BACKGROUND AND OBJECTIVE: Radiation therapy plays an essential role in the treatment of primary or metastatic CNS malignancies, but radiation-induced adverse effects remain a significant risk. Radiation-induced damage of the neural stem cell pool in the hippocampus is thought to be one of the major reasons for the long-term decline in neurocognitive performance, especially in pediatric patients. Here, we investigate the short- and long-term dose-response relationship of neurogenesis, covering a dose range relevant for whole and partial brain irradiation. Furthermore, we evaluate the radioprotective potential of resveratrol, a plant polyphenol, which is newly recognized for its bifunctional tumor-preventive and anti-cancer effects. METHODS: Nestin-CFPnuc C57BL/J6 mice, postnatal day 4-6, were decapitated and hippocampal tissue slices, containing the entorhinal-hippocampal formation, cut on a vibratome and cultured on membrane inserts in culture plates. Slices were irradiated on an x-ray machine (0.2-16 Gy) 14-21 days later. Resveratrol (15 µM) was added 2 h before and 24 h after irradiation (IR). BrdU pulse label was conducted for 48 h after IR. Nestin-positive neural stem cells were counted at a confocal life imaging microscope 0, 2, 4, 14, 25, and 42 days after IR. BrdU-positive cells were evaluated by immunofluorescence staining in cryosectioned slices. Cell viability was assessed by CellTiter-Blue fluorometric assay, 3 and 9 days after IR. Dead cells were labelled by propidium iodide (PI). Cytokine concentrations (IL6, KC, MCP-1) were measured in the slice culture medium by cytometric bead array 4 and 24 h after IR. RESULTS: A dose-dependent decline of nestin-positive neural stem cells together with a decrease of proliferation could be detected already at low doses of 0.2 Gy two days after IR. A partial recovery of the stem cell pool was found at late time points (14 and 42 days after IR). PI staining showed a dose-dependent increase of dead cells, reaching significance at 12 Gy. Resveratrol was able to enhance the cell viability significantly in irradiated slices 3 and 9 days after irradiation (4.5 and 8 Gy). IL6, KC and MCP1 release increased 4 and 24 h after IR at 1.5 Gy (IL6) and 3 Gy (KC, MCP1). CONCLUSION: Relatively low IR doses lead to a decrease of nestin-positive stem cells. Our data indicate that this is a result of increased cell death and decreased proliferation but might also be triggered by an increase of inflammation. The neuroprotective action of resveratrol on irradiated hippocampal tissue warrants further investigation.