Effect of metformin in hypothalamic astrocytes from an immunocompromised mice model

• Published in: Biochimie 2024-08, Vol.223, p.196-205
• Main Authors: Bobermin, Larissa Daniele, da Costa, Daniele Schauren, de Moraes, Aline Daniel Moreira, da Silva, Vanessa Fernanda, de Oliveira, Giancarlo Tomazzoni, Sesterheim, Patrícia, Tramontina, Ana Carolina, Basso, Luiz Augusto, Leipnitz, Guilhian, Quincozes-Santos, André, Gonçalves, Carlos-Alberto
• Format: Article
• Language: English
• Subjects: Astrocytes; Glioprotection; Hypothalamus; IFNα/βR signaling; Metformin; Neuroinflammation
• ISSN: 0300-9084; 1638-6183; 1638-6183
• DOI: 10.1016/j.biochi.2024.04.005

Astrocytes are glial cells that play key roles in neuroinflammation, which is a common feature in diabetic encephalopathy and aging process. Metformin is an antidiabetic compound that shows neuroprotective properties, including in inflammatory models, but astroglial signaling pathways involved are still poorly known. Interferons α/β are cytokines that participate in antiviral responses and the lack of their signaling increases susceptible to viral infections. Here, we investigated the effects of metformin on astrocytes from hypothalamus, a crucial brain region related to inflammatory processes. Astrocyte cultures were derived from interferon α/β receptor knockout (IFNα/βR−/−) and wild-type (WT) mice. Metformin did not change the expression of glial fibrillary acidic protein but caused an anti-inflammatory effect by decreasing pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), as well as increasing gene expression of anti-inflammatory proteins interleukin-10 and Nrf2 (nuclear factor erythroid derived 2 like 2). However, nuclear factor κB p65 and cyclooxygenase 2 were downregulated in WT astrocytes and upregulated in IFNα/βR−/− astrocytes. AMP-activated protein kinase (AMPK), a molecular target of metformin, was upregulated only in WT astrocytes, while sirtuin 1 increased in both mice models. The expression of inducible nitric oxide synthase was decreased in WT astrocytes and heme oxygenase 1 was increased in IFNα/βR−/− astrocytes. Although loss of IFNα/βR-mediated signaling affects some effects of metformin, our results support beneficial roles of this drug in hypothalamic astrocytes. Moreover, paradoxical response of metformin may involve AMPK. Thus, metformin can mediate glioprotection due its effects on age-related disorders in non-diabetic and diabetic encephalopathy individuals. •Lack of IFNα/βR changes inflammatory response in cultured hypothalamic astrocytes.•Metformin has anti-inflammatory effects in hypothalamic astrocytes.•Metformin caused paradoxical response in IFNα/βR−/− astrocytes.•AMPK expression was increased by metformin only in astrocytes from wild type mice.•SIRT1 expression was upregulated in both wild type and IFNα/βR−/− astrocytes.