Treatment with dexamethasone and vitamin D₃ attenuates neuroinflammatory age-related changes in rat hippocampus

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1β (IL-1β) and an increase in IL-1β-induced signaling. Here we demonstrate that the increase in IL-1β concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D ₃. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D₃. The data indicate that dexamethasone and vitamin D₃ ameliorated the age-related increase in IFNγ and suggest that IFNγ may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1β release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D ₃ blocked the lipopolysaccharide increased MHCII mRNA and IL-1β concentration, while the IL-1β-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D₃. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D₃ derives from their ability to downreguate microglial activation.