Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat ModelWeidenfeld J.a · Siegal T.b · Ovadia H.a
aDepartment of Neurology, The Agnes Ginges Center for Human Neurogenetics, and bDepartment of Hematology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
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.
© 2012 S. Karger AG, Basel
- Antoni FA: Hypothalamic control of adrenocorticotropin secretion: advances since the discovery of 41-residue corticotropin-releasing factor. Endocr Rev 1986;7:351–378.
- Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE: Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 2003;24:151–180.
- Feldman S, Conforti N, Weidenfeld J: Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli. Neurosci Biobehav Rev 1995;19:235–240.
- Feldman S, Weidenfeld J: Neural mechanisms involved in the corticosteroid feedback effects on the hypothalamo-pituitary-adrenocortical axis. Prog Neurobiol 1995;45:129–141.
- De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M: Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301.
- Raber J: Unintended effects of cranial irradiation on cognitive function. Toxicol Pathol 2010;38:198–202.
- Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 1995;31:1113–1121.
- Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Lange M, Poulsen HS, Muller J: Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J Clin Endocrinol Metab 2003;88:3149–3154.
- Constine LS, Woolf PD, Cann D, Mick G, McCormick K, Raubertas RF, Rubin P: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993;328:87–94.
- Velickovic N, Djordjevic A, Drakulic D, Stanojevic I, Secerov B, Horvat A: Cranial irradiation modulates hypothalamic-pituitary-adrenal axis activity and corticosteroid receptor expression in the hippocampus of juvenile rat. Gen Physiol Biophys 2009;28(Spec No):219–227.
- Velickovic N, Djordjevic A, Matic G, Horvat A: Radiation-induced hyposuppression of the hypothalamic-pituitary-adrenal axis is associated with alterations of hippocampal corticosteroid receptor expression. Radiat Res 2008;169:397–407.
- Weidenfeld J, Feldman S: Glucocorticoid feedback regulation of adrenocortical responses to neural stimuli: role of CRF-41 and corticosteroid type I and type II receptors. Neuroendocrinology 1993;58:49–56.
- Weidenfeld J, Corcos AP, Wohlman A, Feldman S: Characterization of the 2-deoxyglucose effect on the adrenocortical axis. Endocrinology 1994;134:1924–1931.
- Wohlman A, Yirmiya R, Gallily R, Weidenfeld J: Effect of Mycoplasma fermentans on brain PGE2: role of glucocorticoids and their receptors. Neuroimmunomodulation 2001;9:141–147.
- Weidenfeld J, Rougeot C, Dray F, Feldman S: Adrenocortical response following acute neurogenic stimuli is mediated by CRF-41. Neurosci Lett 1989;107:189–194.
- Bener D, Wohlman A, Itzik A, Yirmiya R, Ben-Hur T, Weidenfeld J: Glucocorticoid resistance following herpes simplex-1 infection: role of hippocampal glucocorticoid receptors. Neuroendocrinology 2007;85:207–215.
- O’Donnell D, Francis D, Weaver S, Meaney MJ: Effects of adrenalectomy and corticosterone replacement on glucocorticoid receptor levels in rat brain tissue: a comparison between Western blotting and receptor binding assays. Brain Res 1995;687:133–142.
- Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 1991;12:118–134.
- Feldman S, Weidenfeld J: Further evidence for the central effect of dexamethasone at the hypothalamic level in the negative feedback mechanism. Brain Res 2002;958:291–296.
- Herman JP, Schafer MK, Young EA, Thompson R, Douglass J, Akil H, Watson SJ: Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis. J Neurosci 1989;9:3072–3082.
- Feldman S, Weidenfeld J: The dorsal hippocampus modifies the negative feedback effect of glucocorticoids on the adrenocortical and median eminence CRF-41 responses to photic stimulation. Brain Res 1993;614:227–232.
- Sapolsky RM, Krey LC, McEwen BS: Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. Proc Natl Acad Sci USA 1984;81:6174–6177.
- Sapolsky RM: Why stress is bad for your brain. Science 1996;273:749–750.
- Jover-Mengual T, Miyawaki T, Latuszek A, Alborch E, Zukin RS, Etgen AM: Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway. Brain Res 2010;1321:1–12.
- Kureshi SA, Hofman FM, Schneider JH, Chin LS, Apuzzo ML, Hinton DR: Cytokine expression in radiation-induced delayed cerebral injury. Neurosurgery 1994;35:822–829; discussion 829–830.
- Kyrkanides S, Moore AH, Olschowka JA, Daeschner JC, Williams JP, Hansen JT, Kerry O’Banion M: Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res Mol Brain Res 2002;104:159–169.
- Miller AH, Pariante CM, Pearce BD: Effects of cytokines on glucocorticoid receptor expression and function. Glucocorticoid resistance and relevance to depression. Adv Exp Med Biol 1999;461:107–116.
- Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, Miller AH: The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinology 1999;140:4359–4366.
- Silverman MN, Pearce BD, Biron CA, Miller AH: Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 2005;18:41–78.
- Oakley RH, Sar M, Cidlowski JA: The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 1996;271:9550–9559.
- Webster JC, Oakley RH, Jewell CM, Cid- lowski JA: Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA 2001;98:6865–6870.
- Siegal T, Pfeffer MR: Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability. Int J Radiat Oncol Biol Phys 1995;31:57–64.
- Siegal T, Pfeffer MR, Meltzer A, Shezen E, Nimrod A, Ezov N, Ovadia H: Cellular and secretory mechanisms related to delayed radiation-induced microvessel dysfunction in the spinal cord of rats. Int J Radiat Oncol Biol Phys 1996;36:649–659.
- Yuan H, Gaber MW, McColgan T, Naimark MD, Kiani MF, Merchant TE: Radiation-induced permeability and leukocyte adhesion in the rat blood-brain barrier: modulation with anti-ICAM-1 antibodies. Brain Res 2003;969:59–69.
- Moravan MJ, Olschowka JA, Williams JP, O’Banion MK: Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat Res 2011;176:459–473.
- Zhu W, Zheng H, Shao X, Wang W, Yao Q, Li Z: Excitotoxicity of TNFalpha derived from KA activated microglia on hippocampal neurons in vitro and in vivo. J Neurochem 2010;114:386–396.
- Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR: Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003;63:4021–4027.
- Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR: Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 2004;188:316–330.
- Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA: Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 2011;476:458–461.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.