Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model

Abstract

Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI.

The Extent of Irradiation-Induced Long-Term Visceral Organ Damage Depends on Cranial/Brain Exposure

“…We also detected late increase (50 days after irradiation) in corticosterone plasma levels in hind limbs-protected rats only. Delayed effect of brain irradiation such as impairment of the negative feedback exerted by glucocorticoids has been described recently in rats [ 40 ]. Therefore the late corticosterone increase we report here may be related to an impairment of the negative feedback, resulting in enhanced release of adrenal corticosterone.…”

Antagonism of Dexamethasone to Radiation Bystander Effect and Its Re-transmission

“…Weidenfeld J reported that animal base and stress-induced corticosterone levels increased at 9 and 20 weeks after whole brain irradiation, and negative feedback from glucocorticoids was impaired. It may be due to an abnormal reaction of the hippocampus-pituitary-adrenal cortex (HPA) axis, which may play an important role in regulating the feedback effect of glucocorticoids [16]. Surace L reports dexamethasone, which has limited complement activation and anti-tumor effects of the immune system during radiotherapy [17].…”

Clinical features and diagnosis of secondary adrenal insufficiency followed complex treatment nonpituitary brain tumors

“…Причина данного явления в настоящий момент неизвестна. В то же время в исследованиях, проведенных на экспериментальных животных, показано возрастание уровней кортизола и АКТГ как в ранний, так и отдаленный периоды после облучения головного мозга [24][25][26]. Не следует забывать и о роли хронического стресса в период диагностики и лечения онкологического заболевания, который, возможно, приводит к гиперстимуляции гипоталамо-гипофизарно-надпочечниковой оси.…”

“…Несмотря на то что в ряде отечественных руководств именно АКТГ на фоне ТИГ обсуждается как самый чувствительный маркер ВНН [13], с нашей точки зрения, исследование данного показателя нецелесообразно, поскольку не дает дополнительной информации для диагностики и определения тактики ведения ВНН, однако увеличивает стоимость обследования. Большинство существующих в настоящий момент рекомендаций по диагностике ВНН ориентируется только на уровень максимального кортизола [3,25].…”