Neuroprotective effect of herbal extracts inhibiting soluble epoxide hydrolase (sEH) and cyclooxygenase (COX) against chemotherapy-induced cognitive impairment in mice.

Chemotherapy-induced cognitive impairment (CICI) is a novel clinical condition characterized by memory, learning, and motor function deficits. Oxidative stress and inflammation are potential factors contributing to chemotherapy's adverse effects on the brain. Inhibition of soluble epoxide hydrolase (sEH) has been proven effective in neuroinflammation and reversal of memory impairment. The research aims to evaluate the memory protective effect of sEH inhibitor and dual inhibitor of sEH and COX and compare its impact with herbal extracts with known nootropic activity in an animal model of CICI. In vitro sEH, the inhibitory activity of hydroalcoholic extracts of Sizygium aromaticum, Nigella sativa, and Mesua ferrea was tested on murine and human sEH enzyme as per the protocol, and IC50 was determined. Cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and fluorouracil (5 mg/kg) combination (CMF) were administered intraperitoneally to induce CICI. The known herbal sEH inhibitor, Lepidium meyenii and the dual inhibitor of COX and sEH (PTUPB) were tested for their protective effect in the CICI model. The herbal formulation with known nootropic activity viz Bacopa monnieri and commercial formulation (Mentat) were also used to compare the efficacy in the CICI model. Behavioral parameter such as cognitive function was assessed by Morris Water Maze besides investigating oxidative stress (GSH and LPO) and inflammatory (TNFα, IL-6, BDNF and COX-2) markers in the brain. CMF-induced CICI, which was associated with increased oxidative stress and inflammation in the brain. However, treatment with PTUPB or herbal extracts inhibiting sEH preserved spatial memory via ameliorating oxidative stress and inflammation. S. aromaticum and N. sativa inhibited COX2, but M. Ferrea did not affect COX2 activity. Lepidium meyenii was the least effective, and mentat showed superior activity over Bacopa monnieri in preserving memory. Compared to untreated animals, the mice treated with PTUPB or hydroalcoholic extracts showed a discernible improvement in cognitive function in CICI.

Chemical characterization of the polyphenolic rich fraction of Thunbergia erecta and its therapeutic potential against doxorubicin and cyclophosphamide-induced cognitive impairment in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Thunbergia erecta (Benth.) was traditionally used as anxiolytic, sedative and antidepressant. AIM OF THE STUDY: The study aimed to characterize T. erecta leaf ethyl acetate fraction of alcohol extract (TEAF) and evaluate its neuroprotective effect on doxorubicin and cyclophosphamide-induced chemobrain. MATERIALS AND METHODS: Chemical profiling of TEAF was done using (Liquid chromatography coupled with mass (LC-ESI-MS/MS). In vivo chemobrain model was performed by cognitive impairment induced by doxorubicin and cyclophosphamide. Behavioral assessments included moris water maze, y maze, novel object recognition task and passive avoidance tests. Histological examination and oxidative stress markers were investigated. Protein expression of HMDGB1/RAGE/pNF-κB pathway markers was done using western blotting. All results were applied to hippocampus and prefrontal cortex of rats. Molecular docking was done within the active sites of Human Receptor for Advanced Glycation Endproducts (RAGE) using Discovery studio software. RESULTS: Twenty-one phytoconstituents, mostly polyphenolics, were characterized in TEAF of which eleven compounds were tentatively identified for the first time from T. erecta leaves where rosmarinic acid (11) represents the most prevailing compound. TEAF resulted in a marked dose-dependent amelioration of the histopathological changes evidenced by normal histological structure demonstrated in the hypocampal gesture of rats. TEAF demonstrated an enhanced memory and learning functioning in the different behavioral tests assessed especially at 200 mg/kg. It showed significant long-term spatial memory enhancement manifested by 50.32% increase in probe trial relative to chemobrain-induced group. It showed pronounced antioxidant activity evidenced by the significant elevation of prefrontal cortical and hippocampal reduced glutathione levels by 2.45 and 2.65 folds, respectively relative to the chemobrain-induced group. The pronounced reduction in hydrogen peroxide (1.24-1.93 folds) and malondialdehyde levels (1.42-2.60 folds) with significant elevation of catalase activity (12.65-31.47%) induced by TEAF supported its potent antioxidant activity. TEAF reversed the inflammatory cytokines release induced by chemotherapy via its interference with HMGB1/RAGE pathway suppressing the expression of HMBG1, RAGE, p65 (NF-kB), and IL-1ß. In silico studies showed that rosmarinic acid displayed the best fitting at the active site of RAGE (ΔG = -40.39 kcal/mol). CONCLUSIONS: Thunbergia erecta can act as a promising remedy for chemobrain that further consolidates its traditional importance.

The Managing Cancer and Living Meaningfully (CALM) Intervention Alleviates Chemotherapy-Related Cognitive Impairment in Patients with Breast Cancer by Modulating Pan-Immune-Inflammation Values.

BACKGROUND: The number of patients with breast cancer is increasing worldwide, resulting in a growing number of patients with chemotherapy-related cognitive impairment (CRCI), which seriously affects their quality of life. CRCI is associated with inflammatory factors and systemic inflammatory markers such as pan-immune-inflammation value (PIV) and monocyte-to-lymphocyte ratio (MLR), which can reflect the level of inflammation in the body. While the Managing Cancer and Living Meaningfully (CALM) intervention has been demonstrated to alleviate CRCI in patients with breast cancer, the specific mechanism remains unclear. OBJECTIVE: This study evaluated the impact of the CALM intervention on systemic inflammation. METHODS: Ninety patients with breast cancer with CRCI were enrolled and randomized into care as usual (CAU) and CALM intervention groups. All patients were assessed using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Mini-Mental State Exam (MMSE), and Functional Assessment of Cancer Therapy-Breast (FACT-B) before and after the CAU/CALM intervention. The blood levels of inflammatory markers were also analyzed before and after the intervention. RESULTS: Compared to the CAU group, the CALM group showed significantly improved cognitive function and significantly decreased PIV (P < .05). PIV was significantly negatively correlated with FACT-Cog (P < .05). The levels of other inflammatory markers, including MLR, neutrophil-to-lymphocyte ratio (NLR), granulocyte-to-lymphocyte ratio (GLR), and systemic immune-inflammation index (SII), were also reduced in the CALM group. CONCLUSION: PIV is an important marker of inflammation. The CALM intervention may improve the cognitive function of patients by regulating the systemic inflammation marker PIV through the neuroimmune axis.

Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial.

BACKGROUND: Chemotherapy-related cognitive impairment (CRCI) is highly prevalent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the preventive effects of probiotics on CRCI development and underlying mechanisms. METHODS: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats. RESULTS: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8-dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats. CONCLUSION: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8-dien-7-ol. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www.chictr.org.cn/showproj.aspx?proj=24294].

Dietary agents in mitigating chemotherapy-related cognitive impairment (chemobrain or chemofog): first review addressing the benefits, gaps, challenges and ways forward.

Chemobrain or chemofog is one of the important but less investigated side effects, where the cancer survivors treated with chemotherapy develop long-term cognitive impairments, affecting their quality of life. The biological mechanisms triggering the development of chemobrain are largely unknown. However, a literature study suggests the generation of free radicals, oxidative stress, inflammatory cytokines, epigenetic chromatin remodeling, decreased neurogenesis, secretion of brain-derived neurotropic factor (BDNF), dendritic branching, and neurotransmitter release to be the cumulative contributions to the ailment. Unfortunately, there is no means to prevent/mitigate the development and intensity of chemobrain. Given the lack of effective prevention strategies or treatments, preclinical studies have been underway to ascertain the usefulness of natural products in mitigating chemobrain in the recent past. Natural products used in diets have been shown to provide beneficial effects by inhibition of free radicals, oxidative stress, inflammatory processes, and/or concomitant upregulation of various cell survival proteins. For the first time, this review focuses on the published effects of astaxanthin, omega-3 fatty acids, ginsenoside, cotinine, resveratrol, polydatin, catechin, rutin, naringin, curcumin, dehydrozingerone, berberine, C-phycocyanin, the higher fungi Cordyceps militaris, thyme (Thymus vulgaris) and polyherbal formulation Mulmina™ in mitigating cognitive impairments in preclinical models of study, and also addresses their potential neuro-therapeutic mechanisms and applications in preventing/ameliorating chemobrain.

The Promise of Nutrient-Derived Bioactive Compounds and Dietary Components to Ameliorate Symptoms of Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors.

OPINION STATEMENT: One of the most burdensome symptoms reported by breast cancer patients is chemotherapy-related neurocognitive impairment. It is estimated that of the 11 million cancer survivors in the USA, 22% of them are breast cancer patients. The National Cancer Institute classified chemotherapy-related cognitive impairment (CRCI) as one of the most debilitating sequelae of cancer therapy, limiting this patient population from recommencing their lives prior to the diagnosis of breast cancer. Currently, there are no strategies that are established to prevent, mitigate, or treat CRCI. In addition to surviving cancer, quality of life is critical to cancer survivors. Based on the multiple and complex biological and psychosocial etiology, the varying manifestation and extent of cognitive decline documented in breast cancer survivors, possibly attributed to varying combinations of chemotherapy and dose and duration of therapy, multimodal interventions combining promising nutrient-derived bioactive compounds with antioxidant and anti-inflammatory properties, in addition to structured cognitive training and exercise regimens, can work synergistically to reduce inflammation and oxidative stress with significant improvement in cognitive function resulting in improvements in quality of life of breast cancer survivors.

Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. ß values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. Conclusions and Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Managing Cancer and Living Meaningfully (CALM) Intervention on Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors.

Objective: To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully (CALM), which is used to reduce chemotherapy-related cognitive impairment (CRCI), relieve psychological distress, and improve quality of life (QOL) in Chinese breast cancer survivors (BCs). Methods: Seventy-four BCs were enrolled in this study. All patients were randomly assigned to either the CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Distress Thermometer (DT), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) before and after CALM or CAU application to BCs with CRCI. We compared the differences in all these scores between the CALM group and the control group and analyzed the correlation between cognitive function and QOL. Results: Compared with the CAU group, the performance of the CALM group on the FACT-Cog, DT, and FACT-B showed significant differences before and after CALM (t = -18.909, -5.180, -32.421, P = .000, .000, .000, respectively). Finally, there was a positive correlation between cognitive function and QOL in breast cancer patients before (r = 0.579, P = .000) and after (r = 0.797, P = .000) treatment. Conclusions: The present results indicated that CALM has salutary effects on the improvement of cognitive impairment and QOL and relieves psychological distress in breast cancer patients, which may be due to a positive correlation between psychological distress and cognitive function or QOL.

Chemotherapy-related cognitive impairment in patients with breast cancer based on MRS and DTI analysis.

The purpose of this study is to investigate chemotherapy-related cognitive impairment (CRCI) in breast cancer patients, analyze absolute concentration and structural changes of metabolites in different brain regions by multimodal neuroimaging technology, and explore correlation between them. Breast cancer patients with chemotherapy treatment group (Ctx+, N = 24) and control group without treatment (Ctx-, N = 20) underwent neuropsychological tests, multivoxel magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before and after chemotherapy. Regions of interest (ROls) in magnetic resonance scan include bilateral posterior cingulate gyrus (PCG), bilateral dorsal thalamus (DT), bilateral lenticular nucleus (LN), bilateral posterior horn of the lateral ventricle paratrigonal white matter (PWM). In MRS, absolute concentrations of N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), total creatine (tCr), glutamine + glutamate (Glx) were quantified using LC Model and SAGE software. In DTI, we used fractional anisotropy (FA) and mean diffusivity (MD) to reflect white matter integrity. In Ctx+ patients, scores of functional assessment of cancer treatment cognition test (FACT-Cog), perceived cognitive impairments (PCI), impact of perceived impairments on quality of life (QOL), perceived cognitive abilities (PCA), auditory-verbal learning test (AVLT) recognition and clock drawing test (CDT) were lower than those before chemotherapy (p < 0.05). In MRS, Ctx+ patients had significantly lower NAA values in bilateral PCG, DT, respectively. The concentrations of tCr were observed to decline in bilateral PCG and right DT. Glx values decreased in right DT. Cho values decreased significantly in bilateral DT. In DTI, Ctx+ patients had lower FA values in bilateral PCG compared with patients before chemotherapy. Among imaging metrics and cognitive scores, positive correlations were observed between changes in AVLT recognition scores and changes in NAA values in bilateral PCG (left PCG: r = 0.470, p < 0.01; right PCG: r = 0.500, p < 0.01). Positive correlations were also found between changes in AVLT recognition and changes in FA values in bilateral PCG (left PCG: r = 0.513, p < 0.01; right PCG: r = 0.563, p < 0.01). Chemotherapy can lead to a decrease in memory function, accompanied by changes in brain metabolite concentration and white matter integrity in some parts of brain.

Electroacupuncture trigeminal nerve stimulation plus body acupuncture for chemotherapy-induced cognitive impairment in breast cancer patients: An assessor-participant blinded, randomized controlled trial.

Chemotherapy causes various side effects, including cognitive impairment, known as 'chemobrain'. In this study, we determined whether a novel acupuncture mode called electroacupuncture trigeminal nerve stimulation plus body acupuncture (EA/TNS + BA) could produce better outcomes than minimum acupuncture stimulation (MAS) as controls in treating chemobrain and other symptoms in breast cancer patients. In this assessor- and participant-blinded, randomized controlled trial, 93 breast cancer patients under or post chemotherapy were randomly assigned to EA/TNS + BA (n = 46) and MAS (n = 47) for 2 sessions per week over 8 weeks. The Montreal Cognitive Assessment (MoCA) served as the primary outcome. Digit span test was the secondary outcomes for attentional function and working memory. The quality of life and multiple functional assessments were also evaluated. EA/TNS + BA treated group had much better performance than MAS-treated group on reverse digit span test at Week 2 and Week 8, with medium effect sizes of 0.53 and 0.48, respectively, although no significant differences were observed in MoCA score and prevalence of chemobrain between the two groups. EA/TNS + BA also markedly reduced incidences of diarrhoea, poor appetite, headache, anxiety, and irritation, and improved social/family and emotional wellbeing compared to MAS. These results suggest that EA/TNS + BA may have particular benefits in reducing chemotherapy-induced working memory impairment and the incidence of certain digestive, neurological, and distress-related symptoms. It could serve as an effective intervention for breast cancer patients under and post chemotherapy (trial registration: https://www.clinicaltrials.gov: NCT02457039).

A mindfulness-based intervention for breast cancer patients with cognitive impairment after chemotherapy: study protocol of a three-group randomized controlled trial.

BACKGROUND: Mindfulness has been applied to improve cancer care by enhancing psychological well-being. However, little is known about its impact on cognitive impairment experienced by cancer patients after chemotherapy. Mindfulness may be relevant in tackling cognitive impairment by decreasing emotional distress and fatigue, by decreasing inflammation, and by strengthening functional brain connectivity. The aim of the present study protocol is to evaluate the efficacy and mechanisms of a mindfulness-based intervention to reduce cognitive impairment in breast cancer patients after chemotherapy. METHODS/DESIGN: The present study is a three-arm, parallel-group, randomized controlled trial with assessments at baseline, 1 to 3 weeks after the intervention and at 3 months' follow-up. One hundred and twenty breast cancer patients who ended treatment a minimum of 6 months and a maximum of 5 years before, and who have cognitive complaints, will be enrolled. They will be randomized into one of the following three study arms: (1) a mindfulness-based intervention group (n = 40), (2) an active control condition based on physical training (n = 40), or (3) a treatment as usual (TAU) control group (n = 40). Both the mindfulness-based intervention and the active control condition consist of four group sessions (3 h for the mindfulness condition and 2 h for the physical training) spread over 8 weeks. The primary outcomes will be cognitive symptoms as measured by the Cognitive Failure Questionnaire and changes in functional brain connectivity in the attention network. Secondary outcomes will be (1) levels of emotional distress, fatigue, mindfulness, quality of life; (2) neurocognitive tests; (3) structural and functional brain changes using MR imaging and (4) measures of inflammation. DISCUSSION: The study will examine the impact of a mindfulness-based intervention on cognitive impairment in breast cancer patients. If the findings of this study confirm the effectiveness of a mindfulness-based program to reduce cognitive impairment, it will be possible to improve quality of life for ex-cancer patients. We will inform health care providers about the potential use of a mindfulness-based intervention as a non-pharmaceutical, low-threshold mental health intervention to improve cognitive impairment after cancer. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03736460. Retrospectively registered on 8 November 2018.

Polydatin ameliorates chemotherapy-induced cognitive impairment (chemobrain) by inhibiting oxidative stress, inflammatory response, and apoptosis in rats.

Most breast cancer survivors receiving chemotherapy have severe cognitive impairment, often referred to as "chemobrain." Polydatin (PLD) is known to have many biological activities. Thus, this study aimed to determine whether symptoms of chemobrain can be prevented or relieved by PLD. The chemobrain models were established by intraperitoneal injection of doxorubicin (DOX, 2 mg/kg) in rats once a week for 4 weeks (DOX group and DOX+PLD group). In the PLD group and DOX+PLD group, PLD (50 mg/kg) was administered orally to rats every day. We found that PLD treatment significantly protected against DOX-induced learning and memory impairment, restored hippocampal histopathological architecture. Furthermore, PLD suppressed DOX-induced oxidative stress through up-regulating Nrf2, inhibited inflammatory response by activating the NF-κB pathway, and reduced hippocampal apoptosis. Therefore, the present study indicated that PLD offered neuroprotection against DOX-induced chemobrain. PLD may assist in preventing chemobrain after chemotherapy in patients with cancers.