Involvement of cyclooxygenase-2 in lipopolysaccharide-induced impairment of the newborn cell survival in the adult mouse dentate gyrus

There is growing evidence indicating that neurogenesis in adulthood is influenced by certain types of the central diseases such as neuroinflammation, however, its mechanism is not fully understood. This study was, therefore, designed to examine the effects of lipopolysaccharide (LPS), a bacterial endotoxin known to cause the neuroinflammation, on the neurogenesis in the dentate gyrus of adult mice using the bromodeoxyuridine (BrdU)-pulse chase method. LPS failed to affect the number of BrdU-labeled cells in the dentate gyrus 2 h after BrdU injection, indicating no effects of LIPS on the proliferation of the neural stem cells (NSCs). On the other hand, we found that LPS dose-dependently (0.1, 0.5, 1 mg/kg) decreased the number of BrdU-labeled cells 7 and 21 days after BrdU injection. We also observed that LPS increased cell death in the dentate gyrus using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, suggesting that LPS impaired the survival of newborn cells derived from the NSCs. The double-immunostaining for BrdU and specific cell type markers revealed that LPS did not alter the commitment of the NSCs to the neurons and astrocytes. The systemic injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and NS398, a selective COX-2 inhibitor, but not SC560, a selective COX-1 inhibitor, did not only ameliorate LPS-induced suppression of the newborn cell survival, they fully protected against the LPS effect. Furthermore, the central injection of NS398 also ameliorated LPS-induced suppression of the newborn cell survival in the dentate gyrus. The treatment with LPS increased the expression of COX-2 protein 7 h and 7 days after the injection in the dentate gyrus. These results suggest that LPS impairs the survival of newly generated cells derived from the NSCs in the dentate gyrus without affecting the differentiation fate, and these effects of LPS were mediated presumably by COX-2 expression in the dentate gyrus. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.