Abstract
Cranial irradiation (IR) is commonly used to treat primary brain tumors and metastatic diseases. However, cranial IR-treated patients often develop vascular abnormalities later in life that increase their risk for cerebral ischemia. Studies in rodents have demonstrated that IR impairs maintenance of the neural stem/precursor cell (NSPC) pool and depletes neurogenesis. We and others have previously shown that stroke triggers NSPC proliferation in the subventricular zone and migration towards the stroke-injured neocortex. Whether this response is sustained in the irradiated brain remains unknown. Here, we demonstrate that cranial IR in mice at an early postnatal age significantly reduced the number to neuronal progenitors responding to cortical stroke in adults. This was accompanied by a reduced number of microglia/macrophages in the peri-infarct cortex; however, the astrocytic response was not altered. Our findings indicate that IR impairs the endogenous repair capacity in the brain in response to stroke, hence pointing to another side effect of cranial radiotherapy which requires further attention.
Highlights
Cranial irradiation (IR) is a routine clinical treatment for primary brain tumors and metastasis, it causes long-lasting side effects in cancer survivors such as neurocognitive s equelae[1,2,3,4]
On postnatal day 5 (P5), when littermate pups were delivered from the breeding facility, 68 mice were randomly assigned to four experimental groups: Control animals that were only subjected to anesthesia (Ctrl), irradiation only (IR), cortical ischemia only (IS) and mice exposed to both irradiation and cortical ischemia (IR + IS) (Fig. 1A)
We first assessed the effect of IR and/or ischemia on weight gain by determining body weight at P5, postnatal day 9 (P9), P30, every 5 days between P50 and P70, as well as P80 (Fig. 1B)
Summary
Cranial irradiation (IR) is a routine clinical treatment for primary brain tumors and metastasis, it causes long-lasting side effects in cancer survivors such as neurocognitive s equelae[1,2,3,4]. This has been problematic in pediatric patients, as their brain is still d eveloping[5]. Cerebral ischemia increases NSPC proliferation in the SVZ and re-routes migration of the neuronal progenitors towards the injury s ite[21,22,23,24,25,26] Whether this progenitor cell response to stroke is affected by IR remains unknown. The peri-infarct area, and we demonstrate that IR significantly diminishes stroke-induced NSPC response and accumulation of microglia/macrophages (MG/MQs) in the peri-infarct area
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