title: Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's Disease Models.
abstract: Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both β amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents.
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.|Institute of Natural Products and Green Chemistry, School of Light Industry and Chemical Engineering, Guangdong University of Technology , Guangzhou 510003, People's Republic of China.
authors: Wei
authors: W
authors: Zhou
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Guifa
authors: G
authors: Zhong
authors: Department of Pharmacy, South China Center of Innovative Pharmaceuticals , Guangzhou 510663, People's Republic of China.
authors: Sihai
authors: S
authors: Fu
authors: The First Affiliated Hospital of Guangzhou Medical University , Guangzhou 510120, People's Republic of China.
authors: Hui
authors: H
authors: Xie
authors: Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang 110016, People's Republic of China.
authors: Tianyan
authors: T
authors: Chi
authors: Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang 110016, People's Republic of China.
authors: Luyi
authors: L
authors: Li
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Xiurong
authors: X
authors: Rao
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Shaogao
authors: S
authors: Zeng
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Dengfeng
authors: D
authors: Xu
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Hao
authors: H
authors: Wang
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Guoqing
authors: G
authors: Sheng
authors: Department of Pharmacy, South China Center of Innovative Pharmaceuticals , Guangzhou 510663, People's Republic of China.
authors: Xing
authors: X
authors: Ji
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Xiaorong
authors: X
authors: Liu
authors: Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang 110016, People's Republic of China.
authors: Xuefei
authors: X
authors: Ji
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Donghai
authors: D
authors: Wu
authors: Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang 110016, People's Republic of China.
authors: Libo
authors: L
authors: Zou
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Micky
authors: M
authors: Tortorella
authors: Department of Pharmacy, South China Center of Innovative Pharmaceuticals , Guangzhou 510663, People's Republic of China.
authors: Kejian
authors: K
authors: Zhang
authors: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
authors: Wenhui
authors: W
authors: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005260:Female; D007189:Indans / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; C000620652:GIBH-130; D007189:Indans; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010879:Piperazines; D010880:Piperidines; D011724:Pyridazines; C074636:amyloid beta-protein (25-35); D000077265:Donepezil; D008559:Memantine
keywords: Alzheimer’s disease; animal models; inhibitor; neuroinflammation