Abstract
Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30 Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20 mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1β, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.
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References
Ballesteros-Zebadua P, Chavarria A, Celis MA, Paz C, Franco-Perez J (2012) Radiation-induced neuroinflammation and radiation somnolence syndrome. CNS Neurol Disord Drug Targets 11(7):937–949
Bishop-Bailey D, Bystrom J (2009) Emerging roles of peroxisome proliferator-activated receptor-beta/delta in inflammation. Pharmacol Ther 124(2):141–150
Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D (1991) Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest 88(2):691–695
Chen H, Chong ZZ, De Toledo SM, Azzam EI, Elkabes S, Souayah N (2016) Delayed activation of human microglial cells by high dose ionizing radiation. Brain Res. doi:10.1016/j.brainres.2016.06.002
Chiang CS, Hong JH, Stalder A, Sun JR, Withers HR, McBride WH (1997) Delayed molecular responses to brain irradiation. Int J Radiat Biol 72(1):45–53
Cochran DC, Chan MD, Aklilu M, Lovato JF, Alphonse NK, Bourland JD, Urbanic JJ, McMullen KP, Shaw EG, Tatter SB, Ellis TL (2012) The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery. J Neurosurg 116(5):978–983
Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 100(23):13632–13637
Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ (2001) Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32(5):911–926
Greene-Schloesser D, Robbins ME (2012) Radiation-induced cognitive impairment—from bench to bedside. Neuro-Oncology 14(Suppl 4):iv37–iv44
Greene-Schloesser D, Moore E, Robbins ME (2013) Molecular pathways: radiation-induced cognitive impairment. Clin Cancer Res 19(9):2294–2300
Hadjipavlou-Litina D, Garnelis T, Athanassopoulos CM, Papaioannou D (2009) Kukoamine A analogs with lipoxygenase inhibitory activity. J Enzyme Inhib Med Chem 24(5):1188–1193
Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155
Kalinin S, Richardson JC, Feinstein DL (2009) A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 6(5):431–437
Khuntia D, Brown P, Li J, Mehta MP (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24(8):1295–1304
Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81(3):302–313
Kyrkanides S, Moore AH, Olschowka JA, Daeschner JC, Williams JP, Hansen JT, Kerry O’Banion M (2002) Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res Mol Brain Res 104(2):159–169
Lee WH, Sonntag WE, Mitschelen M, Yan H, Lee YW (2010) Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain. Int J Radiat Biol 86(2):132–144
Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, Mustafa R, Riddle DR, Zhao W, Chan MD, Robbins ME (2012) Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res 178(1):46–56
Madsen TM, Kristjansen PE, Bolwig TG, Wortwein G (2003) Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119(3):635–642
Mattei D, Djodari-Irani A, Hadar R, Pelz A, de Cossío LF, Goetz T, Matyash M, Kettenmann H, Winter C, Wolf SA (2014) Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun 38:175–184
Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR (2003) Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 63(14):4021–4027
Monje ML, Palmer T (2003) Radiation injury and neurogenesis. Curr Opin Neurol 16(2):129–134
Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765
Mori K, Tani M, Kamata K, Kawamura H, Urata Y, Goto S, Kuwano M, Shibata S, Kondo T (2000) Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells. Free Radic Res 33(2):157–166
Nowak E, Etienne O, Millet P, Lages CS, Mathieu C, Mouthon MA, Boussin FD (2006) Radiation-induced H2AX phosphorylation and neural precursor apoptosis in the developing brain of mice. Radiat Res 165(2):155–164
Oh SB, Park HR, Jang YJ, Choi SY, Son TG, Lee J (2013) Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by gamma-ray radiation. Br J Pharmacol 168(2):421–431
Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, VandenBerg SR, Fike JR (2004) Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res 162(1):39–47
Raju U, Gumin GJ, Tofilon PJ (1999) NF kappa B activity and target gene expression in the rat brain after one and two exposures to ionizing radiation. Radiat Oncol Investig 7(3):145–152
Ramanan S, Kooshki M, Zhao W, Hsu FC, Robbins ME (2008) PPARalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways. Free Radic Biol Med 45(12):1695–1704
Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME (2009) The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys 75(3):870–877
Ramanan S, Zhao W, Riddle DR, Robbins ME (2010) Role of PPARs in radiation-induced brain injury. PPAR Res 1–12
Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR (2004) Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188(2):316–330
Rola R, Zou Y, Huang TT, Fishman K, Baure J, Rosi S, Milliken H, Limoli CL, Fike JR (2007) Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic Biol Med 42(8):1133–1145
Roman DD, Sperduto PW (1995) Neuropsychological effects of cranial radiation: current knowledge and future directions. Int J Radiat Oncol Biol Phys 31(4):983–998
Santa-Cecilia FV, Socias B, Ouidja MO, Sepulveda-Diaz JE, Acuña L, Silva RL, Michel PP, Del-Bel E, Cunha TM, Raisman-Vozari R (2016) Doxycycline suppresses microglial activation by inhibiting the p38 MAPK and NF-κB signaling pathways. Neurotox Res 29(4):447–459
Schnegg CI, Kooshki M, Hsu FC, Sui G, Robbins ME (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(9):1734–1743
Schnegg CI, Greene-Schloesser D, Kooshki M, Payne VS, Hsu FC, Robbins ME (2013) The PPARdelta agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radic Biol Med 61:1–9
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410(6826):372–376
Slepko N, Levi G (1996) Progressive activation of adult microglial cells in vitro. Glia 16(3):241–246
Son EW, Rhee DK, Pyo S (2006) Gamma-irradiation-induced intercellular adhesion molecule-1 (ICAM-1) expression is associated with catalase: activation of Ap-1 and JNK. J Toxicol Environ Health A 69(24):2137–2155
Stupp R, Warren PM, Martin J, Michael W, Barbara F, Martin JB et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The N Engl J Med 352(10):987–996
Tada E, Parent JM, Lowenstein DH, Fike JR (2000) X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 99(1):33–41
Tofilon PJ, Fike JR (2000) The radioresponse of the central nervous system: a dynamic process. Radiat Res 153(4):357–370
Zhang L, Li K, Sun R, Zhang Y, Ji J, Huang P, Yang H, Tian Y (2014) Minocycline ameliorates cognitive impairment induced by whole-brain irradiation: an animal study. Radiat Oncol 9:281
Zhang Y, Cheng Z, Wang C, Ma H, Meng W, Zhao Q (2016) Neuroprotective effects of kukoamine a against radiation-induced rat brain injury through inhibition of oxidative stress and neuronal apoptosis. Neurochem Res. doi:10.1007/s11064-016-1967-0
Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645–660
Acknowledgments
This work was supported by the National Science and Technology Major Project, People’s Republic of China (Project number: 2014ZX09J14101-05C). We thank Dr. Jing for language proofreading.
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All animal handling and experiments were performed in strict accordance with Shenyang Pharmaceutical University Experimental Animal Care Guidelines based on the National Animal Ethical Policies.
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Zhang, Y., Gao, L., Cheng, Z. et al. Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1. Neurotox Res 31, 259–268 (2017). https://doi.org/10.1007/s12640-016-9679-4
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DOI: https://doi.org/10.1007/s12640-016-9679-4