Futoquinol improves Aß25-35-induced memory impairment in mice by inhibiting the activation of p38MAPK through the glycolysis pathway and regulating the composition of the gut microbiota.

Futoquinol (Fut) is a compound extracted from Piper kadsura that has a nerve cell protection effect. However, it is unclear whether Fut has protective effects in Alzheimer's disease (AD). In this study, we aimed to explore the therapeutic effect of Fut in AD and its underlying mechanism. UPLC-MS/MS method was performed to quantify Fut in the hippocampus of mice brain. The cognition ability, neuronal and mitochondria damage, and levels of Aß1-42, Aß1-40, p-Tau, oxidative stress, apoptosis, immune cells, and inflammatory factors were measured in Aß25-35-induced mice. The content of bacterial meta-geometry was predicted in the microbial composition based on 16S rDNA. The protein levels of HK II, p-p38MAPK, and p38MAPK were detected. PC-12 cells were cultured in vitro, and glucose was added to activate glycolysis to further explore the mechanism of action of Fut intervention in AD. Fut improved the memory and learning ability of Aß25-35 mice, and reduced neuronal damage and the deposition of Aß and Tau proteins. Moreover, Fut reduced mitochondrial damage, the levels of oxidative stress, apoptosis, and inflammatory factors. Fut significantly inhibited the expression of HK II and p-p38MAPK proteins. The in vitro experiment showed that p38MAPK was activated and Fut action inhibited after adding 10 mM glucose. Fut might inhibit the activation of p38MAPK through the glycolysis pathway, thereby reducing oxidative stress, apoptosis, and inflammatory factors and improving Aß25-35-induced memory impairment in mice. These data provide pharmacological rationale for Fut in the treatment of AD.

[Effect of aqueous extract of Corni Fructus on Aß_(25-35)-induced brain injury and neuroinflammation in mice with Alzheimer's disease].

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on ß-amyloid protein 25-35(Aß_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aß_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of ß-amyloid protein 1-42(Aß_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aß_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol with ß-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aß_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aß_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aß_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aß_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aß_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.

Two polyphenols isolated from Corallodiscus flabellata B. L. Burtt ameliorate amyloid ß-protein induced Alzheimer's disease neuronal injury by improving mitochondrial homeostasis.

Corallodiscus flabellata B. L. Burtt (CF) is a Chinese folk herb with reported potential for the treatment of Alzheimer's disease (AD). 3,4-Dihydroxyphenylethanol-8-O-[4-O-trans-caffeoyl-ß-D-apiofuranosyl-(1→3)-ß-D-glucopyranosyl (1→6)][1]-ß-D-glucopyranoside (SDC-1-8) and hydroxytyrosol (HT) are two polyphenolic compounds isolated from CF. The aim of this study was to investigate the protective effects of SDC-1-8 and HT on an Aß25-35-induced AD model and to study the underlying mechanism. The AD mouse model was established using a brain injection of amyloid ß-protein 25-35 (Aß25-35, 200 µM), followed by continuous administration of SDC-1-8 and HT for 4 weeks, and found that they improved cognitive dysfunction; ameliorated neuronal damage and apoptosis; decreased oxidative stress, and mitochondrial fission protein levels; and increased mitochondrial fusion protein levels in AD mice. Moreover, SDC-1-8 and HT inhibited mitochondrial membrane depolarization, reduced intracellular stored Ca2+ levels, enhanced mitochondrial respiration, increased mitochondrial fusion, and decreased mitochondrial division in Aß25-35-induced PC12 cells even in the presence of mdivi-1. Furthermore, molecular docking simulations showed that SDC-1-8 and HT interacted with dynamin-related protein 1 with higher affinity than mitofusin 1. Thus, it is summarized that SDC-1-8 and HT may have neuroprotective effects by balancing the abnormalities of mitochondrial fission and fusion, and SDC-1-8 and HT are the components providing the therapeutic basis of CF.