A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice
| Autor: | Andreas Springer, Petra Huehnchen, Matthias Endres, Dorette Freyer, Wolfgang Boehmerle |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
drug effects [Hippocampus] drug effects [Neural Stem Cells] metabolism [Hippocampus] Pharmacology Hippocampal formation 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit Hippocampus chemically induced [Cognition Disorders] Mice 0302 clinical medicine Neural Stem Cells metabolism [Calcium] Cognitive decline biology Calpain Caspase 3 adverse effects [Paclitaxel] Neurogenesis metabolism [Memory Disorders] chemically induced [Memory Disorders] Neural stem cell Psychiatry and Mental health Original Article metabolism [Calpain] Paclitaxel prevention & control [Cognition Disorders] prevention & control [Memory Disorders] 03 medical and health sciences Cellular and Molecular Neuroscience Lithium Carbonate metabolism [Cognition Disorders] medicine Animals metabolism [Caspase 3] Humans ddc:610 Progenitor cell Biological Psychiatry Cell Proliferation Memory Disorders drug effects [Cell Proliferation] Cell growth business.industry Neurotoxicity medicine.disease Mice Inbred C57BL 030104 developmental biology therapeutic use [Lithium Carbonate] biology.protein Calcium Cognition Disorders business 030217 neurology & neurosurgery |
| Zdroj: | Translational Psychiatry 7(8), e1185-e1185 (2017). doi:10.1038/tp.2017.149 Translational Psychiatry |
| DOI: | 10.1038/tp.2017.149 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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