Abstract
Approximately 7 million people are reported to be undergoing radiotherapy (RT) at any one time in the world. However, it is still not possible to prevent damage to secondary organs that are off-target. This study, therefore, investigated the potential adverse effects of RT on the brain, using cognitive, histopathological, and biochemical methods, and the counteractive effect of the α2-adrenergic receptor agonist dexmedetomidine. Thirty-two male Sprague Dawley rats aged 5–6 months were randomly allocated into four groups: untreated control, and RT, RT + dexmedetomidine-100, and RT + dexmedetomidine-200-treated groups. The passive avoidance test was applied to all groups. The RT groups received total body X-ray irradiation as a single dose of 8 Gy. The rats were sacrificed 24 h after X-ray irradiation, and following the application of the passive avoidance test. The brain tissues were subjected to histological and biochemical evaluation. No statistically significant difference was found between the control and RT groups in terms of passive avoidance outcomes and 8-hydroxy-2′- deoxyguanosine (8-OHdG) positivity. In contrast, a significant increase in tissue MDA and GSH levels and positivity for TUNEL, TNF-α, and nNOS was observed between the control and the irradiation groups (p < 0.05). A significant decrease in these values was observed in the groups receiving dexmedetomidine. Compared with the control group, gradual elevation was determined in GSH levels in the RT group, followed by the RT + dexmedetomidine-100 and RT + dexmedetomidine-200 groups. Dexmedetomidine may be beneficial in countering the adverse effects of RT in the cerebral and hippocampal regions.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akpınar O, Nazıroğlu M, Akpınar H (2017) Different doses of dexmedetomidine reduce plasma cytokine production, brain oxidative injury, PARP and caspase expression levels but increase liver oxidative toxicity in cerebral ischemia-induced rats. Brain Res Bull 130:1–9
Allen C, Her S, Jaffray DA (2017) Radiotherapy for cancer: present and future. Adv Drug Deliv Rev 109:1–2. https://doi.org/10.1016/j.addr.2017.01.004
Apoptosis R, Shun C (1996) Oligodendrocytes in the adult rat spinal cord undergo. Cancer Res 56:5417–5422
Atkinson S, Li YQ, Wong CS (2003) Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord. Int J Radiat Oncol Biol Phys 57:1093–1100. https://doi.org/10.1016/S0360-3016(03)00735-1
Ayala A, Muñoz MF, Argüelle S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:1–32. https://doi.org/10.1155/2014/360438
Balkwill F (2006) TNF-α in promotion and progression of cancer. Cancer Metastasis Rev 25:409–416. https://doi.org/10.1007/s10555-006-9005-3
Begolly S, Olschowka JA, Love T et al (2018) Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia 66:846–861. https://doi.org/10.1002/glia.23288
Bentzen SM (2006) Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6:702–713. https://doi.org/10.1038/nrc1950
Burnet NG, Wurm R, Nyman J, Peacock JH (1996) Normal tissue radiosensitivity—how important is it? Clin Oncol 8:25–34. https://doi.org/10.1016/S0936-6555(05)80035-4
Cai S, Shi GS, Cheng HY et al (2017) Exosomal miR-7 mediates bystander autophagy in lung after focal brain irradiation in mice. Int J Biol Sci 13:1287–1296. https://doi.org/10.7150/ijbs.18890
Cai YE, Xu H, Yan J et al (2014) Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review). Mol Med Rep 9:1542–1550. https://doi.org/10.3892/mmr.2014.2034
Cakmak G, Miller LM, Zorlu F, Severcan F (2012) Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study. Arch Biochem Biophys 520:67–73. https://doi.org/10.1016/j.abb.2012.02.012
Cakmak G, Severcan M, Zorlu F, Severcan F (2016) Structural and functional damages of whole body ionizing radiation on rat brain homogenate membranes and protective effect of amifostine. 3002 https://doi.org/10.1080/09553002.2016.1230237
Chen N, Xu RJ, Wang LL et al (2018) Protective effects of magnesium sulfate on radiation ınduced brain ınjury in rats. Curr Drug Deliv 15:1159–1166. https://doi.org/10.2174/1567201815666180124112200
Chie S, Glenn TG, Kathleen RL et al (1997) Apoptosis in the subependyma of young adult rats after single and fractionated doses of X-rays. Cancer Res 57:2694–2702
Conner KR, Forbes ME, Lee WH et al (2011) AT1 receptor antagonism does not ınfluence early radiation-ınduced changes in microglial activation or neurogenesis in the normal rat brain. Radiat Res 176:71–83. https://doi.org/10.1667/rr2560.1
Cui L, Pierce D, Light KE et al (2010) Sublethal total body irradiation leads to early cerebellar damage and oxidative stress. Curr Neurovasc Res 7:125–135
D’Avella D, Cicciarello R, Angileri FF et al (1998) Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications. Acta Neurochir (wien) 71:282–284
Diserbo M, Agin A, Lamproglou I et al (2002) Blood-brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study. Can J Physiol Pharmacol 80:670–678. https://doi.org/10.1139/y02-070
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671
El-maraghi EF, Abdel-fattah KI, Soliman SM, El-sayed WM (2018) Taurine provides a time-dependent amelioration of the brain damage induced by γ -irradiation in rats. J Hazard Mater 359:40–46. https://doi.org/10.1016/j.jhazmat.2018.07.005
Ellis JM (2005) Cholinesterase inhibitors in the treatment of dementia. J Am Osteopath Assoc 105:145–158. https://doi.org/10.1016/s0924-977x(00)80101-7
Ellman GL (1959) Tissue sulfyd groups. Arch Biochem Biophys 82:70–77
Erkal HŞ, Batçioǧlu K, Serin M et al (2006) The evaluation of the oxidant injury as a function of time following brain irradiation in a rat model. Neurochem Res 31:1271–1277. https://doi.org/10.1007/s11064-006-9159-y
Fardid R, Salajegheh A, Mosleh-Shirazi MA et al (2017) Melatonin ameliorates the production of COX-2, iNOS, and the formation of 8-OHdG in non-targeted lung tissue after pelvic irradiation. Cell J 19:324–331. https://doi.org/10.22074/cellj.2016.3857
Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837. https://doi.org/10.1093/eurheartj/ehr304
Gaber MW, Sabek OM, Fukatsu K et al (2003) Differences in ICAM-1 and TNF-α expression between large single fraction and fractionated irradiation in mouse brain. Int J Radiat Biol 79:359–366. https://doi.org/10.1080/0955300031000114738
Ganesan MK, Jovanovic M, Secerov B et al (2014) Radiation protection from whole-body gamma irradiation (6.7 Gy): Behavioural effects and brain protein-level changes by an aminothiol compound GL2011 in the Wistar rat. Amino Acids 46:1681–1696. https://doi.org/10.1007/s00726-014-1728-9
Gao Y, Wang P, Wang Z et al (2019) Serum 8-hydroxy-2′-deoxyguanosine level as a potential biomarker of oxidative DNA damage ınduced by ıonizing radiation in human peripheral blood. Dose-Response 17. https://doi.org/10.1177/1559325818820649
Gupta M, Mishra SK, Kumar BSH et al (2017) Early detection of whole body radiation induced microstructural and neuroinflammatory changes in hippocampus: a diffusion tensor imaging and gene expression study. J Neurosci Res 95:1067–1078. https://doi.org/10.1002/jnr.23833
Hartl BA, Ma HSW, Hansen KS et al (2017) The effect of radiation dose on the onset and progression of radiation-ınduced brain necrosis in the rat model. Int J Radiat Biol 93:676–682. https://doi.org/10.1080/09553002.2017.1297902.The
Haveman J, Geerdink AG, Rodermond HM (1998) TNF, IL-1 and IL-6 in circulating blood after total-body and localized irradiation in rats. Oncol Rep 5:679–683
Hoffman A, Alfon J, Habib G et al (1994) The effect of immunosuppression by total-body irradiation on the pharmacodynamics of centrally active drugs in rats
Hong JH, Chiang CS, Campbell IL et al (1995) Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33:619–626. https://doi.org/10.1016/0360-3016(95)00279-8
Huang Z, Huang PL, Panahian N et al (1994) Effects of cerebral ıschemia in mice deficient in neuronal nitric oxide synthase. 23–25
Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ (2014) Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg 133:1–12. https://doi.org/10.1097/01.prs.0000440818.23647.0b
Hur W, Yoon SK (2017) Molecular pathogenesis of radiation-induced cell toxicity in stem cells. Int J Mol Sci 18. https://doi.org/10.3390/ijms18122749
Hwang SY, Jung JS, Kim TH et al (2006) Ionizing radiation induces astrocyte gliosis through microglia activation. Neurobiol Dis 21:457–467. https://doi.org/10.1016/j.nbd.2005.08.006
Ji S, Tian Y, Lu Y et al (2014) Irradiation-Induced Hippocampal Neurogenesis Impairment Is Associated with Epigenetic Regulation of Bdnf Gene Transcription 1577:77–88. https://doi.org/10.1016/j.brainres.2014.06.035
Jiang X, Engelbach JA, Yuan L et al (2014a) Anti-VEGF antibodies mitigate the development of radiation necrosis in mouse brain. Clin Cancer Res 20:2695–2702. https://doi.org/10.1158/1078-0432.CCR-13-1941
Jiang X, Perez-Torres CJ, Thotala D et al (2014b) A GSK-3β inhibitor protects against radiation necrosis in mouse brain. Int J Radiat Oncol Biol Phys 89:714–721. https://doi.org/10.1016/j.ijrobp.2014.04.018
Jiang ZJ, Wang CY, Xie X et al (2015) Schizandrin ameliorates ovariectomy-induced memory impairment, potentiates neurotransmission and exhibits antioxidant properties. Br J Pharmacol 172:2479–2492. https://doi.org/10.1111/bph.13078
Kamiryo T, Kassell NF, Thai QA et al (1996) Histological changes in the normal rat brain after gamma irradiation. Acta Neurochir (wien) 138:451–459. https://doi.org/10.1007/BF01420308
Kim J-S, Lee H-J, Kim J et al (2008) Transient ımpairment of hippocampus-dependent learning and memory in relatively low-dose of acute radiation syndrome is associated with ınhibition of hippocampal neurogenesis. J Radiat Res 49:517–526. https://doi.org/10.1269/jrr.08020
Kurita H, Kawahara N, Asai A et al (2001) Radiation-induced apoptosis of oligodendrocytes in the adult rat brain. Neurol Res 23:869–874. https://doi.org/10.1179/016164101101199324
Kutanis D, Erturk E, Besir A et al (2016) Dexmedetomidine acts as an oxidative damage prophylactic in rats exposed to ionizing radiation. J Clin Anesth 34:577–585. https://doi.org/10.1016/j.jclinane.2016.06.031
Lampron A, Lessard M, Rivest S (2012) Effects of myeloablation, peripheral chimerism, and whole-body ırradiation on the entry of bone marrow-derived cells into the brain. Cell Transplant 21:1149–1159. https://doi.org/10.3727/096368911X593154
Lander ES (2015) Placebo effects in medicine. N Engl J Med 373:8–9. https://doi.org/10.1056/NEJMp1506446
Lestaevel P, Clarençon D, Gharib A et al (2003) Nitric oxide voltammetric measurements in the rat brain after gamma ırradiation. Radiat Res 160:631–636. https://doi.org/10.1667/rr3079
Li J, Zhang G, Meng Z, Wang L (2016) Neuroprotective effect of acute melatonin treatment on hippocampal neurons against irradiation by inhibition of caspase-3. Exp Ther Med 11:2385–2390. https://doi.org/10.3892/etm.2016.3215
Lipp LL (2014) Brain perfusion and oxygenation. Crit Care Nurs Clin North Am 26:389–398. https://doi.org/10.1016/j.ccell.2014.04.008
Luo X, Zheng X, Huang H (2016) Protective effects of dexmedetomidine on brain function of glioma patients undergoing craniotomy resection and its underlying mechanism. Clin Neurol Neurosurg 146:105–108. https://doi.org/10.1016/j.clineuro.2016.05.004
Magura IS, Rozhmanova OM (1997) Oxidative stress and neurodegenerative disorders. Biopolym Cell 13:513–515. https://doi.org/10.7124/bc.0004B0
Makale MT, Mcdonald CR, Hattangadi-Gluth J, Kesari S (2017) Brain irradiation and long-term cognitive disability: current concepts. Nat Rev Neurol 13:52–64. https://doi.org/10.1038/nrneurol.2016.185
Manda K, Ueno M, Anzai K (2008) Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of α-lipoic acid. Behav Brain Res 187:387–395. https://doi.org/10.1016/j.bbr.2007.09.033
Mansour HH, Ismael NER, Hafez HF et al (2014) Ameliorative effect of septilin, an ayurvedic preparation against γ-irradiation-induced oxidative stress and tissue injury in rats. 51:135–141
Mansour SZ, Moawed FSM, Elmarkaby SM (2017) Protective effect of 5, 7-dihydroxyflavone on brain of rats exposed to acrylamide or γ-radiation. J Photochem Photobiol B Biol 175:149–155. https://doi.org/10.1016/j.jphotobiol.2017.08.034
Mickley GA, Ferguson JL, Mulvihill MA, Nemeth TJ (1989) Progressive behavioral changes during the maturation of rats with early radiation-induced hypoplasia of fascia dentata granule cells. Neurotoxicol Teratol 11:385–393. https://doi.org/10.1016/0892-0362(89)90012-3
Morelli JN, Runge VM, Ai F et al (2011) An ımage-based approach to understanding the physics of MR artifacts. Radiographics 31:849–866. https://doi.org/10.1148/rg.313105115
Murphy ES, Xie H, Merchant TE et al (2015) Review of cranial radiotherapy-induced vasculopathy. J Neurooncol 122:421–429. https://doi.org/10.1007/s11060-015-1732-2
Nakano T, Okamoto H (2009) Dexmedetomidine-induced cerebral hypoperfusion exacerbates ischemic brain injury in rats. J Anesth 23:378–384. https://doi.org/10.1007/s00540-009-0777-9
Oh SB, Park HR, Jang YJ et al (2013) Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation. Br J Pharmacol 168:421–431. https://doi.org/10.1111/j.1476-5381.2012.02142.x
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Olsen RHJ, Weber S, Akinyeke T, Raber J (2017) Enhanced cued fear memory following post-training whole body irradiation of 3-month-old mice. Behav Brain Res 319:181–187. https://doi.org/10.1002/cncr.27633.Percutaneous
Park MK, Kim S, Jung U et al (2012) Effect of acute and fractionated irradiation on hippocampal neurogenesis. Molecules 17:9462–9468. https://doi.org/10.3390/molecules17089462
Peißner W, Kocher M, Treuer H, Gillardon F (1999) Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. 61–68
Požgain I, Požgain Z, Degmečić D (2014) Placebo and nocebo effect: a mini-review. Psychiatr Danub 26:100–107
Prinzen FW, Lawrence CJ, van Leeuwen CJ, de Lange S (1994) Effect of the alpha2-adrenergic agonist dexmedetomidine on nutrient blood flow to various organs in anaesthetised dogs. J Cardiothorac Vasc Anesth 8:82
Raber J, Rola R, Lefevour A et al (2004) Radiation-Induced Cognitive Impairments Are Associated with Changes in Indicators of Hippocampal Neurogenesis 47:39–47
Refaat R, Sarhan D, Kotb M et al (2018) Post-irradiation protective effects of ectoine on brain and testicles in male mice. Pharmacol Reports 70:304–308. https://doi.org/10.1016/j.pharep.2017.10.002
Reinhold HS, Calvo W, Hopewell JW, Van Den Berg AP (1990) Development of blood vessel-related radiation damage in the fimbria of the central nervous system. Int J Radiat Oncol Biol Phys 18:37–42. https://doi.org/10.1016/0360-3016(90)90264-K
Ren X, Ma H, Zuo Z (2016) Dexmedetomidine postconditioning reduces brain ınjury after brain hypoxia-ıschemia in neonatal rats. J Neuroimmune Pharmacol 11:238–247. https://doi.org/10.1007/s11481-016-9658-9
Richard CAH, Wilcox BD, Loegering DJ (2000) IgG-coated erythrocytes augment LPS-stimulated TNF-α secretion, TNF-α mRNA levels, and TNF-α mRNA stability in macrophages. Biochem Biophys Res Commun 271:70–74. https://doi.org/10.1006/bbrc.2000.2594
Rojas DB, Gemelli T, De Andrade RB et al (2012) Administration of histidine to female rats induces changes in oxidative status in cortex and hippocampus of the offspring. Neurochem Res 37:1031–1036. https://doi.org/10.1007/s11064-012-0703-7
Rola R, Raber J, Rizk A et al (2004) Radiation-Induced Impairment of Hippocampal Neurogenesis Is Associated with Cognitive Deficits in Young Mice 188:316–330. https://doi.org/10.1016/j.expneurol.2004.05.005
Ruitenberg MJ, Wells J, Bartlett PF et al (2017) Enrichment increases hippocampal neurogenesis independent of blood monocyte-derived microglia presence following high-dose total body irradiation. Brain Res Bull 132:150–159. https://doi.org/10.1016/j.brainresbull.2017.05.013
Schoeler M, Loetscher PD, Rossaint R et al (2012) Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol 12. https://doi.org/10.1186/1471-2377-12-20
Sharma S, Singla N, Chadha VD, Dhawan DK (2019) A concept of radiation hormesis: stimulation of antioxidant machinery in rats by low dose ionizing radiation. Hell J Nucl Med 22:43–48. https://doi.org/10.1967/s002449910958
Singh VK, Ducey EJ, Brown DS, Whitnall MH (2012) A review of radiation countermeasure work ongoing at the Armed Forces Radiobiology Research Institute. Int J Radiat Biol 88:296–310. https://doi.org/10.3109/09553002.2012.652726
Stewart B, Wild C (2014) World Cancer Report 2014
Sun R, Zhang LY, Chen LS, Tian Y (2016) Long-term outcome of changes in cognitive function of young rats after various/different doses of whole brain irradiation. Neurol Res 38:647–654. https://doi.org/10.1080/01616412.2016.1188483
Tan YF, Rosenzweig S, Jaffray D, Wojtowicz JM (2011) Depletion of new neurons by image guided irradiation. Front Neurosci 5:1–8. https://doi.org/10.3389/fnins.2011.00059
U.S. Food and Drug Administration (1999) Precedex. https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21038lbl.pdf
Uzdensky A, Demyanenko S, Fedorenko G et al (2017) Protein profile and morphological alterations in penumbra after focal photothrombotic ınfarction in the rat cerebral cortex. Mol Neurobiol 54:4172–4188. https://doi.org/10.1007/s12035-016-9964-5
Vannorsdall TD (2017) Cognitive changes related to cancer therapy. Med Clin North Am 101:1115–1134. https://doi.org/10.1016/j.mcna.2017.06.006
Voevodskaya NV, Vanin AF (1992) Gamma-irradiation potentiates L-arginine-dependent nitric oxide formation in mice. Biochem Biophys Res Commun 186:1423–1428
Wang Y, Han R, Zuo Z (2016) Dexmedetomidine–induced neuroprotection: is it translational? Transl Perioper Pain Med 1:15–19. https://doi.org/10.5993/AJHB.40.1.1.The
Wefel JS, Kesler SR, Noll KR, Schagen SB (2015) Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive ımpairment in adults. CA Cancer J Clin 65:123–138. https://doi.org/10.3322/caac.21258.Clinical
Yamanaka D, Kawano T, Nishigaki A et al (2017) Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 31:25–35. https://doi.org/10.1007/s00540-016-2264-4
Yan J, Liu Y, Zhao Q et al (2016) 56Fe irradiation-induced cognitive deficits through oxidative stress in mice. Toxicol Res (camb) 5:1672–1679. https://doi.org/10.1039/c6tx00282j
Yang L, Yang J, Li G et al (2017) Pathophysiological responses in rat and mouse models of radiation-ınduced brain ınjury. Mol Neurobiol 54:1022–1032. https://doi.org/10.1007/s12035-015-9628-x
Yildirim Ö, Čomoǧlu S, Yardimci S et al (2007) Melatonin treatment for prevention of oxidative stress: involving histopathological changes. Gen Physiol Biophys 26:126–132
Yoneoka Y, Satoh M, Akiyama K et al (1999) An experimental study of radiation-induced cognitive dysfunction in an adult rat model. Br J Radiol 72:1196–1201
Zaman MS, Hupp EW, Lancaster FE (1992) Brain myelination in rats treated with ıonizing radiation in utero. J Environ Sci Heal Part B 27:621–638. https://doi.org/10.1080/03601239209372803
Zhang X, Wang J, Qian W et al (2015) Dexmedetomidine inhibits inducible nitric oxide synthase in lipopolysaccharide-stimulated microglia by suppression of extracellular signal-regulated kinase. Neurol Res 37:238–245. https://doi.org/10.1179/1743132814y.0000000426
Zhang X, Wang J, Qian W et al (2014) Dexmedetomidine inhibits tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminal kinases. Inflammation 37:942–949. https://doi.org/10.1007/s10753-014-9814-4
Zhu YM, Wang CC, Chen L et al (2013) Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res 1494:1–8. https://doi.org/10.1016/j.brainres.2012.11.047
Funding
Recep Tayyip Erdogan University Scientific Research Support Fund (TU-2018–934) granted financial support for this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Research Involving Animals
All applicable international, national, and institutional guidelines for the care and use of animals were followed.
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Çınar, S., Tümkaya, L., Mercantepe, T. et al. Can Dexmedetomidine Be Effective in the Protection of Radiotherapy-Induced Brain Damage in the Rat?. Neurotox Res 39, 1338–1351 (2021). https://doi.org/10.1007/s12640-021-00379-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-021-00379-1