title: Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Dupuis
authors.affiliation: Department of Pediatrics, Neurology division and Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Mazarati
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.|AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desnous
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Vibol
authors.initials: V
authors.lastname: Chhor
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Tifenn
authors.initials: T
authors.lastname: Le Charpentier
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Csaba
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.|AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: INSERM, U1141, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dournaud
authors.affiliation: INSERM, U1141, 75019, Paris, France. stephane.auvin@inserm.fr.|Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019, Paris, France. stephane.auvin@inserm.fr.|AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019, Paris, France. stephane.auvin@inserm.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Auvin
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000209:etiology* / Q000821:virology; D018792:Encephalitis, Viral / Q000150:complications*; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects; D008911:Minocycline / Q000627:therapeutic use; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
chemical_list: D000927:Anticonvulsants; D000998:Antiviral Agents; D016207:Cytokines; D012333:RNA, Messenger; D008911:Minocycline; D011070:Poly I-C
keywords: Encephalitis; Epileptogenesis; Kindling; Microglia; Minocycline; Toll-like receptor; Virus