Luteolin alleviates cognitive impairment in Alzheimer’s disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation

• Published in: Acta pharmacologica Sinica Vol. 43; no. 4; pp. 840 - 849
• Main Authors: Kou, Jie-jian, Shi, Jun-zhuo, He, Yang-yang, Hao, Jiao-jiao, Zhang, Hai-yu, Luo, Dong-mei, Song, Jun-ke, Yan, Yi, Xie, Xin-mei, Du, Guan-hua, Pang, Xiao-bin
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01-04-2022; Nature Publishing Group
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Animals; Antioxidants; Astrocytes; Biomedical and Life Sciences; Biomedicine; Cell proliferation; Cognitive ability; Cognitive Dysfunction - drug therapy; Cyclooxygenase-2; Disease Models, Animal; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoribonucleases - pharmacology; Endoribonucleases - therapeutic use; Flavonoids; Glial fibrillary acidic protein; Glioma cells; IL-1β; Immunology; Inflammation; Interleukin 6; Internal Medicine; Lipopolysaccharides; Luteolin - pharmacology; Luteolin - therapeutic use; Medical Microbiology; Memory; Mice; Mice, Transgenic; Neurodegenerative diseases; Neuroinflammatory Diseases; Neuroprotection; Nitric-oxide synthase; Pharmacology/Toxicology; Protein Serine-Threonine Kinases; Rats; Spatial discrimination learning; Spatial memory; Transgenic mice; Tumor necrosis factor-α; Vaccine; luteolin; 3 × Tg-AD mice; Alzheimer’s disease; neuroinflammation; C6 cells; astrocyte; endoplasmic reticulum stress
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00702-8

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer’s disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg
−1
 · d
−1
, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1β, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.