Abstract
BackgroundInfectious 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.MethodsTo 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.ResultsPIC 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.ConclusionsHippocampal 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0773-6) contains supplementary material, which is available to authorized users.
Highlights
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
Minocycline, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal interleukin 1β (IL-1β) levels at both ages
The levels of proinflammatory cytokines were consistent with the reverse transcriptase-PCR findings and indicated increases in the levels of IL-1β, interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) after polycytidylic acid (PIC) exposure (Fig. 1c)
Summary
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. Infectious encephalitides are most often associated with seizures during the infection period [1, 2] and are established risk factors for the development of epilepsy at later times [1, 3, 4]. A significant proportion (65%) of the animals with acute symptomatic seizures develops spontaneous recurrent seizures later in life [10] In this model, macrophages have been shown to be associated with seizures during the acute phase of encephalitis, while neuronal loss and inflammation contribute to epileptogenesis [8, 12]
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