Minocycline and antipsychotics inhibit inflammatory responses in BV-2 microglia activated by LPS via regulating the MAPKs/ JAK-STAT signaling pathway

Abstract

Abstract Background Abnormal activation of microglia is involved in the pathogenesis of schizophrenia. Minocycline and antipsychotics have been reported to be effective in inhibiting the activation of microglia and thus alleviating the negative symptoms of patients with schizophrenia. However, the specific molecular mechanism by which minocycline and antipsychotics inhibit microglial activation is not clear. In this study, we aimed to explore the molecular mechanism of treatment effect of minocycline and antipsychotics on schizophrenia. Methods Microglia cells were activated by lipopolysaccharide (LPS) and further treated with minocycline, haloperidol, and risperidone. Then cell morphology, specific marker, cytokines, and nitric oxide production process, and the proteins in related molecular signaling pathways in LPS-activated microglia were compared among groups. Results The study found that minocycline, risperidone, and haloperidol significantly inhibited morphological changes and reduced the expression of OX-42 protein induced by LPS. Minocycline significantly decreased the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β). Risperidone also showed significant decrease in the production of IL-6 and TNF-α, while haloperidol only showed significant decrease in the production of IL-6. Minocycline, risperidone, and haloperidol were found to significantly inhibit nitric oxide (NO) expression, but had no effect on inducible nitric oxide synthase (iNOS) expression. Both minocycline and risperidone were effective in decreasing the activity of c‑Jun N‑terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinases (MAPKs) signal pathway. Additionally, minocycline and risperidone were found to increase the activity of phosphorylated-p38. In contrast, haloperidol only suppressed the activity of ERK. Minocycline also suppressed the activation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), while risperidone and haloperidol only suppressed the activation of STAT3. Conclusions The results demonstrated that minocycline and risperidone exert stronger anti-inflammatory and neuroprotective effects stronger than haloperidol, through MAPKs and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in BV2 cells stimulated with LPS, revealing the underlying mechanisms of minocycline and atypical antipsychotics in the treatment of negative schizophrenia symptoms.

Keywords

• Antipsychotics
• LPS
• Minocycline
• Risperidone
• Haloperidol
• MAPKs