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.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Zhou W,Zhong G,Fu S,Xie H,Chi T,Li L,Rao X,Zeng S,Xu D,Wang H,Sheng G,Ji X,Liu X,Ji X,Wu D,Zou L,Tortorella M,Zhang K,Hu Wdoi
10.1021/acschemneuro.6b00125subject
Has Abstractpub_date
2016-11-16 00:00:00pages
1499-1507issue
11issn
1948-7193journal_volume
7pub_type
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