Dexmedetomidine attenuates neuroinflammation-mediated hippocampal neurogenesis impairment in sepsis-associated encephalopathy mice through central α2A-adrenoceptor

Abstract

Abstract Sepsis-associated encephalopathy (SAE), one of the common complications of sepsis, is associated with higher ICU mortality, prolonged hospitalization and long-term cognitive decline. Sepsis can induce neuroinflammation, which negatively affects hippocampal neurogenesis. Dexmedetomidine has been shown to protect against SAE. However, the potential mechanism remains unclear. In this study, we added lipopolysaccharide (LPS)-stimulated astrocytes-conditioned media (LPS-CM) to neural stem cells (NSCs) culture, which were pretreated with dexmedetomidine in the presence or absence of the α2-adrenoceptor antagonist yohimbine or the α2A-adrenoceptor antagonist BRL-44408. LPS-CM impaired the neurogenesis of NSCs, characterized by decreased proliferation, enhanced gliogenesis and declined viability. Dexmedetomidine alleviated LPS-CM-induced impairments of neurogenesis in a dose-dependent manner. Yohimbine, as well as BRL-44408, reversed the effects of dexmedetomidine. We established a mouse model of SAE by cecal ligation and perforation (CLP). CLP induced astrocyte-related neuroinflammation and hippocampal neurogenesis deficits, companied with learning and memory decline, which was reversed by dexmedetomidine. The effect of dexmedetomidine was blocked by BRL-44408. Collectively, our findings support the conclusion that dexmedetomidine can protect against SAE, likely mediated by the combination of inhibiting neuroinflammation via astrocytic α2A-adrenoceptor with attenuating neuroinflammation-induced hippocampal neurogenesis deficits via NSCs α2A-adrenoceptor.