Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline. Animal models of AD deposit senile plaques and exhibit structural and functional deficits in neurons and neural networks. An effective treatment would prevent or restore these deficits, including calcium dyshomeostasis observed with in-vivo imaging. Methods: We examined the effects of DA-9803, a multimodal botanical drug, in 5XFAD and APP/PS1 transgenic mice which underwent daily oral treatment with 30 or 100 mg/kg DA-9803 or vehicle alone. Behavioral testing and longitudinal imaging of amyloid deposits and intracellular calcium in neurons with multiphoton microscopy was performed. Results: Chronic administration of DA-9803 restored behavioral deficits in 5XFAD mice and reduced amyloid-β levels. DA-9803 also prevented progressive amyloid plaque deposition in APP/PS1 mice. Elevated calcium, detected in a subset of neurons before the treatment, was restored and served as a functional indicator of treatment efficacy in addition to the behavioral readout. In contrast, mice treated with vehicle alone continued to progressively accumulate amyloid plaques and calcium overload. Conclusions: In summary, treatment with DA-9803 prevented structural and functional outcome measures in mouse models of AD. Thus, DA-9803 shows promise as a novel therapeutic approach for Alzheimer’s disease. Electronic supplementary material The online version of this article (10.1186/s13195-018-0338-2) contains supplementary material, which is available to authorized users

Anti-Inflammatory Activity of Glabralactone, a Coumarin Compound from Angelica sinensis, via Suppression of TRIF-Dependent IRF-3 Signaling and NF-kappa B Pathways

The dried root of Angelica sinensis (A. sinensis) has been widely used in Chinese traditional medicine for various diseases such as inflammation, osteoarthritis, infections, mild anemia, fatigue, and high blood pressure. Searching for the secondary metabolites of A. sinensis has been mainly conducted. However, the bioactivity of coumarins in the plant remains unexplored. Therefore, this study was designed to evaluate the anti-inflammatory activity of glabralactone, a coumarin compound from A. sinensis, using in vitro and in vivo models, and to elucidate the underlying molecular mechanisms of action. Glabralactone effectively inhibited nitric oxide production in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells. The downregulation of LPS-induced mRNA and protein expression of iNOS, TNF-alpha, IL-1 beta, and miR-155 was found by glabralactone. The activation of NF-kappa B and TRIF-dependent IRF-3 pathway was also effectively suppressed by glabralactone in LPS-stimulated macrophages. Glabralactone (5 and 10 mg/kg) exhibited an in vivo anti-inflammatory activity with the reduction of paw edema volume in carrageenan-induced rat model, and the expressions of iNOS and IL-1 beta proteins were suppressed by glabralactone in the paw soft tissues of the animal model. Taken together, glabralactone exhibited an anti-inflammatory activity in in vitro and in vivo models. These findings reveal that glabralactone might be one of the potential components for the anti-inflammatory activity of A. sinensis and may be prioritized in the development of a chemotherapeutic agent for the treatment of inflammatory diseases.N

Additional file 1: Figure S1. of Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

Showing DA-9803 does not chemically interfere with the binding of methoxy-XO4 to amyloid plaques. A–C Fluorescent images of methoxy-XO4 amyloid plaques after preincubation with (A) DA-9803 (27 sections from one APP/PS1 mouse), (B) PBS (30 sections from one mouse), and (C) vehicle compound (29 sections from one mouse). D Fluorescence intensity of individual amyloid plaques across conditions. Scale bar, 100 μm. Mean ± SEM. (PDF 748 kb

Additional file 2: Figure S2. of Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

Showing methoxy-XO4 stained amyloid plaque burden and MAP2 immunoreactivity in postmortem hippocampus after treatment with vehicle or DA-9803. A–C Fluorescent images of MAP2-positive neurons (A), methoxy-XO4-labeled plaques (B), and colocalization of MAP2 and methoxy-XO4 (C) in APP/PS1 mice treated daily with the vehicle compound (n = 14 sections from seven mice). D–F Fluorescent images of MAP2-positive neurons (D), methoxy-XO4-labeled plaques (E), and colocalization of MAP2 and methoxy-XO4 (F) in APP/PS1 mice treated daily with 100 mg/kg DA-9803 (n = 17 sections from five mice). Scale bar, 100 μm. G Percentage of cortex occupied by methoxy-XO4-positive plaques across conditions. Mean ± SEM. *p < 0.05. (PDF 2111 kb