell lines (hiPSCs) from patients with and without Chemotherapy-Induced Peripheral Neuropathy (CIPN) and Post Chemotherapy Cognitive Impairment (PCCI).

BackgroundThe changes in inflammation and tumor biomarkers are associated with the anti-tumor immunological processes. Early detection and intervention are of great significance to the clinical management of cancer-related diseases. Peripheral blood biomarkers [e.g., neutrophil-to-lymphocyte ratio (NLR), carcinoembryonic antigen (CEA), and carbohydrate antigen 153 (CA153)] are obtained in real-timely, conveniently, and less invasively, and proved to availably predicted the disease states and prognosis of various cancers, including breast cancer (BC). Inflammation and poor disease management promote cognitive impairment. Chemotherapy-related cognitive impairment (CRCI) hazard long-term survival and quality of life (QOL) of BC patients, but its correlation with NLR, CEA, and CA153 is not clear.PurposeThis study aimed to investigate changes in NLR, CEA, and CA153 levels before and after chemotherapy and their correlation with CRCI in patients with early-stage BC.Materials and methodsThe 187 patients with BC who were measured for NLR, CEA, and CA153 values within the first 24 hours of admission, were assigned into two groups: the before/after chemotherapy group (BCG/ACG). The ACG was assigned into two subgroups based on the cognitive assessment results: the cognitive normal/impaired group (CNG/CIG). Patients’ self-perceived cognitive impairments were evaluated using a mini-mental state examination (MMSE), prospective and retrospective memory (PM and RM) questionnaire (PRMQ), and functional assessment of cancer therapy-cognitive function version 3 (FACT-Cog, version 3, including CogPCI, CogOth, CogPCA, and CogQOL). Their QOL was also evaluated.ResultsThe NLR and CA153 levels were elevated after chemotherapy (BCG vs ACG: Z = −1.996 and −1.615, P = 0.046 and 0.106, respectively), and significantly elevated in patients with CRCI (BCG vs CIG: Z = −2.444 and -2.293, P = 0.015 and 0.022; respectively). However, there was not reach significant difference in CEA levels between the four groups. In addition, there was a weak to moderate correlation between peripheral blood biomarkers (NLR, CEA, and CA153) levels and CRCI (r = −0.404, −0.205, −0.322; respectively; P < 0.001). Cognitive impairment scores (MMSE, PM, RM, and FACT-Cog) had a strong correlation with QOL in patients with early-stage BC (r = −0.786, 0.851, 0.849, and 0.938; respectively; P < 0.001).ConclusionNLR and CA153 m be valuable diagnostic adjuncts of CRCI, and CRCI has a strong correlation with QOL in patients with early-stage BC.

Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts the quality of life. Despite extensive research into the multifactorial causes of CICI, there are no FDA approved drugs available to prevent it and the interpatient variability in susceptibility to CICI is not well understood. Among pediatric cancer survivors, those with the E4 allele of Apolipoprotein E (ApoE) are more likely to exhibit cognitive dysfunction than those with the more prevalent ApoE3 allele, suggesting the ApoE4 allele increases susceptibility to CICI. To mimic a curative pediatric treatment regimen, in our experimental model, five-week-old rats homozygous for either human ApoE3 or ApoE4 allele were treated with doxorubicin (DOXO) (2mg/kg/week for 4 weeks) or saline. ApoE4 rats were more likely than ApoE3 rats to exhibit DOXO-induced impairments in visual memory. However, there was no difference between ApoE3 and ApoE4 rats in sensitivity to DOXO-induced spatial memory impairments. Contrast-enhanced magnetic resonance imaging (MRI) was done to evaluate the blood-brain barrier (BBB) integrity because of literature suggesting that the ApoE4 allele contributes to BBB weakness. However, no significant difference was observed in the BBB integrity between ApoE3 and ApoE4 rats. To delve deeper into the neuropathological basis of DOXO-induced cognitive impairment on the ApoE4 allele, ongoing experiments involve immunohistochemical analyses targeting neurogenic changes in neural stem cell proliferation (DCX), neuronal maturation (Syn and PSD95), as well as glial differentiation (Iba1 and GFAP) in brain regions including hippocampus (dentate gyrus) and cortex. Additionally, to determine the effect of DOXO treatment on ApoE4, we are investigating the role of mitogen-activated protein kinase (MAPK) signaling pathways within brain regions pertinent to memory and recognition. In summary, ApoE genotype contributes to differential susceptibility to CICI. Citation Format: Chadni Patel, Jeremy Willekens, Frank Diglio, Peter Cole. ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7452.