Dataset Information

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

ABSTRACT: Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20?mg?kg^-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230?nm?l^-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2?h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.

SUBMITTER: Huehnchen P

PROVIDER: S-EPMC5611721 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

Huehnchen P P Boehmerle W W Springer A A Freyer D D Endres M M

Translational psychiatry 20170801 8

Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg<sup>-1</sup> paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visu ...[more]

PMID: 28763058

Similar Datasets

Project description:Lactobacillus fermentum CQPC08 (LF-CQPC08) is a newly discovered strain of bacteria isolated and identified from traditional pickled vegetables in Sichuan, China. We used 4-nitroquinoline 1-oxide to establish an experimental tongue cancer mouse model to evaluate the preventive effect of LF-CQPC08 on tongue cancer in vivo. Lactobacillus delbruechii subsp. bulgaricus, is a common commercial strain and is used as a positive control to compare the effect with LF-CQPC08. The preventive strength and mechanism of LF-CQPC08 on tongue cancer were determined by measuring the biochemical indicators in mouse serum and tissues. Our results showed LF-CQPC08 inhibits the decline of splenic index, thymus index, percentage of phagocytic macrophages, and phagocytic index effectively. LF-CQPC08 also increased levels of mouse serum granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), immunoglobulin (Ig)G, IgM levels of serum interleukin (IL)-4, IL-12, tumor necrosis factor-alpha, and interferon-gamma levels, thereby inhibiting the decline in immunity caused by tongue cancer. It also increased the activity levels of superoxide dismutase and glutathione peroxidase and decreased the levels of malondialdehyde in the tissues of the tongue cancer mouse model, thereby suppressing the oxidative stress damage in the tissue caused by tongue cancer. Through quantitative PCR, LF-CQPC08 upregulated the mRNA expression of nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione-S-transferases-π (GST-π), and Bcl-2-associated X protein (Bax), and downregulated the mRNA expression of p53, p63, p73, phosphatase and tensin homolog (PTEN), B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL) in the tongue tissues of the tongue cancer mouse. These results indicated that LF-CQPC08 reduced the influence of tongue cancer on the immune system and oxidative balance and improved the immunity and enhanced antioxidant capacity of the mouse model, thereby preventing tongue cancer. LF-CQPC08 could be used as a microbial resource with a preventive effect on tongue cancer.

Project description:INTRODUCTION:A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells. METHODS:We utilized a tobacco carcinogen-induced lung tumor mouse model by treatment with 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether an AI combined with nonsteroidal anti-inflammatory drugs results in greater lung tumor prevention effects compared to single-agent treatment. RESULTS:Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single-agent treatments and was accompanied by maximum decreases in circulating β-estradiol (E2) and interleukin-6, tumor-infiltrating macrophages, and tumoral Ki67, phospho-mitogen-activated protein kinase, phospho-signal transducer and activator of transcription 3, and interleukin-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment. CONCLUSIONS:Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti-inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.

Dataset Information

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

Publications

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets