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
