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

Abstract

Background 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.

Microglia Involves in the Immune Inflammatory Response of Poststroke Depression: A Review of Evidence

“…Moreover, inflammation is also involved in PSD development [ 68 , 69 ]. Considerable evidence indicates that inflammation is involved in the occurrence and development of PSD through related inflammatory pathways by producing inflammatory mediators [ 70 , 71 ].…”

Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression

“…Moreover, emerging data have shown that plant-derived compounds can exert neuroprotective effects that prevent neurological disorders in depression. For instance, ganoderic acid A [ 227 ], asperosaponin VI [ 228 ], 20( S )-protopanaxadiol [ 229 ], scutellarin [ 230 ], astragalin [ 231 ], hesperidin [ 232 ], 5- O -methylvisammioside [ 233 ], ginkgolide B [ 234 ], leonurine [ 235 ], ferulic acid [ 236 ], and (+)-sesamin [ 69 ] were found to inactivate microglia in stress-induced depression models. Recent information concerning the antidepressant activity of phytochemicals through regulation of microglial polarization is illustrated in Table 2 .…”

Inflammatory pathophysiological mechanisms implicated in postpartum depression

“…On the other hand, microglial M1/M2 polarization plays important roles in mediating the balance between activation and suppression in inflammation ( Nakagawa and Chiba, 2014 ). Many studies have demonstrated that M1 (pro-inflammatory) polarization was related to depression ( Kalkman and Feuerbach, 2016 ; Zhang, L. et al, 2021 ). It needs more researches to explore whether these pathomechanisms are also relevant to PPD.…”