Wogonin mitigates microglia-mediated synaptic over-pruning and cognitive impairment following epilepsy

• Published in: Phytomedicine (Stuttgart) 2024-12, Vol.135, p.156222, Article 156222
• Main Authors: Hu, Yang, Qi, Honggang, Yang, Jiurong, Wang, Feiyu, Peng, Xintao, Chen, Xiang, Zhu, Xinjian
• Format: Article
• Language: English
• Subjects: AKT; Animals; cognition; cognitive disorders; Cognitive dysfunction; Cognitive Dysfunction - drug therapy; cytokines; Disease Models, Animal; Epilepsy; Epilepsy - drug therapy; Flavanones - pharmacology; flavonoids; fluorescence; Forkhead Box Protein O1 - metabolism; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; homeostasis; intraperitoneal injection; Male; Maze Learning - drug effects; memory; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; microparticles; neuroglia; Neuronal Plasticity - drug effects; neurons; Neuroprotective Agents - pharmacology; phagocytosis; Phagocytosis - drug effects; Pilocarpine; Scutellaria baicalensis; Scutellaria baicalensis - chemistry; Status Epilepticus - chemically induced; Status Epilepticus - drug therapy; Synapses - drug effects; Synaptic pruning; Wogonin
• ISSN: 0944-7113; 1618-095X; 1618-095X
• DOI: 10.1016/j.phymed.2024.156222

•Excessive phagocytosis and synaptic pruning by microglia induce memory and cognitive impairments in mice post-epilepsy.•Wogonin alleviates microglial inflammation and excessive phagocytosis by activating the AKT/FoxO1 pathway. Epilepsy, a neurological disorder characterized by recurrent abnormal neuronal discharges, leading to brain dysfunction and imposing significant psychological and economic burdens on patients. Microglia, the resident immune cells within the central nervous system (CNS), play a crucial role in maintaining CNS homeostasis. However, activated microglia can excessively prune synapses, exacerbating neuronal damage and cognitive dysfunction following epilepsy. Wogonin, a flavonoid from Scutellaria Baicalensis, has known neuroprotective effects via anti-inflammatory and antioxidative mechanisms, but its impact on microglial activation and synaptic pruning in neurons post-epilepsy remains unclear. Synaptic density was assessed using presynaptic marker Synaptophysin and postsynaptic marker Psd-95, and microglial phagocytosis was evaluated with fluorescent microspheres. Pilocarpine-induced mouse model of status epilepticus was used to evaluate synaptic density changes of mouse hippocampus following an intraperitoneal injection of wogonin (50 and 100 mg/kg). Memory and cognitive function in mice were subsequently evaluated using the Y-maze, object recognition, and Morris water maze tests. Single-cell sequencing was employed to investigate the underlying causes of microglial state alterations, followed by experimental validation. Microglia were transitioned to an activated state post-epilepsy, exhibiting significantly enhanced phagocytic capacity. Correspondingly, levels of synaptophysin and Psd-95 were markedly reduced in neurons. Treatment with wogonin (100 mg/kg) significantly increased neuronal synaptic density and improved learning and memory deficits in epileptic mice. Further investigation revealed that wogonin inhibits the release of pro-inflammatory cytokines and synaptic phagocytosis of microglia by activating the AKT/FoxO1 pathway. Wogonin could alleviate excessive synaptic pruning of epileptic neurons by microglia and improve cognitive dysfunction of epileptic mice via the AKT/FoxO1 pathway. [Display omitted]