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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains

Authors: Nina Dupuis, Andrey Mazarati, Béatrice Desnous, Vibol Chhor, Bobbi Fleiss, Tifenn Le Charpentier, Sophie Lebon, Zsolt Csaba, Pierre Gressens, Pascal Dournaud, Stéphane Auvin

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation.

Methods

To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis.

Results

PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1β (IL-1β) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1β in the hippocampus in both P14 and P75 rats.

Conclusions

Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral–induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1β levels at both ages.
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Literature
1.
Getts DR, Balcar VJ, Matsumoto I, Muller M, King NJ. Viruses and the immune system: their roles in seizure cascade development. J Neurochem. 2008;104:1167–76.CrossRefPubMed
2.
3.
Annegers JF, Hauser WA, Beghi E, Nicolosi A, Kurland LT. The risk of unprovoked seizures after encephalitis and meningitis. Neurology. 1988;38:1407–10.CrossRefPubMed
4.
Rocca WA, Sharbrough FW, Hauser WA, Annegers JF, Schoenberg BS. Risk factors for complex partial seizures: a population-based case-control study. Ann Neurol. 1987;21:22–31.CrossRefPubMed
5.
6.
Davison KL, Crowcroft NS, Ramsay ME, Brown DW, Andrews NJ. Viral encephalitis in England, 1989-1998: what did we miss? Emerg Infect Dis. 2003;9:234–40.CrossRefPubMedPubMedCentral
7.
Nicolosi A, Hauser WA, Beghi E, Kurland LT. Epidemiology of central nervous system infections in Olmsted County, Minnesota, 1950-1981. J Infect Dis. 1986;154:399–408.CrossRefPubMed
8.
Cusick MF, Libbey JE, Patel DC, Doty DJ, Fujinami RS. Infiltrating macrophages are key to the development of seizures following virus infection. J Virol. 2013;87:1849–60.CrossRefPubMedPubMedCentral
9.
Kirkman NJ, Libbey JE, Wilcox KS, White HS, Fujinami RS. Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia. 2010;51:454–64.CrossRefPubMed
10.
Stewart KA, Wilcox KS, Fujinami RS, White HS. Development of postinfection epilepsy after Theiler’s virus infection of C57BL/6 mice. J Neuropathol Exp Neurol. 2010;69:1210–9.CrossRefPubMedPubMedCentral
11.
Stringer J. Models available for infection-induced seizures. In: Pitkänen AS PA, Moshé SL, editors. Models of Seizures and Epilepsy. Burlington: Elsevier Academic Press; 2006. p. 521–6.CrossRef
12.
Libbey JE, Fujinami RS. Neurotropic viral infections leading to epilepsy: focus on Theiler’s murine encephalomyelitis virus. Futur Virol. 2011;6:1339–50.CrossRef
13.
Kaushik DK, Gupta M, Basu A. Microglial response to viral challenges: every silver lining comes with a cloud. Front Biosci (Landmark Ed). 2011;16:2187–205.CrossRef
14.
Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol. 2012;86:2900–10.CrossRefPubMedPubMedCentral
15.
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8.CrossRefPubMed
16.
Doyle S, Vaidya S, O’Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity. 2002;17:251–63.CrossRefPubMed
17.
18.
Kwon YS, Pineda E, Auvin S, Shin D, Mazarati A, Sankar R. Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. J Neuroinflammation. 2013;10:30.CrossRefPubMedPubMedCentral
19.
Ravizza T, Noe F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis. 2008;31:327–33.CrossRefPubMed
20.
Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006;176:3804–12.CrossRefPubMed
21.
Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21:2580–8.PubMed
22.
Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166:7527–33.CrossRefPubMed
23.
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 U S A. 1999;96:13496–500.CrossRefPubMedPubMedCentral
24.
Scholz S, Sela E, Blaha L, Braunbeck T, Galay-Burgos M, Garcia-Franco M, Guinea J, Kluver N, Schirmer K, Tanneberger K, et al. A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment. Regul Toxicol Pharmacol. 2013;67:506–30.CrossRefPubMed
25.
Chhor V, Le Charpentier T, Lebon S, Ore MV, Celador IL, Josserand J, Degos V, Jacotot E, Hagberg H, Savman K, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun. 2013;32:70–85.CrossRefPubMedPubMedCentral
26.
Thery C, Chamak B, Mallat M. Cytotoxic effect of brain macrophages on developing. Eur J Neurosc. 1991;3:1155–64.CrossRef
27.
Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. In: Coligan JE et al., editors. Current protocols in immunology, Chapter 14:Unit 14 11. 2008.
28.
Mazarati A, Shin D, Auvin S, Sankar R. Age-dependent effects of topiramate on the acquisition and the retention of rapid kindling. Epilepsia. 2007;48:765–73.CrossRefPubMedPubMedCentral
29.
Mazarati A, Wu J, Shin D, Kwon YS, Sankar R. Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study. Epilepsia. 2008;49:1777–86.CrossRefPubMedPubMedCentral
30.
Sankar R, Auvin S, Kwon YS, Pineda E, Shin D, Mazarati A. Evaluation of development-specific targets for antiepileptogenic therapy using rapid kindling. Epilepsia. 2010;51:39–42.CrossRefPubMedPubMedCentral
31.
Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–24.CrossRefPubMed
32.
Libbey JE, Kennett NJ, Wilcox KS, White HS, Fujinami RS. Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection. J Virol. 2011;85:6913–22.CrossRefPubMedPubMedCentral
33.
Galic MA, Riazi K, Henderson AK, Tsutsui S, Pittman QJ. Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. Neurobiol Dis. 2009;36:343–51.CrossRefPubMedPubMedCentral
34.
Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci. 1999;19:5054–65.PubMed
35.
Dube C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol. 2005;57:152–5.CrossRefPubMedPubMedCentral
36.
Heida JG, Pittman QJ. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia. 2005;46:1906–13.CrossRefPubMed
37.
Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology. 2013;69:16–24.CrossRefPubMed
38.
Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, Vezzani A. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011;8:304–15.CrossRefPubMedPubMedCentral
39.
Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis. 2008;29:142–60.CrossRefPubMed
40.
Garrido-Mesa N, Zarzuelo A, Galvez J. What is behind the non-antibiotic properties of minocycline? Pharmacol Res. 2013;67:18–30.CrossRefPubMed
41.
Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem. 2000;275:31199–203.CrossRefPubMed
42.
Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 2005;94:819–27.CrossRefPubMed
43.
Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ, Snyder EY, Eichler ME, Friedlander RM. Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci U S A. 2004;101:3071–6.CrossRefPubMedPubMedCentral
44.
Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke. 2006;37:1087–93.CrossRefPubMed
45.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15.CrossRefPubMedPubMedCentral
46.
Abraham J, Fox PD, Condello C, Bartolini A, Koh S. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis. 2012;46:425–30.CrossRefPubMedPubMedCentral
47.
Beheshti Nasr SM, Moghimi A, Mohammad-Zadeh M, Shamsizadeh A, Noorbakhsh SM. The effect of minocycline on seizures induced by amygdala kindling in rats. Seizure. 2013;22:670–4.CrossRefPubMed
48.
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;24:314–8.CrossRefPubMedPubMedCentral
49.
Arnoux I, Hoshiko M, Diez AS, Audinat E. Paradoxical effects of minocycline in the developing mouse somatosensory Cortex. Glia. 2014;62:399–410.CrossRefPubMed
Metadata
Title
Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains
Authors
Nina Dupuis
Andrey Mazarati
Béatrice Desnous
Vibol Chhor
Bobbi Fleiss
Tifenn Le Charpentier
Sophie Lebon
Zsolt Csaba
Pierre Gressens
Pascal Dournaud
Stéphane Auvin
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0773-6

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