Irradiation to the immature brain attenuates neurogenesis and exacerbates subsequent hypoxic-ischemic brain injury in the adult

Cranial radiotherapy is common in pediatric oncology. Our purpose was to investigate if irradiation (IR) to the immature brain would increase the susceptibility to hypoxic-ischemic injury in adulthood. The left hemisphere of postnatal day 10 (P10) mice was irradiated with 8 Gy and subjected to hypoxia-ischemia (HI) on P60. Brain injury, neurogenesis and inflammation were evaluated 30 days after HI. IR alone caused significant hemispheric tissue loss, or lack of growth (2.8 +/- 0.42 mm3, p < 0.001). Tissue loss after HI (18.2 +/- 5.8 mm3, p < 0.05) was synergistically increased if preceded by IR (32.0 +/- 3.5 mm3, p < 0.05). Infarct volume (5.1 +/- 1.6 mm3) nearly doubled if HI was preceded by IR (9.8 +/- 1.2 mm3, p < 0.05). Pathological scoring revealed that IR aggravated hippocampal, cortical and striatal, but not thalamic, injury. Hippocampal neurogenesis decreased > 50% after IR but was unchanged by HI alone. The number of newly formed microglia was three times higher after IR + HI than after HI alone. In summary, IR to the immature brain produced long-lasting changes, including decreased hippocampal neurogenesis, subsequently rendering the adult brain more susceptible to HI, resulting in larger infarcts, increased hemispheric tissue loss and more inflammation than in non-irradiated brains.