Abstract
BackgroundStatus epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. The extent and temporal profiles of activation of these processes are well known in the adult brain, but less so in the developing brain. We have now further elucidated to what extent inflammation is activated by SE by investigating the acute expression of several cytokines and subacute glial reactivity in the postnatal rat hippocampus.MethodsSE was induced by an intraperitoneal (i.p.) injection of kainic acid (KA) in 9- and 21-day-old (P9 and P21) rats. The mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), glial-derived neurotrophic factor (GDNF), interferon gamma (IFN-γ), and transforming growth factor-beta 1 (TGF-β1) were measured from 4 h up to 3 days after KA injection with real-time quantitative PCR (qPCR). IL-1β protein expression was studied with ELISA, GFAP expression with western blotting, and microglial and astrocyte morphology with immunohistochemistry 3 days after SE.ResultsSE increased mRNA expression of IL-1β, TNF-α and IL-10 mRNA in hippocampus of both P9 and P21 rats, their induction being more rapid and pronounced in P21 than in P9 rats. MMP-9 expression was augmented similarly in both age groups and GDNF expression augmented only in P21 rats, whereas neither IFN-γ nor TGF-β1 expression was induced in either age group. Microglia and astrocytes exhibited activated morphology in the hippocampus of P21 rats, but not in P9 rats 3 d after SE. Microglial activation was most pronounced in the CA1 region and also detected in the basomedial amygdala.ConclusionOur results suggest that SE provokes an age-specific cytokine expression in the acute phase, and age-specific glial cell activation in the subacute phase as verified now in the postnatal rat hippocampus. In the juvenile hippocampus, transient increases in cytokine mRNA expression after SE, in contrast to prolonged glial reactivity and region-specific microglial activity after SE, suggest that the inflammatory response is changed from a fulminant and general initial phase to a more moderate and specific subacute response.
Highlights
Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus
In contrast to adult brain, SE-induced acute activation of inflammatory processes seems to be age- regulated in the developing postnatal rat brain, e.g. postnatal-day 21 (P21) rats exhibit pronounced inflammatory responses within 24 h after SE in hippocampus whereas this is not seen in P9 rats [6,8]
The temporal behaviour of glial cells after SE is incompletely known in P9 and P21 rat hippocampus, since there are no in vivo studies at these ages in which the reactivity of glial cells has been investigated beyond 24 h after KAinduced SE
Summary
Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. In contrast to adult brain, SE-induced acute activation of inflammatory processes seems to be age- regulated in the developing postnatal rat brain, e.g. postnatal-day 21 (P21) rats exhibit pronounced inflammatory responses (increases in COX-2 and proinflammatory cytokine expression, and glial cell reactivity) within 24 h after SE in hippocampus whereas this is not seen in P9 rats [6,8]. Whether SE leads to augmented expression of other cytokines involved in inflammation has remained unaddressed in the developing hippocampus Such factors include anti-inflammatory cytokines, matrix metalloproteinases, growth factors and interferons. The temporal behaviour of glial cells after SE is incompletely known in P9 and P21 rat hippocampus, since there are no in vivo studies at these ages in which the reactivity of glial cells has been investigated beyond 24 h after KAinduced SE
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