Broussochalcone A Alleviates Cognitive Impairment in Scopolamine-Induced Mice As a Potent Β-Amyloid Aggregation Inhibitor and Changes Blood and Brain Metabolite Profiles.

ETHNOPHARMACOLOGICAL RELEVANCE:Broussonetia papyrifera (BP) has been used for traditional medicine in amelioration of cognitive decline. Accumulation of β-amyloid (Aβ) plaques majorly contributed to the pathogenesis of Alzheimer's disease (AD). AIM OF THE STUDY:This study aimed to investigate the role of broussochalcone A (BCA), a bioactive constituent of BP, in alleviation of cognitive impairment via Aβ aggregation inhibition in model mice. METHODS:We screened a potent Aβ aggregation inhibitor from a herbal library and analyzed its effect on improving cognitive functions in model mice and principal protein expression. In addition, we compared the metabolite profiling of blood and tissues. We used the aggregation inhibition assay to screen 960 herbal compounds using Aβ42-, and a leading compound was selected based on drug-like properties. Animal behavioral tests including the Morris water maze were performed using scopolamine (SCO)-treated mice. Western blotting and histopathological analysis were performed. Key compounds in the blood, hippocampus, and cortex were analyzed to compare the metabolic profiles. RESULTS:BCA was a potent Aβ aggregation inhibitor (IC50 = 1.75 ± 0.021 μM) with a predicted binding energy of -6.405 kcal/mol, and nontoxic to MDCK and SH-SY5Y cells. Molecular dynamics simulation revealed that the atomic contact numbers of BCA with Aβ were highly fluctuated during 100 ns; however, the transient contacts might prevent the aggregation. Cognitive function was significantly improved in BCA-treated mice in behavioral tests. Western blotting and histopathological analysis demonstrated that BCA treatment attenuated apoptosis, preserved hippocampal pyramidal neuron integrity, and alleviated SCO-induced spatial memory impairment. Metabolite profiling demonstrated that BCA modulated the metabolic pathways related to energy metabolism, redox homeostasis, amino acid turnover, and lipid metabolism in the serum and brain tissues, partially attenuating SCO-associated metabolic alterations. CONCLUSIONS:BCA is a potent Aβ aggregation inhibitor and exhibits significant cognitive improvement, as well as neuroprotective effects, decreasing inflammation, and retaining neuron structures. In addition, BCA induced distinct metabolic alterations in the serum and brain tissues compared to SCO. These results strongly support the use of BCA as a promising candidate for the amelioration of cognitive impairment and application to AD therapeutics.