Introduction: Tumors of the central nervous system are the second most frequent tumors in children. Modern therapies have increased greatly the number of cured patients. This leads to new challenges in reducing the therapy-related morbidity. Radiotherapy to the juvenile brain is known to cause debilitating cognitive alterations. Although different mechanisms have been implicated, decreased neurogenesis seems to be one of the most affected. Lithium, a long-known mood stabilizer, has been shown to have
neuroprotective and neurogenic effects in rodent models of brain irradiation. Lithium’s mechanisms of action seem multiple, depending on the subtype of cells or time-points. It seems particularly to increase neural stem/progenitor cell (NSPC) proliferation in neurogenic regions of the brain such as the hippocampus. There are, however, no studies concerning a delayed onset of lithium treatment taking place long after irradiation to the juvenile brain.
Materials and methods: In this study we assessed neurogenesis in vivo in C57BL/6 female mice after they received a single 4 Gy whole-brain irradiation dose at post-natal day 21 (PND2) and had been randomly assigned to 0.24 % Li2CO3 chow from PND49 to 77. Neurogenesis in the hippocampus was studied at PND77, 91 and 105.
Results: Irradiation drastically reduced neurogenesis at virtually all time-points after lithium discontinuation. Assessment of bromodeoxyuridine incorporation (BrdU) in dividing NSPCs proved that under lithium treatment proliferation of the NSPCs increased significantly by 86% at PND77. Interestingly, lithium discontinuation at PND77 allowed new-born cells to differentiate, as shown with doublecortin (DCX) immunostaining and BrdU-DCX co-labelling coupled with morphological analysis at PND91. Moreover, we found increased neuronal survival but no increase in the immature phenotype at PND105, proving that lithium had a transient effect on neurogenesis.
Conclusion: Altogether, our findings are of great relevance for further clinical investigations and applications.