Systemic administration of lipopolysaccharide induces molecular and morphological alterations in the hippocampus

A systemic inflammatory reaction may have detrimental effects on the organism, including the central nervous system. Previous studies have indicated that lipopolysaccharide (LPS)-evoked systemic inflammation induces pathological alterations in the mouse midbrain, especially in the substantia nigra. The aim of the present study was to investigate whether the hippocampus is also affected after an intraperitoneal (i.p.) injection of LPS. We focussed on the dynamics of proinflammatory gene expression and the processes leading to neuronal cell death. A systemic inflammatory response in C57BL/6 mice was induced by an i.p. injection of LPS (1 mg/kg b.w.). The genetic, biochemical and morphological alterations were analysed up to 96 h after LPS administration using quantitative PCR, immunochemical, immunocytochemical and electron microscopic methods. Real-time PCR analysis indicated an altered expression of several genes, mainly responsible for arachidonic acid release and metabolism, in the hippocampus 96 h after the systemic administration of LPS. Three hours after LPS treatment, the level of mRNA for iNOS, COX-2 and TNF alpha was increased; then, after 6-24 h, it rose for TLR4 and cPLA2. The expression of 5-LOX and 12-LOX was increased at 12-24 and 24-48 h after LPS injection, respectively. Our data demonstrate for the first time the sequential activation of the expression of several pro-inflammatory genes responsible for the maintenance of the inflammatory response. Moreover, the electron microscopy studies presented the stimulation of apoptosis-inducing factor (AlF)-mediated death signalling and cathepsin B-related autophagy or necrosis. These biochemical and morphological alterations in the hippocampus, which were induced by systemic inflammation, may be responsible for the impairment of cognition function observed previously. (C) 2010 Elsevier B.V. All rights reserved.