Abstract
Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.
Highlights
The late-appearing neurocognitive decline observed in longitudinal follow-ups in children who receive cranial radiotherapy as tumour treatment remains a salient clinical issue and demands development of appropriate intervention strategies [1, 2]
The aim of this study was to investigate the effects of different concentrations of LiCl on hippocampal neural stem/progenitor cells (NSPCs) from the young, developing brain after irradiation in vitro in order to predict the response in vivo
Two relevant concentrations were chosen based on previous findings, including our own (Zanni et al, unpublished), showing that lithium at therapeutic doses (0.6–1.2 mmol/L) appears to accumulate in brain structures containing a higher proportion of cell bodies in general and in neurogenic regions in particular, suggesting that the brain concentrations may not reflect those in the blood [41, 42]
Summary
The late-appearing neurocognitive decline observed in longitudinal follow-ups in children who receive cranial radiotherapy as tumour treatment remains a salient clinical issue and demands development of appropriate intervention strategies [1, 2]. Irradiation of the juvenile brain is known to cause more severe damage in comparison to the adult brain. This may, at least partly, be explained by the higher neural stem/progenitor cell (NSPC) turnover in the young, differences in dynamic cell-autonomous regulation, as well as regional differences in growth [6,7,8,9,10]. Compelling evidence supports the notion that irradiation-induced deregulation of the hippocampal NSPC cell cycle and growth leads to a further cascade of events in the neurogenic process that likely correlates with neurocognitive decline [18, 19]. The irradiation-induced effects on NSPC intrinsic properties include activation of the DNA damage response (DDR) due to the formation of DNA adducts, induced by single and double strand breaks, initially characterised by an increase in phosphorylated γH2AX, which may lead to cell cycle arrest through activation of cell cycle checkpoints kinases and apoptosis [25, 26]
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