Morinda officinalis oligosaccharides alleviate depressive‐like behaviors in post‐stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation

• Published in: CNS neuroscience & therapeutics 2021-12, Vol.27 (12), p.1570-1586
• Main Authors: Li, Zhifang, Xu, Hexiang, Xu, Yi, Lu, Guanfeng, Peng, Qiwei, Chen, Jiefang, Bi, Rentang, Li, Jianzhuang, Chen, Shengcai, Li, Hongkai, Jin, Huijuan, Hu, Bo
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Apoptosis; ATP; Behavior; Behavior, Animal - drug effects; Clinical trials; Datasets; Depression - drug therapy; Depression - etiology; Disease Models, Animal; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - pharmacology; FDA approval; Gene expression; Hippocampus; Hippocampus - drug effects; Immunofluorescence; Inflammasomes; Inflammasomes - drug effects; Inflammation; Ischemia; Lipopolysaccharides; Male; Medical research; Mental depression; Microglia; Morinda; Morinda officinalis oligosaccharides; Neuroinflammatory Diseases - drug therapy; NLR Family, Pyrin Domain-Containing 3 Protein - drug effects; NLRP3 inflammasome; Oligosaccharides; Original; Polymerase chain reaction; post‐stroke depression; Pyrin protein; Rats; Rats, Sprague-Dawley; Reverse transcription; Rodents; Signal transduction; Software; Stroke; Stroke - complications; Sucrose; Therapeutic targets; Traditional Chinese medicine
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13732

Aims Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive‐like behaviors in post‐stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation. Methods Behavioral tests were performed to evaluate the effect of MOOs on depressive‐like behaviors in PSD rats. The effects of MOOs on the expression of IL‐18, IL‐1β, and nucleotide‐binding domain leucine‐rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT‐PCR), immunofluorescence and Western blot analysis. Adeno‐associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence. Results MOOs can alleviate depressive‐like behaviors in PSD rats. PSD rats showed increased expression of IL‐18, IL‐1β, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive‐like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive‐like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL‐18, IL‐1β, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF‐κB p65 signaling pathway. Conclusion Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD. MOOs can ameliorate depressive‐like behaviors and hippocampal inflammation in PSD rat models via suppressing microglial NLRP3 inflammasome activation and IκB/NF‐κB p65 pathway.