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

• Published in: Neurochemical research 2022-03, Vol.47 (3), p.768-780
• Main Authors: Silwal, Ashok, House, Austin, Sandoval, Karin, Vijeth, Shaluah, Umbaugh, David, Crider, Albert, Mobayen, Shirin, Neumann, William, Witt, Ken A.
• Format: Article
• Language: English
• Subjects: Agonists; Antioxidants; Biochemistry; Biomedical and Life Sciences; Biomedicine; Catalase; Cell Biology; Cell viability; Cytokines; Cytokines - metabolism; Gene Expression; Genes; Humans; IL-1β; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Interleukin 10; Interleukin 6; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Microglia; Microglia - metabolism; Neurochemistry; Neurology; Neurosciences; Original Paper; Oxidants; Oxidizing agents; Phagocytosis; Receptors; Receptors, Somatostatin - genetics; Receptors, Somatostatin - metabolism; Somatostatin; Somatostatin receptors; Tumor necrosis factor-α
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-021-03482-z

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) (0 nM, 10 nM, 1000 nM) against lipopolysaccharide (LPS)-induced inflammation (0, 10 or 100 ng/ml) over 6 or 24 h 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 6 h SMI showed no effect across all conditions. At 24 h SMI (10 and 1000 nM) upregulated Sstr4 expression under inflammatory and non-inflammatory conditions. At 24 h SMI downregulated expression of the inflammatory cytokines Tnf-α (1000 nM within all LPS concentrations) and Il-6 (10 nM within 0 and 10 ng/ml LPS). At 24 h 10 nM SMI upregulated Il-10 , while 1000 nM upregulated Catalase under inflammatory and non-inflammatory conditions. At 24 h Msr1 and Cd33 were upregulated by 1000 nM SMI under non-inflammatory conditions, while Trem1 was downregulated by 10 and 1000 nM 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.