Early postnatal irradiation-induced age-dependent changes in adult mouse brain: MRI based characterization.

BACKGROUND: Brain radiation exposure, in particular, radiotherapy, can induce cognitive impairment in patients, with significant effects persisting for the rest of their life. However, the main mechanisms leading to this adverse event remain largely unknown. A study of radiation-induced injury to multiple brain regions, focused on the hippocampus, may shed light on neuroanatomic bases of neurocognitive impairments in patients. Hence, we irradiated BALB/c mice (male and female) at postnatal day 3 (P3), day 10 (P10), and day 21 (P21) and investigated the long-term radiation effect on brain MRI changes and hippocampal neurogenesis. RESULTS: We found characteristic brain volume reductions in the hippocampus, olfactory bulbs, the cerebellar hemisphere, cerebellar white matter (WM) and cerebellar vermis WM, cingulate, occipital and frontal cortices, cerebellar flocculonodular WM, parietal region, endopiriform claustrum, and entorhinal cortex after irradiation with 5 Gy at P3. Irradiation at P10 induced significant volume reduction in the cerebellum, parietal region, cingulate region, and olfactory bulbs, whereas the reduction of the volume in the entorhinal, parietal, insular, and frontal cortices was demonstrated after irradiation at P21. Immunohistochemical study with cell division marker Ki67 and immature marker doublecortin (DCX) indicated the reduced cell division and genesis of new neurons in the subgranular zone of the dentate gyrus in the hippocampus after irradiation at all three postnatal days, but the reduction of total granule cells in the stratum granulosun was found after irradiation at P3 and P10. CONCLUSIONS: The early life radiation exposure during different developmental stages induces varied brain pathophysiological changes which may be related to the development of neurological and neuropsychological disorders later in life.

The Disparity of Impairment of Neurogenesis and Cognition After Acute or Fractionated Radiation Exposure in Adolescent BALB/c Mice.

The effect of acute X-ray irradiation with 2 Gy or fractionated exposure with 0.2 Gy continuously for 10 days (0.2 Gy × 10 = 2 Gy) was evaluated in the postnatal day 21 (P21) BALB/c mouse model. Both acute and fractionated irradiation induced impairment of cell proliferation and neurogenesis in the subgranular zone of the dentate gyrus labeled by Ki67 and doublecortin, respectively. Parvalbumin immunopositive interneurons in the subgranular zone were also reduced significantly. However, the 2 patterns of irradiation did not affect animal weight gain when measured at ages of P90 and P180 or 69 and 159 days after irradiation. Behavioral tests indicated that neither acute nor fractionated irradiation with a total dose of 2 Gy induced deficits in the contextual fear or spatial memory and memory for novel object recognition. Animal motor activity was also not affected in the open-field test. The disparity of the impairment of neurogenesis and unaffected cognition suggests that the severity of impairment of neurogenesis induced by acute or fractionated irradiation with a total dose of 2 Gy at P21 may not be worse enough to induce the deficit of cognition.

The Neuroprotective Effect of Amitriptyline on Radiation-Induced Impairment of Hippocampal Neurogenesis.

The radioprotective effect of amitriptyline, an inhibitor of acid sphingomyelinase (ASMase), on radiation-induced impairment of hippocampal neurogenesis, loss of interneuron, and animal weight changes was investigated in BALB/c mice by immunostaining of biomarkers for cell division (Ki67), immature neurons (doublecortin or DCX), and interneurons (parvalbumin or PV) in the dentate gyrus (DG) of hippocampus. The results indicated that preirradiation (with 10 mg/kg, 2 times per day, for 7 consecutive days) or postirradiation (with 10 mg/kg, 2 times per day, for 14 consecutive days) treatment (pretreatment or posttreatment) with intraperitoneal injection of amitriptyline prevented the loss of newly generated neurons, proliferating cells, and interneurons in the subgranular zone of the DG. At the molecular level, pretreatment or posttreatment inhibited the expression of sphingomyelin phosphodiesterase 1 (SMPD1) gene which codes for ASMase. The pretreatment for 7 days also prevented radiation-induced weight loss from 2 to 3 weeks, but not within 1 week after irradiation. On the other hand, the posttreatment with amitriptyline for 14 days could improve animal weight gain from 4 to 6 weeks after irradiation. The present study suggests that amitriptyline may be a promising candidate radio-neuroprotective drug to improve radiation-induced impairment of hippocampal neurogenesis and relevant neurological and neuropsychological disorders.