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Identification of aminopyridazine-derived antineuroinflammatory agents effective in an Alzheimer's mouse model.

ABSTRACT: Targeting neuroinflammation may be a new strategy to combat Alzheimer's disease. An aminopyridazine 1b previously reported as a novel antineuroinflammatory agent was considered to have a potential therapeutic effect for Alzheimer's disease. In this study, we further explored the chemical space to identify more potent antineuroinflammatory agents and validate their in vivo efficacy in an animal model. Compound 14 was finally identified as an effective agent with comparable in vivo efficacy to the marketed drug donepezil in counteracting spatial learning and working memory impairment in an A?-induced Alzheimer's mouse model.

SUBMITTER: Zhou W

PROVIDER: S-EPMC4025747 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Identification of aminopyridazine-derived antineuroinflammatory agents effective in an Alzheimer's mouse model.

Zhou Wei W Zhong Guifa G Rao Xiurong X Xie Hui H Zeng Shaogao S Chi Tianyan T Zou Libo L Wu Donghai D Hu Wenhui W

ACS medicinal chemistry letters 20120904 11

Targeting neuroinflammation may be a new strategy to combat Alzheimer's disease. An aminopyridazine 1b previously reported as a novel antineuroinflammatory agent was considered to have a potential therapeutic effect for Alzheimer's disease. In this study, we further explored the chemical space to identify more potent antineuroinflammatory agents and validate their in vivo efficacy in an animal model. Compound 14 was finally identified as an effective agent with comparable in vivo efficacy to the ...[more]

PMID: 24900405

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-β peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore, the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs), a class of small non-coding RNAs of 22-25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD). We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in the 3xTg-AD mice.

Dataset Information

Identification of aminopyridazine-derived antineuroinflammatory agents effective in an Alzheimer's mouse model.

Publications

Identification of aminopyridazine-derived antineuroinflammatory agents effective in an Alzheimer's mouse model.

Similar Datasets

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