Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis

•GRb1 activated mitophagy to reduce ROS and decrease astrocytic pyroptosis.•GRb1 enhanced synaptic plasticity by inhibiting astrocytic pyroptosis.•An increase in synaptic plasticity improved depression-like behavior. Astrocytes play a vital role in offering functional support for neurons, which are related to the pathogenic mechanism of depression. Ginsenoside Rb1 (GRb1) is demonstrated with antidepressant-like activities. We aimed to investigate whether GRb1 can inhibit mitophagy-mediated astrocytic pyroptosis to protect neurons in depression. Model rats were subjected to chronic unpredictable mild stress (CUMS) for determining the in vivo antidepressant activity of GRb1. The mitophagy-mediated antipyroptosis role of GRb1 was assessed in lipopolysaccharide (LPS) + ATP-stimulated astrocytes. The mechanism by which GRb1 protects synaptic plasticity was investigated using hippocampal neurons incubated in an astrocyte medium. The rat depressive-like behaviors were determined through sucrose preference, forced swimming, and the open-field tests. Escitalopram was used in the anti-depression control of GRb1. Cyclosporin A (CsA), a mitophagy inhibitor, and interleukin (IL)-1β were used to reverse the role of GRb1 in mitophagy and pyroptosis, respectively. GRb1 inhibited LPS-induced inflammation and activation in the astrocytes and repressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Also, GRb1 repressed LPS + ATP-promoted astrocytic pyroptosis. During GRb1 treatment, the activation of mitophagy with a decrease in ROS was observed in LPS + ATPs-stimulated astrocytes. CsA enhanced GRb1-decreased ROS and promoted astrocytic pyroptosis. The GRb1-treated astrocyte medium suppressed neuron death and increased neuron viability and synaptic density. Escitalopram and GRb1 improved the depressive-like behaviors of the rats. GRb1 activated mitophagy and inhibited astrocytic activation and pyroptosis in rats with depression. It also reduced impairments in synaptic structures and increased synaptic density in depressive-like rats. IL-1β increased astrocytic pyroptosis and reversed GRb1-enhanced synaptic plasticity in the rats exposed to CUMS. There were no statistical changes in depressive-like behaviors between GRb1 and Escitalopram groups. GRb1 modulates mitophagy and the NF-κB pathway to inhibit astrocytic pyroptosis, thereby maintaining neurological homeostasis by repressing inflammation and enhancing synaptic plasticity. [Display omit