Atomoxetine suppresses nitric oxide synthesis induced by lipopolysaccharide in BV-2 microglia cells through the modulation of STAT1 and STAT3.

Atomoxetine (ATX), a selective noradrenaline reuptake inhibitor that is widely used to treat attention-deficit hyperactivity disorder, has recently been suggested to exert neuroprotective effects by modulating inflammatory responses in the central nervous system, particularly in microglial cells. In this study, we investigated the effect of ATX on BV-2 microglial cells. Upon administration of 50  µM ATX, a significant suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) production was observed. This suppression was associated with a decrease in the expression of inducible nitric oxide synthase (iNOS). To elucidate the upstream regulatory mechanisms, we examined components of the nuclear factor-kappa B (NFκB) signaling cascade. ATX slightly increased the phosphorylation ratio of NFκB, suggesting that NFκB signaling is not involved in the modulation of iNOS expression by ATX. ATX also did not change the phosphorylation ratio of nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor alpha (IκBα). In contrast, both total Akt and phosphorylated Akt levels were decreased by ATX treatment. We further explored the effect of ATX on the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, which is known to regulate iNOS expression. Administration of ATX reduced the expression and phosphorylation of STAT1, resulting in a decreased STAT1 phosphorylation ratio. Conversely, while total STAT3 expression was reduced, its phosphorylation ratio increased, reflecting a more complex regulatory interaction. Collectively, these findings suggested that ATX exerts multifaceted effects on key inflammatory signaling pathways, notably modulating iNOS expression through simultaneous regulation of the STAT1 and STAT3.