Background/Aims: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. Methods: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether nonsteroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (1) chemokine production (CCL2 and CINC-1), (2) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-ß), and (3) NF-κB activity. Results: Concurrent treatment with minocycline, but not indomethacin, prevented GC endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-κB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus - factors that normally restrain inflammatory responses. Conclusions: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part by increasing the neurotoxicity of CNS inflammation.

Keywords:
Inflammation, Excitotoxicity, Stress, Minocycline, NF-κB
1.
Munhoz CD, Sorrells SF, Caso JR, Scavone C, Sapolsky RM: Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J Neurosci 2010;30:13690-13698.
2.
Sorrells SF, Caso JR, Munhoz CD, Hu CK, Tran KV, Miguel ZD, Chien BY, Sapolsky RM: Glucocorticoid signaling in myeloid cells worsens acute CNS injury and inflammation. J Neurosci 2013;33:7877-7889.
3.
Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM: The stressed CNS: when glucocorticoids aggravate inflammation. Neuron 2009;64:33-39.
4.
Dhabhar FS: Enhancing versus suppressive effects of stress on immune function: Implications for immunoprotection and immunopathology. Neuroimmunomodulation 2009;16:300-317.
5.
Yeager MP, Guyre PM, Munck AU: Glucocorticoid regulation of the inflammatory response to injury. Acta Anaesthesiol Scand 2004;48:799-813.
6.
Frank MG, Miguel ZD, Watkins LR, Maier SF: Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun 2009;24:19-30.
7.
Smyth GP, Stapleton PP, Freeman TA, Concannon EM, Mestre JR, Duff M, Maddali S, Daly JM: Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappab activation in macrophages. J Surg Res 2004;116:253-261.
8.
Viswanathan K, Dhabhar FS: Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Natl Acad Sci USA 2005;102:5808-5813.
9.
Barber AE, Coyle SM, Marano MA, Fischer E, Calvano SE, Fong Y, Moldawer LL, Lowry SF: Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J Immunol 1993;150:1999-2006.
10.
Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O'Shea JJ, Chrousos GP, Bornstein SR: Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002;16:61-71.
11.
Perry VH: Stress primes microglia to the presence of systemic inflammation: implications for environmental influences on the brain. Brain Behav Immun 2007;21:45-46.
12.
Goujon E, Parnet P, Laye S, Combe C, Kelley KW, Dantzer R: Stress downregulates lipopolysaccharide-induced expression of proinflammatory cytokines in the spleen, pituitary, and brain of mice. Brain Behav Immun 1995;9:292-303.
13.
Dhabhar FS, McEwen BS: Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun 1997;11:286-306.
14.
Bowers SL, Bilbo SD, Dhabhar FS, Nelson RJ: Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun 2008;22:105-113.
15.
de Pablos RM, Villaran RF, Arguelles S, Herrera AJ, Venero JL, Ayala A, Cano J, Machado A: Stress increases vulnerability to inflammation in the rat prefrontal cortex. J Neurosci 2006;26:5709-5719.
16.
Munhoz CD, Lepsch LB, Kawamoto EM, Malta MB, Lima Lde S, Avellar MC, Sapolsky RM, Scavone C: Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappab in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci 2006;26:3813-3820.
17.
Dinkel K, MacPherson A, Sapolsky RM: Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 2003;84:705-716.
18.
Sapolsky RM: Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1996;1:1-19.
19.
Stein-Behrens BA, Elliott EM, Miller CA, Schilling JW, Newcombe R, Sapolsky RM: Glucocorticoids exacerbate kainic acid-induced extracellular accumulation of excitatory amino acids in the rat hippocampus. J Neurochem 1992;58:1730-1735.
20.
Elliott EM, Sapolsky RM: Corticosterone impairs hippocampal neuronal calcium regulation - possible mediating mechanisms. Brain Res 1993;602:84-90.
21.
McIntosh LJ, Sapolsky RM: Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture. Exp Neurol 1996;141:201-206.
22.
De Bosscher K, Vanden Berghe W, Haegeman G: The interplay between the glucocorticoid receptor and nuclear factor-kappab or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 2003;24:488-522.
23.
Goujon E, Parnet P, Cremona S, Dantzer R: Endogenous glucocorticoids down regulate central effects of interleukin-1 beta on body temperature and behaviour in mice. Brain Res 1995;702:173-180.
24.
Uz T, Dwivedi Y, Savani PD, Impagnatiello F, Pandey G, Manev H: Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain. J Neurochem 1999;73:693-699.
25.
Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA: Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 1997;94:2007-2012.
26.
Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH: Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 2005;1050:130-137.
27.
Takemiya T, Maehara M, Matsumura K, Yasuda S, Sugiura H, Yamagata K: Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. Neurosci Res 2006;56:103-110.
28.
Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ: Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain 2008;131:3019-3033.
29.
Monje ML, Toda H, Palmer TD: Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003;302:1760-1765.
30.
Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J: A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 199;96:13496-13500.
31.
Sapolsky R, Brooke S, Stein-Behrens B: Methodologic issues in studying glucocorticoid-induced damage to neurons. J Neurosci Methods 1995;58:1-15.
32.
MacPherson A, Dinkel K, Sapolsky R: Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hippocampal cultures. Exp Neurol 2005;194:376-383.
33.
Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005;308:1314-1318.
34.
Waters JC: Accuracy and precision in quantitative fluorescence microscopy. J Cell Biol 2009;185:1135-1148.
35.
Zhao S, Fernald RD: Comprehensive algorithm for quantitative real-time polymerase chain reaction. J Comput Biol 2005;12:1047-1064.
36.
Rong Y, Baudry M: Seizure activity results in a rapid induction of nuclear factor-kappa b in adult but not juvenile rat limbic structures. J Neurochem 1996;67:662-668.
37.
Wang DD, Englot DJ, Garcia PA, Lawton MT, Young WL: Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 2012;24:314-318.
38.
Kim HS, Suh YH: Minocycline and neurodegenerative diseases. Behav Brain Res 2009;196:168-179.
39.
Sapolsky RM, Pulsinelli WA: Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 1985;229:1397-1400.
40.
Biber K, Neumann H, Inoue K, Boddeke HW: Neuronal ‘on' and ‘off' signals control microglia. Trends Neurosci 2007;30:596-602.
41.
Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000;290:1768-1771.
42.
Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J: Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 2004;46:369-379.
43.
Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010;468:253-262.
44.
Sapolsky RM, Romero LM, Munck AU: How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 2000;21:55-89.
45.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006;9:917-924.
46.
Nair A, Bonneau RH: Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 2006;171:72-85.
47.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 1998;95:10896-10901.
48.
Bhavsar PK, Sukkar MB, Khorasani N, Lee KY, Chung KF: Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-kappaB. FASEB J 2008;22:1807-1816.
49.
Wiegers GJ, Reul JM: Induction of cytokine receptors by glucocorticoids: functional and pathological significance. Trends Pharmacol Sci 1998;19:317-321.
50.
Roy M, Sapolsky RM: The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis. Neuroendocrinology 2003;77:24-31.
51.
Yeager MP, Rassias AJ, Pioli PA, Beach ML, Wardwell K, Collins JE, Lee HK, Guyre PM: Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin. Crit Care Med 2009;37:2727-2732.
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2014
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