Ganoderic Acid A-Mediated Modulation of Microglial Polarization is Involved in Depressive-Like Behaviors and Neuroinflammation in a Rat Model of Post-Stroke Depression

Ling Zhang,1 Lei Zhang,2 Rubo Sui1 1Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China; 2College of Nursing, Jinzhou Medical University, Jinzhou, People’s Republic of ChinaCorrespondence: Lei ZhangCollege of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Guta District, Jinzhou, 121001, Liaoning Province, People’s Republic of ChinaEmail zhanglei7812713@163.comBackground: Post-stroke depression (PSD) is a common complication after stroke. Ganoderic acid A (GAA), one of the main bioactive Ganoderma triterpenoids, exerts preventive and therapeutic effects in many diseases. However, the function of GAA in PSD has not been well studied.Methods: PSD model was established via stimulating rats with chronic unpredictable mild stress stimulations (CUMS) after middle cerebral artery occlusion (MCAO). Rats were treated with GAA before CUMS. Depressive-like behaviors were investigated by body weight alteration, open field test (OFT), and sucrose preference test (SPT). Neuronal damage was evaluated by hematoxylin and eosin (HE) staining and Western blotting. Inflammation was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Microglial polarization was analyzed via qRT-PCR and Western blotting. The extracellular signal-regulated kinase (ERK)/cAMP-response element-binding protein (CREB) pathway was analyzed by Western blotting, and inactivated by the inhibitor PD98059 (PD).Results: GAA attenuated PSD-induced depressive-like behaviors in rats. GAA mitigated PSD-induced neuronal damage and reduced BDNF and NGF levels in the cerebral hippocampus. GAA weakened PSD-induced inflammatory response in the cerebral hippocampus. GAA prevented pro-inflammatory (M1) polarization and promoted anti-inflammatory (M2) polarization, as indicated by decreased iNOS and CD86 levels and increased Arg-1 and CD206 levels. GAA restored the PSD-induced inactivation of the ERK/CREB pathway. GAA regulated M1/M2 microglial polarization by activating the ERK/CREB pathway.Conclusion: GAA alleviated the depressive-like behaviors and brain inflammation in PSD rats, indicating its potential for PSD therapy.Keywords: ganoderic acid A, post-stroke depression, neuronal damage, inflammation, microglial polarization, extracellular signal-regulated kinase