Gastrodin programs an Arg-1+ microglial phenotype in hippocampus to ameliorate depression- and anxiety-like behaviors via the Nrf2 pathway in mice

Abstract

Background: Regulating the microglial phenotype is an attractive strategy for treating diseases of the central nervous system such as depression and anxiety. Gastrodin can quickly cross the blood-brain barrier and mitigate microglia-mediated inflammation, which widely used to treat a variety of central nervous system diseases associated with microglial dysfunction. However, the molecular mechanism by which gastrodin regulates the functional phenotype of microglia remains unclear.

Purpose: Since the transcription factor "nuclear factor erythroid 2-related factor 2″ (Nrf2) is associated with the anti-inflammatory effects of gastrodin, we hypothesized that gastrodin induces Nrf2 expression in microglia and thereby programs an anti-inflammatory phenotype.

Study design: Male C57BL/6 mice, treated or not with gastrodin, were given lipopolysaccharide (LPS) at 0.25 mg/kg/d for 10 days to induce chronic neuroinflammation. The effects of gastrodin on microglial phenotypes, neuroinflammation and depression- and anxiety-like behaviors were evaluated. In another experiment, animals were treated with Nrf2 inhibitor ML385 throughout the 13-day gastrodin intervention period.

Methods: The effects of gastrodin on depression- and anxiety-like behaviors were evaluated through the sucrose preference test, forced swimming test, open field test and elevated plus-maze test; as well as its effects on morphology and molecular and functional phenotypes of hippocampal microglia through immunohistochemistry, real-time PCR and enzyme-linked immunosorbent assays.

Results: Chronic exposure to LPS caused hippocampal microglia to secrete inflammatory cytokines, their somata to enlarge, and their dendrites to lose branches. These changes were associated with depression- and anxiety-like behaviors. Gastrodin blocked these LPS-induced alterations and promoted an Arg-1⁺ microglial phenotype that protected neurons from injury. The effects of gastrodin were associated with Nrf2 activation, whereas blockade of Nrf2 antagonized gastrodin.

Conclusion: These results suggest that gastrodin acts via Nrf2 to promote an Arg-1⁺ microglial phenotype, which buffers the harmful effects of LPS-induced neuroinflammation. Gastrodin may be a promising drug against central nervous system diseases that involve microglial dysfunction.

Keywords: Arginase 1; Depression; Gastrodin; Lipopolysaccharide; Microglia; Nuclear factor erythroid 2-related factor 2.