Inhibiting leukocyte-endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no-reflow after arterial recanalization in ischemic stroke.

AIMS: Despite successful vascular recanalization in stroke, one-fourth of patients have an unfavorable outcome due to no-reflow. The pathogenesis of no-reflow is fully unclear, and therapeutic strategies are lacking. Upon traditional Chinese medicine, Tongxinluo capsule (TXL) is a potential therapeutic agent for no-reflow. Thus, this study is aimed to investigate the pathogenesis of no-reflow in stroke, and whether TXL could alleviate no-reflow as well as its potential mechanisms of action. METHODS: Mice were orally administered with TXL (3.0 g/kg/d) after transient middle cerebral artery occlusion. We examined the following parameters: neurological function, no-reflow, leukocyte-endothelial cell interactions, HE staining, leukocyte subtypes, adhesion molecules, and chemokines. RESULTS: Our results showed stroke caused neurological deficits, neuron death, and no-reflow. Adherent and aggregated leukocytes obstructed microvessels as well as leukocyte infiltration in ischemic brain. Leukocyte subtypes changed after stroke mainly including neutrophils, lymphocytes, regulatory T cells, suppressor T cells, helper T type 1 (Th1) cells, Th2 cells, B cells, macrophages, natural killer cells, and dendritic cells. Stroke resulted in upregulated expression of adhesion molecules (P-selectin, E-selectin, and ICAM-1) and chemokines (CC-chemokine ligand (CCL)-2, CCL-3, CCL-4, CCL-5, and chemokine C-X-C ligand 1 (CXCL-1)). Notably, TXL improved neurological deficits, protected neurons, alleviated no-reflow and leukocyte-endothelial cell interactions, regulated multiple leukocyte subtypes, and inhibited the expression of various inflammatory mediators. CONCLUSION: Leukocyte-endothelial cell interactions mediated by multiple inflammatory factors are an important cause of no-reflow in stroke. Accordingly, TXL could alleviate no-reflow via suppressing the interactions through modulating various leukocyte subtypes and inhibiting the expression of multiple inflammatory mediators.

Fire Acupuncture versus conventional acupuncture to treat spasticity after stroke: A systematic review and meta-analysis.

BACKGROUND: Post-stroke spasm is currently a complex clinical problem that remains to be resolved. Due to its excellent efficacy and few side effects, clinicians have used fire acupuncture to treat post-stroke spasticity in China. OBJECTIVES: The purpose of this study was to evaluate the clinical efficacy of fire acupuncture compared with conventional acupuncture to treat post-stroke spasms and provide a detailed summary of the commonly used acupoints. METHODS: Eight databases (MEDLINE/PubMed, Web of Science, the Cochrane database, EMBASE, CBM, CNKI, WanFang, and VIP) were searched for randomized controlled trials (RCTs) published from database inception through August 30, 2020. RCTs that compared fire acupuncture with conventional acupuncture as a treatment intervention for patients with spasticity after stroke were included. Revman 5.3 software was used to calculate risk ratios (RR) and standard mean differences (SMD) with 95% confidence intervals (CI). Methodological evaluation or critical appraisal of the included articles was assessed using RoB-2. RESULTS: Sixteen studies with a total of 1,118 patients were included. Although according to the standards of the Rob 2.0 tool, most studies are considered to have some problems. Comprehensive analysis of the results revealed a consistent trend indicating several advantages of using fire needles compared to conventional acupuncture in treating post-stroke spasms, including the effective rate, recovery rate, and improvement of multiple scales represented by MAS. Concerning secondary outcomes, using the scales of FMA, BI, or NDS in this random model meta-analysis, fire acupuncture exhibited better performance compared to acupuncture [SMD = 2.27, 95%CI [1.40,3.13 (random-effects model) ], [SMD = 1.46,95% CI [1.03,1.90 (random-effects model)], and [SMD = 0.90, 95%CI [0.44,1.35 (random-effects model)], respectively, with moderately high heterogeneity. When the effective rate was used as an outcome in the subgroup analysis, fire needles performed better than conventional acupuncture with respect to damage to the upper or lower limbs, and the thickness and depth of acupuncture. When the modified Ashworth scale (MAS) was used as the outcome, and the damage occurred in the lower extremity, the acupuncture depth exceeded 15mm, or the duration of stroke was longer than six months, the fire needles did not perform better than conventional acupuncture, [SMD = 0.01, 95%CI [-0.47,0.48 (fix-effects model)], [SMD = 0.21 [-0.51,0.93(random-effects model)], and [SMD = 0.76, 95%CI [-0.08,1.60 (random-effects model)], respectively. The acupoints identified with the highest frequencies in this study were Yang-meridian, including LI11-Quchi (nine times), LI4-Hegu (seven times), and ST36-Zusanli (five times). Moreover, no serious adverse effects were reported in any of the studies included in this analysis. CONCLUSIONS: Despite several limitations, this was the first meta-analysis to focus on the treatment of post-stroke spasticity using fire needle acupuncture compared with conventional acupuncture. Our results confirmed that fire needles could provide a better clinical effect than conventional acupuncture, which will help standardize fire needle treatment strategies for post-stroke spasms.

Fuzhisan ameliorates Aß production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

Accumulation of amyloid-ß (Aß) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3ß (GSK3ß) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3ß. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aß production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3ß signaling which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan.

The aim of this study was to investigate the effects of fuzhisan (FZS, 10mg/day), a Chinese herbal medicine, on cerebral glucose metabolism and neuropsychological metrics in patients with mild-to-moderate Alzheimer's disease (AD). This was a 12-week, randomized, double-blind, placebo-controlled pilot study. Twenty-two subjects were randomly assigned to groups that received FZS (n=12) or placebo (n=10). Positron emission tomography (PET) was used to study the regional cerebral metabolic rate of glucose consumption (rCMRglc) at baseline and week 12. We evaluated the clinical efficacy of FZS on cognition and behavioral functions using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Neuropsychiatric Index (NPI), respectively. Compared with placebo, FZS significantly improved ADAS-Cog scores and NPI scores at week 12. Moreover, FZS treatment favorably improved rCMRglc in the bilateral temporal and parietal cortices, hippocampus, and posterior cingulate gyrus. These results suggest that FZS treatment may have a positive effect on cognition, behavioral functions, and rCMRglc in mild-to-moderate AD patients.

Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons.

It has been shown that ß-amyloid (Aß) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aß(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aß(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aß(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aß(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.

Inhibition of glycogen synthase kinase-3ß by Angelica sinensis extract decreases ß-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons.

Increasing evidence has shown that ß-amyloid (Aß) induces hyperphosphorylation of tau and contributes to Aß toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3ß (GSK-3ß) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3ß. The inhibitory control of GSK-3ß, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. We revealed that AS extract significantly attenuated Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of AS extract against Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, AS extract reversed the Aß(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Aß toxicity is likely mediated by the PI3K/Akt/GSK-3ß signal pathway.

Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3ß pathway in ginsenoside Rb1's attenuation of beta-amyloid-induced neurotoxicity and tau phosphorylation.

Ginseng has long been used to alleviate many ailments, particularly those associated with aging and memory deterioration. In the present study we aimed to investigate the neuroprotective effects of ginsenoside Rb1, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. Cortical neurons were pre-treated with ginsenoside Rb1 (20, 40, 100 µM) or LiCl (1, 5, 10 mM) for 24 h, and then were co-treated with 20 µM Aß(1-42) for 12 h. In some experiments to evaluate the mechanism of Rb1 action, a PI3K inhibitor (LY294002 10 µM) was co-administered with Rb1 for the 24-h pretreatment. We revealed that Rb1 significantly attenuated Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473)-Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of Rb1 against Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, Rb1 reversed the Aß(1-42)-induced decrease in phosphorylation cyclic AMP response element binding (CREB) protein, which could also be blocked by the PI3K inhibitor. All these findings suggest that Rb1 may represent a potential treatment strategy for Alzheimer's disease.