{Reference Type}: Journal Article
{Title}: Panobinostat, a Histone Deacetylase Inhibitor, Reduces LPS-Induced Expression of Inducible Nitric Oxide Synthase in Rat Immortalized Microglia HAPI Cells.
{Author}: Hara H;Manome A;Kamiya T;
{Journal}: Biol Pharm Bull
{Volume}: 47
{Issue}: 6
{Year}: 2024
{Factor}: 2.264
{DOI}: 10.1248/bpb.b24-00111
{Abstract}: Microglia, resident immune cells in the central nervous system (CNS), play a critical role in maintaining CNS homeostasis. However, microglia activated in response to brain injury produce various inflammatory mediators, including nitric oxide (NO) and proinflammatory cytokines, leading to considerable neuronal damage. NO generated by inducible NO synthase (iNOS) rapidly reacts with superoxide to form a highly toxic product, peroxynitrite. Therefore, iNOS is considered to be a putative therapeutic target for cerebral ischemia. Here, we examined the effects of panobinostat (Pano), a histone deacetylase inhibitor, on lipopolysaccharide (LPS)-induced iNOS expression using rat immortalized microglia HAPI cells. Pano inhibited LPS-induced expression of iNOS mRNA and NO production in a dose-dependent manner; however, it had little effect on the LPS-induced activation of c-Jun N-terminal kinase (JNK) and p38 or nuclear translocation of nuclear factor-κB (NF-κB). The interferon-β (IFN-β)/signal transducer and activator of transcription (STAT) pathway is essential for LPS-induced iNOS expression in macrophages/microglia. We also examined the effects of Pano on LPS-induced IFN-β signaling. Pano markedly inhibited LPS-induced IFN-β expression and subsequent tyrosine phosphorylation of STAT1. However, the addition of IFN-β restored the decreased STAT1 phosphorylation but not the decreased iNOS expression. In addition, Pano inhibited the LPS-increased expression of octamer binding protein-2 and interferon regulatory factor 9 responsible for iNOS expression, but IFN-β addition also failed to restore the decreased expression of these factors. Thus, we conclude that the inhibitory effects of Pano are due not only to the inhibition of the IFN-β/STAT axis but also to the downregulation of other factors not involved in this axis.