The impact of high and low dose ionising radiation on the central nervous system

Harada, 2014, Radiation dose rates now and in the future for residents neighboring restricted areas of the fukushima daiichi nuclear power plant, Proc. Natl. Acad. Sci. USA, 111, E914, 10.1073/pnas.1315684111 Australian Radiation Protection and Nuclear Safety Agency, Ionising Radiation and Health, 2015. Seong, 2016, Is the linear no-threshold dose-response paradigm still necessary for the assessment of health effects of low dose radiation?, J. Korean Med. Sci., 31, S10, 10.3346/jkms.2016.31.S1.S10 ICRP, Low-dose extrapolation of radiation-related cancer risk. Icrp publication 99. Ann. ICRP, 2005, 35. Calabrese, 2015, Historical foundations of hormesis, Homeopathy, 104, 83, 10.1016/j.homp.2015.01.001 Doss, 2012, Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data, Dose Response, 10, 584, 10.2203/dose-response.12-023.Doss Doss, 2014, Low dose radiation adaptive protection to control neurodegenerative diseases, Dose Response, 12, 277, 10.2203/dose-response.13-030.Doss Tang, 2015, Molecular mechanisms of low dose ionizing radiation-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability, Int J. Radiat. Biol., 91, 13, 10.3109/09553002.2014.937510 Luckey, 1982, Physiological benefits from low levels of ionizing radiation, Health Phys., 43, 771, 10.1097/00004032-198212000-00001 Gori, 2012, Biological effects of low-dose radiation: Of harm and hormesis, Eur. Heart J., 33, 292, 10.1093/eurheartj/ehr288 Calabrese, 2015, Hormesis within a mechanistic context, Homeopathy, 104, 90, 10.1016/j.homp.2015.01.002 H. Coutard, Principles of x ray therapy of malignant diseases, The Lancet, 1934, 224, 1-4,e1,e2,5-8. Becquerel, 1901, The radio-activity of matter, Nature, 63, 396, 10.1038/063396d0 W.C. Röntgen, On a new kind or rays. Journal of the Franklin Institute, 141, 1896, pp. 183–191. Estable-Puig, 1964, Degeneration and regeneration of myelinated fibers in the cerebral and cerebellar cortex following damage from ionizing particle radiation, Acta Neuropathol., 4, 175, 10.1007/BF00684126 Nagai, 2000, Selective vulnerability to radiation in the hippocampal dentate granule cells, Surg. Neurol., 53, 503, 10.1016/S0090-3019(00)00214-7 Acharya, 2014, Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation, Cell Transplant., 23, 1255, 10.3727/096368913X670200 Pospisil, 2015, Hippocampal proton mr spectroscopy as a novel approach in the assessment of radiation injury and the correlation to neurocognitive function impairment: initial experiences, Radiat. Oncol., 10, 10.1186/s13014-015-0518-1 Parihar, 2013, Cranial irradiation compromises neuronal architecture in the hippocampus, Proc. Natl. Acad. Sci. USA, 110, 12822, 10.1073/pnas.1307301110 Ye, 2016, Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production, Exp. Cell Res., 340, 315, 10.1016/j.yexcr.2015.10.026 Limoli, 2004, Radiation response of neural precursor cells: Linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress, Radiat. Res., 161, 17, 10.1667/RR3112 Ma, 2013, Biological effects of low-dose radiation from computed tomography scanning, Int J. Radiat. Biol., 89, 326, 10.3109/09553002.2013.756595 Council, 2006 Morgan, 2013, Issues in low dose radiation biology: the controversy continues. A perspective, Radiat. Res., 179, 501, 10.1667/RR3306.1 Su, 2016, The role of autophagy in modulation of neuroinflammation in microglia, Neuroscience, 319, 155, 10.1016/j.neuroscience.2016.01.035 Banati, 2004, Mitochondria in activated microglia in vitro, J. Neurocytol., 33, 535, 10.1007/s11068-004-0515-7 Moneta, 1993, Cell adhesion molecule expression in the regenerating rat facial nucleus, J. Neuroimmunol., 45, 203, 10.1016/0165-5728(93)90181-W Hurley, 2003, Facial nerve axotomy in aged and young adult rats: analysis of the glial response, Neurobiol. Aging, 24, 511, 10.1016/S0197-4580(02)00097-0 Raivich, 1998, Immune surveillance in the injured nervous system: T-lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration, J. Neurosci., 18, 5804, 10.1523/JNEUROSCI.18-15-05804.1998 Gehrmann, 1995, Microglial turnover in the injured cns: Activated microglia undergo delayed DNA fragmentation following peripheral nerve injury, J. Neuropathol. Exp. Neurol., 54, 680, 10.1097/00005072-199509000-00010 Banati, 1993, Cytotoxicity of microglia, Glia, 7, 111, 10.1002/glia.440070117 Pathipati, 2013, Phenotype and secretory responses to oxidative stress in microglia, Dev. Neurosci., 35, 241, 10.1159/000346159 Boche, 2013, Review: Activation patterns of microglia and their identification in the human brain, Neuropathol. Appl. Neurobiol., 39, 3, 10.1111/nan.12011 Carreira, 2014, Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling, Front. Cell Neurosci., 8, 343, 10.3389/fncel.2014.00343 L'Episcopo, 2012, J. Neurosci., 32, 2062, 10.1523/JNEUROSCI.5259-11.2012 Bisht, 2016, Dark microglia: A new phenotype predominantly associated with pathological states, Glia, 64, 826, 10.1002/glia.22966 Wake, 2009, Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals, J. Neurosci., 29, 3974, 10.1523/JNEUROSCI.4363-08.2009 Di Filippo, 2016, Persistent activation of microglia and nadph drive hippocampal dysfunction in experimental multiple sclerosis, Sci. Rep., 6, 20926, 10.1038/srep20926 Benedek, 2016, Estrogen induces multiple regulatory b cell subtypes and promotes m2 microglia and neuroprotection during experimental autoimmune encephalomyelitis, J. Neuroimmunol., 293, 45, 10.1016/j.jneuroim.2016.02.009 J. Wang, N. Song, H. Jiang, J. Wang, J. Xie, Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim Biophys Acta, 1832, 2013, pp. 618–625. Haas, 2016, Expression of tgfbeta1 and inflammatory markers in the 6-hydroxydopamine mouse model of parkinson's disease, Front. Mol. Neurosci., 9, 7, 10.3389/fnmol.2016.00007 Tang, 2016, Differential roles of m1 and m2 microglia in neurodegenerative diseases, Mol. Neurobiol., 53, 1181, 10.1007/s12035-014-9070-5 Brandenburg, 2016, Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors, Acta Neuropathol., 131, 365, 10.1007/s00401-015-1529-6 Xu, 2016, Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system, Exp. Neurol., 275, 436, 10.1016/j.expneurol.2014.11.004 Chanaday, 2016, Microglia and astrocyte activation in the frontal cortex of rats with experimental autoimmune encephalomyelitis, Neuroscience, 314, 160, 10.1016/j.neuroscience.2015.11.060 Hu, 2012, Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia, Stroke, 43, 3063, 10.1161/STROKEAHA.112.659656 Miron, 2013, M2 microglia and macrophages drive oligodendrocyte differentiation during cns remyelination, Nat. Neurosci., 16, 1211, 10.1038/nn.3469 Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J. Neurosci., 29, 13435, 10.1523/JNEUROSCI.3257-09.2009 Deng, 2012, Radiation-induced c-jun activation depends on mek1-erk1/2 signaling pathway in microglial cells, PLoS One, 7, e36739, 10.1371/journal.pone.0036739 Yin, 2014, Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration, Antioxid. Redox Signal, 20, 353, 10.1089/ars.2012.4774 Yuste, 2015, Implications of glial nitric oxide in neurodegenerative diseases, Front Cell Neurosci., 9, 322, 10.3389/fncel.2015.00322 Liu, 2012, Stat1 mediates oroxylin a inhibition of inos and pro-inflammatory cytokines expression in microglial bv-2 cells, PLoS One, 7, e50363, 10.1371/journal.pone.0050363 Wang, 2006, Dual effects of antioxidants in neurodegeneration: Direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation, Curr. Pharm. Des., 12, 3521, 10.2174/138161206778343109 T.R. Guilarte, M.K. Loth, S.R. Guariglia, Tspo finds nox2 in microglia for redox homeostasis, Trends Pharmacol. Sci., 2016 Chen, 2016, Critical role of the mac1/nox2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration, Curr. Opin. Pharm., 26, 54, 10.1016/j.coph.2015.10.001 J. Haslund-Vinding, G. McBean, V. Jaquet, F. Vilhardt, Nadph oxidases in microglia oxidant production: activating receptors, pharmacology, and association with disease, Br. J. Pharmacol. 2016. N. Sharma, B. Nehru, Apocyanin, a microglial nadph oxidase inhibitor prevents dopaminergic neuronal degeneration in lipopolysaccharide-induced parkinson's disease model. Mol. Neurobiol. 2015.. S. Yadav, S.K. Gandham, R. Panicucci, M.M. Amiji, Intranasal brain delivery of cationic nanoemulsion-encapsulated tnfalpha sirna in prevention of experimental neuroinflammation, Nanomedicine 2016 Rojo, 2014, Redox control of microglial function: molecular mechanisms and functional significance, Antioxid. Redox Signal, 21, 1766, 10.1089/ars.2013.5745 Han, 2012, Control of jnk for an activation of nadph oxidase in lps-stimulated bv2 microglia, Arch. Pharm. Res., 35, 709, 10.1007/s12272-012-0415-1 Levy Nogueira, 2016, Mechanical stress models of alzheimer's disease pathology, Alzheimers Dement, 12, 324, 10.1016/j.jalz.2015.10.005 Jiang, 2016, Trem2 modifies microglial phenotype and provides neuroprotection in p301s tau transgenic mice, Neuropharmacology, 105, 196, 10.1016/j.neuropharm.2016.01.028 Aquilano, 2008, Role of nitric oxide synthases in parkinson's disease: A review on the antioxidant and anti-inflammatory activity of polyphenols, Neurochem. Res., 33, 2416, 10.1007/s11064-008-9697-6 Imai, 2016, Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia, Free Radic. Biol. Med., 91, 154, 10.1016/j.freeradbiomed.2015.12.015 Boll, 2008, Free copper, ferroxidase and sod1 activities, lipid peroxidation and no(x) content in the csf. A different marker profile in four neurodegenerative diseases, Neurochem. Res., 33, 1717, 10.1007/s11064-008-9610-3 Onasanwo, 2016, Inhibition of neuroinflammation in bv2 microglia by the biflavonoid kolaviron is dependent on the nrf2/are antioxidant protective mechanism, Mol. Cell Biochem., 414, 23, 10.1007/s11010-016-2655-8 Kam, 2013, Effects of ionizing radiation on mitochondria, Free Radic. Biol. Med., 65, 607, 10.1016/j.freeradbiomed.2013.07.024 Einor, 2016, Ionizing radiation, antioxidant response and oxidative damage: a meta-analysis, Sci. Total Environ., 548–549, 463, 10.1016/j.scitotenv.2016.01.027 Ji, 2014, Irradiation-induced hippocampal neurogenesis impairment is associated with epigenetic regulation of bdnf gene transcription, Brain Res., 1577, 77, 10.1016/j.brainres.2014.06.035 Osipov, 2013, In vivo gamma-irradiation low dose threshold for suppression of DNA double strand breaks below the spontaneous level in mouse blood and spleen cells, Mutat. Res., 756, 141, 10.1016/j.mrgentox.2013.04.016 Sweet, 2014, Central nervous system effects of whole-body proton irradiation, Radiat. Res., 182, 18, 10.1667/RR13699.1 Roughton, 2013, Irradiation to the young mouse brain impaired white matter growth more in females than in males, Cell Death Dis., 4, e897, 10.1038/cddis.2013.423 Z. Ungvari, A. Podlutsky, D. Sosnowska, Z. Tucsek, P. Toth, F. Deak, T. Gautam, A. Csiszar, W.E. Sonntag, Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: Role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, pp. 1443–1457. Huang, 2015, Oxidative stress and redox regulation on hippocampal-dependent cognitive functions, Arch. Biochem. Biophys., 576, 2, 10.1016/j.abb.2015.03.014 Sridharan, 2015, Understanding cancer development processes after hze-particle exposure: Roles of ros, DNA damage repair and inflammation, Radiat. Res., 183, 1, 10.1667/RR13804.1 Rana, 2013, Altered brain metabolism after whole body irradiation in mice: A preliminary in vivo 1h mrs study, Int J. Radiat. Biol., 89, 212, 10.3109/09553002.2013.734944 Jenrow, 2013, Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment, Radiat. Res., 179, 549, 10.1667/RR3026.1 Hua, 2012, Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats, PLoS One, 7, e52728, 10.1371/journal.pone.0052728 Rola, 2008, Hippocampal neurogenesis and neuroinflammation after cranial irradiation with (56)fe particles, Radiat. Res., 169, 626, 10.1667/RR1263.1 Todorovic, 2015, Antioxidative enzymes in irradiated rat brain-indicators of different regional radiosensitivity, Childs Nerv. Syst., 31, 2249, 10.1007/s00381-015-2807-2 Hekim, 2015, Radiation triggering immune response and inflammation, Cancer Lett., 368, 156, 10.1016/j.canlet.2015.04.016 Osato, 2010, Apoptosis-inducing factor deficiency decreases the proliferation rate and protects the subventricular zone against ionizing radiation, Cell Death Dis., 1, e84, 10.1038/cddis.2010.63 Marples, 2003, An association between the radiation-induced arrest of g2-phase cells and low-dose hyper-radiosensitivity: a plausible underlying mechanism?, Radiat. Res., 160, 38, 10.1667/RR3013 Mizumatsu, 2003, Extreme sensitivity of adult neurogenesis to low doses of x-irradiation, Cancer Res., 63, 4021 Monje, 2013, Functional and structural differences in the hippocampus associated with memory deficits in adult survivors of acute lymphoblastic leukemia, Pedia. Blood Cancer, 60, 293, 10.1002/pbc.24263 Zakhvataev, 2015, Possible scenarios of the influence of low-dose ionizing radiation on neural functioning, Med. Hypotheses, 85, 723, 10.1016/j.mehy.2015.10.020 Raber, 2004, Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis, Radiat. Res., 162, 39, 10.1667/RR3206 Acharya, 2010, Consequences of ionizing radiation-induced damage in human neural stem cells, Free Radic. Biol. Med., 49, 1846, 10.1016/j.freeradbiomed.2010.08.021 Saeed, 2014, Indirect effects of radiation induce apoptosis and neuroinflammation in neuronal sh-sy5y cells, Neurochem. Res., 39, 2334, 10.1007/s11064-014-1432-x Hong, 1995, Induction of acute-phase gene-expression by brain irradiation, Int. J. Radiat. Oncol. Biol. Phys., 33, 619, 10.1016/0360-3016(95)00279-8 Hwang, 2006, Ionizing radiation induces astrocyte gliosis through microglia activation, Neurobiol. Dis., 21, 457, 10.1016/j.nbd.2005.08.006 Raber, 2016, Effects of proton and combined proton and (56)fe radiation on the hippocampus, Radiat. Res., 185, 20, 10.1667/RR14222.1 Bartsch, 2015, The hippocampus in aging and disease: From plasticity to vulnerability, Neuroscience, 309, 1, 10.1016/j.neuroscience.2015.07.084 Conner, 2010, Effects of the at1 receptor antagonist l-158,809 on microglia and neurogenesis after fractionated whole-brain irradiation, Radiat. Res., 173, 49, 10.1667/RR1821.1 Rola, 2004, Indicators of hippocampal neurogenesis are altered by 56fe- particle irradiation in a dose-dependent manner, Radiat. Res., 162, 442, 10.1667/RR3234 M.L. Monje, H. Vogel, M. Masek, K.L. Ligon, P.G. Fisher, T.D. Palmer, Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann. Neurol. 2007, vol. 62, pp. 515–520 Ben Abdallah, 2007, Reversible effect of x-irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice, Hippocampus, 17, 1230, 10.1002/hipo.20358 Monje, 2003, Inflammatory blockade restores adult hippocampal neurogenesis, Science, 302, 1760, 10.1126/science.1088417 Morganti, 2014, Cranial irradiation alters the brain's microenvironment and permits ccr2+ macrophage infiltration, PLoS One, 9, e93650, 10.1371/journal.pone.0093650 Acharya, 2015, Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment, PLoS One, 10, e0128316, 10.1371/journal.pone.0128316 Kalm, 2009, Transient inflammation in neurogenic regions after irradiation of the developing brain, Radiat. Res., 171, 66, 10.1667/RR1269.1 Li, 2015, Aging-like changes in the transcriptome of irradiated microglia, Glia, 63, 754, 10.1002/glia.22782 Davella, 1992, Quantitative study of blood-brain-barrier permeability changes after experimental whole-brain radiation, Neurosurgery, 30, 30, 10.1227/00006123-199201000-00006 Li, 2003, Endothelial apoptosis initiates acute blood-brain barrier disruption after ionizing radiation, Cancer Res., 63, 5950 Pena, 2000, Radiation-induced apoptosis of endothelial cells in the murine central nervous system: Protection by fibroblast growth factor and sphingomyelinase deficiency, Cancer Res., 60, 321 Gaber, 2004, An intravital microscopy study of radiation-induced changes in permeability and leukocyte-endothelial cell interactions in the microvessels of the rat pia mater and cremaster muscle, Brain Res. Protoc., 13, 1, 10.1016/j.brainresprot.2003.11.005 Lee, 2010, Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain, Intl J. Radiat. Biol., 86, 132, 10.3109/09553000903419346 Schnegg, 2012, Ppardelta prevents radiation-induced proinflammatory responses in microglia via transrepression of nf-kappab and inhibition of the pkcalpha/mek1/2/erk1/2/ap-1 pathway, Free Radic. Biol. Med., 52, 1734, 10.1016/j.freeradbiomed.2012.02.032 Dong, 2015, Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice, Int J. Radiat. Biol., 91, 224, 10.3109/09553002.2014.988895 Ramanan, 2008, Pparalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating nf-kappab and ap-1 pathways, Free Radic. Biol. Med., 45, 1695, 10.1016/j.freeradbiomed.2008.09.002 R. Rola, Y. Zou, T.T. Huang, K. Fishman, J. Baure, S. Rosi, H. Milliken, C.L. Limoli, J.R. Fike, Lack of extracellular superoxide dismutase (ec-sod) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic. Biol. Med. 2007, vol. 42, pp. 1133–1145; discussion 1131–1132 Leach, 2001, Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen, Cancer Res., 61, 3894 Ismail, 2016, Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain, J. Photochem. Photobiol. B, 158, 154, 10.1016/j.jphotobiol.2016.02.039 Suman, 2013, Therapeutic and space radiation exposure of mouse brain causes impaired dna repair response and premature senescence by chronic oxidant production, Aging, 5, 607, 10.18632/aging.100587 Fishman, 2009, Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in cuznsod or mnsod, Free Radic. Biol. Med., 47, 1459, 10.1016/j.freeradbiomed.2009.08.016 Liao, 2013, Mitochondrial-targeted human catalase affords neuroprotection from proton irradiation, Radiat. Res., 180, 1, 10.1667/RR3339.1 Parihar, 2015, Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction, Antioxid. Redox Signal, 22, 78, 10.1089/ars.2014.5929 Greene-Schloesser, 2014, Cellular response of the rat brain to single doses of (137)cs gamma rays does not predict its response to prolonged 'biologically equivalent' fractionated doses, Int J. Radiat. Biol., 90, 790, 10.3109/09553002.2014.933915 Yamaoka, 1994, Effects of low-dose x-ray irradiation on biomembrane in brain cortex of aged rats, Free Radic. Biol. Med., 16, 529, 10.1016/0891-5849(94)90132-5 Wang, 2014, Total body 100-mgy x-irradiation does not induce alzheimer's disease-like pathogenesis or memory impairment in mice, J. Radiat. Res., 55, 84, 10.1093/jrr/rrt096 L. Chien, W.K. Chen, S.T. Liu, C.R. Chang, M.C. Kao, K.W. Chen, S.C. Chiu, M.L. Hsu, I.C. Hsiang, Y.J. Chen, et al., Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes i and iii in hippocampal neurons. Oncotarget 2015, vol. 6, pp. 30628–30639. Baulch, 2015, Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles, Redox Biol., 5, 24, 10.1016/j.redox.2015.03.001 Otsuka, 2006, Activation of antioxidative enzymes induced by low-dose-rate whole-body gamma irradiation: Adaptive response in terms of initial DNA damage, Radiat. Res., 166, 474, 10.1667/RR0561.1 Day, 2007, Adaptive response for chromosomal inversions in pkz1 mouse prostate induced by low doses of x radiation delivered after a high dose, Radiat. Res., 167, 682, 10.1667/RR0764.1 Yin, 2003, Gene expression changes in mouse brain after exposure to low-dose ionizing radiation, Int J. Radiat. Biol., 79, 759, 10.1080/09553000310001610961 Lowe, 2009, Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and alzheimer's disease, Radiat. Res., 171, 53, 10.1667/RR1389.1 Silasi, 2004, Selective brain responses to acute and chronic low-dose x-ray irradiation in males and females, Biochem. Biophys. Res. Commun., 325, 1223, 10.1016/j.bbrc.2004.10.166 Kojima, 1999, Elevation of antioxidant potency in the brain of mice by low-dose γ- ray irradiation and its effect on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (mptp)-induced brain damage, Free Radic. Biol. Med., 26, 388, 10.1016/S0891-5849(98)00200-7 El-Ghazaly, 2015, Neuroprotective effect of egb761(r) and low-dose whole-body gamma-irradiation in a rat model of parkinson's disease, Toxicol. Ind. Health, 31, 1128, 10.1177/0748233713487251 Peterson, 1993, Effect of brain irradiation on demyelinating lesions, Neurology, 43, 2105, 10.1212/WNL.43.10.2105 Cook, 1986, Effect of total lymphoid irradiation in chronic progressive multiple-sclerosis, Lancet, 1, 1405, 10.1016/S0140-6736(86)91554-0 C. Devereux, R. Troiano, G. Zito, R.B. Devereux, K.J. Kopecky, R. Friedman, P.C. Dowling, M.P. Hafstein, C. Rohowskykochan, S.D. Cook, Effect of total lymphoid irradiation on functional status in chronic multiple-sclerosis - importance of lymphopenia early after treatment – the pros. Neurology 1988, vol. 38, pp. 32–37. Tsukimoto, 2008, Repeated 0.5-gy γ irradiation attenuates experimental autoimmune encephalomyelitis with up-regulation of regulatory t cells and suppression of il17 production, Radiat. Res., 170, 429, 10.1667/RR1352.1 Shimura, 2014, Effects of low-dose-gamma rays on the immune system of different animal models of disease, Dose Response, 12, 429, 10.2203/dose-response.13-042.Shimura Ina, 2004, Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in mrl-lpr/lprmice, Radiat. Res., 161, 168, 10.1667/RR3120 Kataoka, 2014, Radon inhalation protects against transient global cerebral ischemic injury in gerbils, Inflammation, 37, 1675, 10.1007/s10753-014-9896-z Yoshimoto, 2012, Inhibitory effects of prior low-dose x-irradiation on cold-induced brain injury in mouse, Inflammation, 35, 89, 10.1007/s10753-011-9293-9 Otani, 2012, Low-dose-rate, low-dose irradiation delays neurodegeneration in a model of retinitis pigmentosa, Am. J. Pathol., 180, 328, 10.1016/j.ajpath.2011.09.025 Cobbs, 1996, Manganese superoxide dismutase expression in human central nervous system tumors, Cancer Res., 56, 3192 Russo, 2012, Cellular adaptive response to chronic radiation exposure in interventional cardiologists, Eur. Heart J., 33, 408, 10.1093/eurheartj/ehr263 Eken, 2012, Induced antioxidant activity in hospital staff occupationally exposed to ionizing radiation, Int J. Radiat. Biol., 88, 648, 10.3109/09553002.2012.702295 Tseng, 2014, Functional consequences of radiation-induced oxidative stress in cultured neural stem cells and the brain exposed to charged particle irradiation, Antioxid. Redox Signal, 20, 1410, 10.1089/ars.2012.5134 Veeraraghavan, 2011, Low-dose gamma-radiation-induced oxidative stress response in mouse brain and gut: Regulation by nfkappab-mnsod cross-signaling, Mutat. Res., 718, 44, 10.1016/j.mrgentox.2010.10.006 M .Abdel-Rafei, M. Amin, H. Hasan, Novel effect of daflon and low-dose -radiation in modulation of thioacetamide-induced hepatic encephalopathy in male albino rats. Human & Experimental Toxicology 2016. Katsura, 2016, Effects of chronic low-dose radiation on human neural progenitor cells, Sci. Rep., 6, 20027, 10.1038/srep20027 Banati, 2002, Visualising microglial activation in vivo, GLIA, 40, 206, 10.1002/glia.10144 Banati, 2003, Neuropathological imaging: In vivo detection of glial activation as a measure of disease and adaptive change in the brain, Br. Med. Bull., 65, 121, 10.1093/bmb/65.1.121 B. Janssen, D.J. Vugts, U. Funke, G.T. Molenaar, P.S. Kruijer, B.N. van Berckel, A.A. Lammertsma, A.D. Windhorst, Imaging of neuroinflammation in alzheimer's disease, multiple sclerosis and stroke: Recent developments in positron emission tomography. Biochim. Biophys. Acta, vol. 1862, 2016, pp. 425–441. Ching, 2012, Current paradigm of the 18-kda translocator protein (tspo) as a molecular target for pet imaging in neuroinflammation and neurodegenerative diseases, Insights Imaging, 3, 111, 10.1007/s13244-011-0128-x Fan, 2015, Conditional steroidogenic cell-targeted deletion of tspo unveils a crucial role in viability and hormone-dependent steroid formation, Proc. Natl. Acad. Sci. USA, 112, 7261, 10.1073/pnas.1502670112 Banati, 2014, Positron emission tomography and functional characterization of a complete pbr/tspo knockout, Nat. Commun., 5, 5452, 10.1038/ncomms6452 Middleton, 2015, Guwiyang wurra--'fire mouse': A global gene knockout model for tspo/pbr drug development, loss-of-function and mechanisms of compensation studies, Biochem. Soc. Trans., 43, 553, 10.1042/BST20150039 Wang, 2014, Macroglia-microglia interactions via tspo signaling regulates microglial activation in the mouse retina, J. Neurosci., 34, 3793, 10.1523/JNEUROSCI.3153-13.2014 Banati, 1999, [11c] (r)-pk11195 positron emission tomography imaging of activated microglia in vivo in rasmussen's encephalitis, Neurology, 53, 2199, 10.1212/WNL.53.9.2199 Pappata, 2000, Thalamic microglial activation in ischemic stroke detected in vivo by pet and [(11)c]pk11195, Neurology, 55, 1052, 10.1212/WNL.55.7.1052 Cagnin, 2006, In vivo evidence for microglial activation in neurodegenerative dementia, Acta Neurol. Scand., 114, 107, 10.1111/j.1600-0404.2006.00694.x Cagnin, 2002, In vivo imaging of neuroinflammation, Eur. Neuropsychopharmacol., 12, 581, 10.1016/S0924-977X(02)00107-4 Banati, 2000, The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity, Brain, 123, 2321, 10.1093/brain/123.11.2321 Edison, 2008, Microglia, amyloid, and cognition in alzheimer's disease: an [11c](r)pk11195-pet and [11c]pib-pet study, Neurobiol. Dis., 32, 412, 10.1016/j.nbd.2008.08.001 Gerhard, 2006, In vivo imaging of microglial activation with [11c](r)-pk11195 pet in idiopathic parkinson's disease, Neurobiol. Dis., 21, 404, 10.1016/j.nbd.2005.08.002 Loth, 2016, Tspo in a murine model of sandhoff disease: Presymptomatic marker of neurodegeneration and disease pathophysiology, Neurobiol. Dis., 85, 174, 10.1016/j.nbd.2015.11.001 Varrone, 2015, Positron emission tomography imaging of the 18-kda translocator protein (tspo) with [18f]fempa in alzheimer's disease patients and control subjects, Eur. J. Nucl. Med. Mol. Imaging, 42, 438, 10.1007/s00259-014-2955-8 A. Cagnin, M. Rossor, E.L. Sampson, T. Mackinnon, R.B. Banati, In vivo detection of microglial activation in frontotemporal dementia. Ann. Neurol. vol. 56, 2004, pp. 894–897. Zurcher, 2015, Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [(11)c]-pbr28, Neuroimage Clin., 7, 409, 10.1016/j.nicl.2015.01.009 Turner, 2004, Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11c](r)-pk11195 positron emission tomography study, Neurobiol. Dis., 15, 601, 10.1016/j.nbd.2003.12.012 Rissanen, 2014, In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using pet imaging and the radioligand (1)(1)c-pk11195, J. Nucl. Med., 55, 939, 10.2967/jnumed.113.131698 Corcia, 2012, Molecular imaging of microglial activation in amyotrophic lateral sclerosis, PLoS One, 7, e52941, 10.1371/journal.pone.0052941 Tsartsalis, 2015, Spect imaging of glioma with radioiodinated clinde: Evidence from a mouse gl26 glioma model, EJNMMI Res., 5, 9, 10.1186/s13550-015-0092-4 Werry, 2015, Tspo as a target for glioblastoma therapeutics, Biochem. Soc. Trans., 43, 531, 10.1042/BST20150015 Ma, 2016, Tspo ligand pk11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic lps administration, Brain Res. Bull., 121, 192, 10.1016/j.brainresbull.2016.02.001 Gut, 2013, Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism, Nat. Chem. Biol., 9, 97, 10.1038/nchembio.1136 Scholz, 2015, Targeting translocator protein (18kda) (tspo) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration, J. Neuroinflamm., 12, 201, 10.1186/s12974-015-0422-5 Rupprecht, 2010, Translocator protein (18kda) (tspo) as a therapeutic target for neurological and psychiatric disorders, Nat. Rev. Drug Disco., 9, 971, 10.1038/nrd3295 Zhao, 2016, Mitochondrial translocator protein (tspo) function is not essential for heme biosynthesis, J. Biol. Chem., 291, 1591, 10.1074/jbc.M115.686360 Gatliff, 2012, The 18 kda translocator protein (tspo): a new perspective in mitochondrial biology, Curr. Mol. Med., 12, 356 L. Veenman, J. Alten, K. Linnemannstons, Y. Shandalov, S. Zeno, M. Lakomek, M. Gavish, W. Kugler, Potential involvement of f0f1-atp(synth)ase and reactive oxygen species in apoptosis induction by the antineoplastic agent erucylphosphohomocholine in glioblastoma cell lines : A mechanism for induction of apoptosis via the 18 kda mitochondrial translocator protein. Apoptosis 2010, 15, pp. 753–768. Veenman, 2012, The role of 18kda mitochondrial translocator protein (tspo) in programmed cell death, and effects of steroids on tspo expression, Curr. Mol. Med., 12, 398 Gatliff, 2014, Tspo interacts with vdac1 and triggers a ros-mediated inhibition of mitochondrial quality control, Autophagy, 10, 2279, 10.4161/15548627.2014.991665 Gatliff, 2015, Tspo is a redox regulator of cell mitophagy, Biochem. Soc. Trans., 43, 543, 10.1042/BST20150037 Lin, 2014, Genetic analysis of dtspo, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and aβ42-induced neurodegeneration, Aging Cell, 13, 507, 10.1111/acel.12200 Zeno, 2012, The 18 kda mitochondrial translocator protein (tspo) prevents accumulation of protoporphyrin ix. Involvement of reactive oxygen species (ros), Curr. Mol. Med., 12, 494 Shargorodsky, 2012, The nitric oxide donor sodium nitroprusside requires the 18 kda translocator protein to induce cell death, Apoptosis, 17, 647, 10.1007/s10495-012-0725-2 Santoro, 2016, Tspo-ligands prevent oxidative damage and inflammatory response in c6 glioma cells by neurosteroid synthesis, Eur. J. Pharm. Sci., 88, 124, 10.1016/j.ejps.2016.04.006 Choi, 2011, Translocator protein (18kda)/peripheral benzodiazepine receptor specific ligands induce microglia functions consistent with an activated state, Glia, 59, 219, 10.1002/glia.21091 Batarseh, 2010, Protein kinase cε regulation of translocator protein (18 kda) tspo gene expression is mediated through a mapk pathway targeting stat3 and c-jun transcription factors, Biochemistry, 49, 4766, 10.1021/bi100020e