Novel Somatostatin Receptor-4 Agonist SM-I-26 Mitigates Lipopolysaccharide-Induced Inflammatory Gene Expression in Microglia.

Abstract

Somatostatin receptor subtype 4 (SSTR4) is expressed in BV2 microglia, suggesting that SSTR4 agonists may impact microglia function. This study assessed the high-affinity SSTR4 agonist SM-I-26 (SMI) (0nM, 10nM, 1000nM) against lipopolysaccharide (LPS)-induced inflammation (0, 10 or 100ng/ml) over 6 or 24h in BV2 microglia. Cell viability, nitrite output and mRNA expression changes of genes associated with our target (Sstr4), inflammation (Tnf-α, Il-6, Il-1β, inos), anti-inflammatory and anti-oxidant actions (Il-10, Catalase), and mediators of Aβ binding/phagocytosis (Msr1, Cd33, Trem1, Trem2) were measured. At 6h SMI showed no effect across all conditions. At 24h SMI (10 and 1000nM) upregulated Sstr4 expression under inflammatory and non-inflammatory conditions. At 24h SMI downregulated expression of the inflammatory cytokines Tnf-α (1000nM within all LPS concentrations) and Il-6 (10nM within 0 and 10ng/ml LPS). At 24h 10nM SMI upregulated Il-10, while 1000nM upregulated Catalase under inflammatory and non-inflammatory conditions. At 24h Msr1 and Cd33 were upregulated by 1000nM SMI under non-inflammatory conditions, while Trem1 was downregulated by 10 and 1000nM SMI under mildly inflammatory and non-inflammatory conditions. These results show that SMI had concentration and time-dependent effects on mRNA expression of genes associated with different states of microglial activation. The SMI reduced Tnf-α and Il-6 inflammatory gene expression, and increased Il-10 anti-inflammatory gene expression, identifies anti-inflammatory actions of SSTR4 agonists extend to microglia.