Treatment Of Stroke In China Research Articles

Quality of life and cost consequence of delays in endovascular treatment for acute ischemic stroke in China

BackgroundAlthough endovascular therapy (EVT) improves clinical outcomes in patients with acute ischemic stroke, the time of EVT initiation significantly influences clinical outcomes and healthcare costs. This study evaluated the impact of EVT treatment delay on cost-effectiveness in China.MethodsA model combining a short-term decision tree and long-term Markov health state transition matrix was constructed. For each time window of symptom onset to EVT, the probability of receiving EVT or non-EVT treatment was varied, thereby varying clinical outcomes and healthcare costs. Clinical outcomes and cost data were derived from clinical trials and literature. Incremental cost-effectiveness ratio and incremental net monetary benefits were simulated. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the model. The willingness-to-pay threshold per quality-adjusted life-year (QALY) was set to ¥71,000 ($10,281).ResultsEVT performed between 61 and 120 min after the stroke onset was most cost-effective comparing to other time windows to perform EVT among AIS patients in China, with an ICER of ¥16,409/QALY ($2376) for performing EVT at 61–120 min versus the time window of 301–360 min. Each hour delay in EVT resulted in an average loss of 0.45 QALYs and 165.02 healthy days, with an average net monetary loss of ¥15,105 ($2187).ConclusionsEarlier treatment of acute ischemic stroke patients with EVT in China increases lifetime QALYs and the economic value of care without any net increase in lifetime costs. Thus, healthcare policies should aim to improve efficiency of pre-hospital and in-hospital workflow processes to reduce the onset-to-puncture duration in China.

Increase in Blood-Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling.

AimDisruption of the blood–brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear.MethodsWe investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected.ResultsA significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor.ConclusionTK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.

Panax notoginseng Saponins Attenuate Neuroinflammation through TXNIP-Mediated NLRP3 Inflammasome Activation in Aging Rats.

Microglia-mediated inflammatory responses play a crucial role in aging-related neurodegenerative diseases. The TXNIP/NLRP3 pathway is a key pathway leading to microglial activation. Panax notoginseng Saponins (PNS) have been widely used for the treatment of stroke in China. This study evaluates the anti-neuroinflammatory effect of PNS and investigates the mechanism via TXNIP-mediated NLRP3 inflammasome activation in aging rats. Eighteen-month-old Sprague-Dawley rats were randomly divided into the aging control group and PNS treated groups (n=15 each group). For PNS-treated groups, rats were administrated food with PNS at the doses of 10 mg/kg and 30 mg/kg for consecutive 6 months until they were 24-month old. Rats from the aging control group were given the same food without PNS. Twomonth- old rats were purchased and given the same food until they were 6-months old as the adult control group (n = 15). Then, the cortex and hippocampus were rapidly harvested and deposited. H&E staining was used to assess histo-morphological changes. Western blotting was carried out to detect the protein expression. Immunofluorescence was employed to measure the co-localization of NLRP3, TXNIP and Iba-1. In vitro model was established by LPS+ATP co-incubation in the BV2 microglia cell line. Aging rats exhibited increased activation of microglia, accompanied by a high level of IL-1β expression. Meanwhile, aging rats showed enhanced protein expression of TXNIP and NLRP3 related molecules, which co-localized with microglia. PNS treatment effectively reduced the number of degenerated neurons and reversed the activation of the TXNIP/NLRP3 inflammatory pathway. In vitro results showed that PNS up to 100 μg/ml had no significant toxicity on BV2 microglia. PNS (25, 50 μg/ml) effectively reduced the inflammatory response induced by LPS and ATP co-stimulation, thus inhibiting the expression of TXNIP/NLRP3 pathway-related proteins. PNS treatment improved aging-related neuronal damage through inhibiting TXNIP mediated NLRP3 inflammasome activation, which provided a potential target for the treatment of inflammation-related neurodegenerative diseases.

Xiaoxuming Decoction Regulates Vascular Function by Modulating G Protein-Coupled Receptors: A Molecular Docking Study.

Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.

Dl-3-n-butylphthalide pretreatment attenuates renal ischemia/reperfusion injury

BackgroundRenal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. MethodsThe kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. ResultsNBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. ConclusionOur promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI.

Cost-Effectiveness Analysis of Ginkgolide Injection in the Treatment of Ischemic Stroke Based on a Randomized Clinical Trial.

Objective: To evaluate the long-term cost-effectiveness of ginkgolide plus aspirin compared with placebo plus aspirin treatment of ischemic stroke.Background: Stroke is the leading cause of death and long-term disability in China, with high incidence, high mortality, and heavy disease burden. In addition to Western medicines, Chinese clinical guidelines for diagnosis and treatment of acute ischemic stroke recommend application of Chinese patent medicines. Ginkgolide injection is commonly used in the clinical treatment of stroke in China to promote blood circulation and remove blood stasis. The economy of ginkgolide injection needs to be evaluated.Methods: A Markov model was constructed consisting of four disease states: no significant disability, disability, stroke recurrence, and death. Therapeutic data were taken from the Ginkgolide in Ischemic Stroke Patients with Large Artery Atherosclerosis (GISAA) study. Utilities and transition probabilities were extracted from the literature. Cost data were obtained from the China Health Statistics Yearbook and hospital record survey. Expected costs and quality-adjusted life-years (QALYs) of 13 years of cycles (calculated by average age of subjects and Chinese life expectancy) were calculated through TreeAge Pro11 software. The willingness-to-pay (WTP) threshold was set as the Chinese per capita Gross Domestic Product (GDP) in 2019, CN¥70,892/QALY. The results were analyzed by single factor and probability sensitivity analyses.Results: Ginkgolide plus aspirin had a higher expected per-patient cost than placebo plus aspirin but a higher QALYs. Compared with placebo plus aspirin, ginkgolide plus aspirin produced an incremental cost-effectiveness ratio of CN¥14,866.06/QALY, which is below the WTP threshold. Probabilistic sensitivity analysis suggested the acceptability of ginkgolide plus aspirin was higher than that of placebo plus aspirin.Conclusions: The present cost-effectiveness analysis showed that addition of ginkgolides to conventional treatment is cost-effective at a threshold the Chinese per capita GDP.

Analysis of main risk factors causing stroke in Shanxi Province based on machine learning models

Background:In China, stroke has been the first leading cause of death in recent years. It is a major cause of long-term physical and cognitive impairment, which bring great pressure on the National Public Health System. On the other hand, China is a big country, evaluation of the risk of getting stroke is important for the prevention and treatment of stroke in China. Methods:A data set with 2000 hospitalized stroke patients in 2018 and 27583 residents during the year 2017 to 2020 is analyzed in this study. With the cleaned data, three models on stroke risk levels are built by using machine learning methods. The importance of “8+2” factors from China National Stroke Prevention Project (CSPP) is evaluated via decision tree and random forest models. The importance of more detailed features and their SHAP22SHAP: SHapley Additive exPlanations. values are evaluated and ranked via random forest model. Furthermore, a logistic regression model is applied to evaluate the probability of getting stroke for different risk levels. Results:Among all “8+2” risk factors of getting stroke, the decision tree model reveals that top three factors are Hypertension (0.4995),33The value of importance. Physical Inactivity (0.08486) and Diabetes Mellitus (0.07889), and the random forest model shows that top three factors are Hypertension (0.3966), Hyperlipidemia (0.1229) and Physical Inactivity (0.1146). In addition to “8+2” factors the importance of features for lifestyle information, demographic information and medical measurement are evaluated via random forest model. It shows that top five features are Systolic Blood Pressure (SBP) (0.3670), Diastolic Blood Pressure (DBP) (0.1541), Physical Inactivity (0.0904), Body Mass Index (BMI) (0.0721) and Fasting Blood Glucose (FBG)(0.0531). SHAP values show that DBP, Physical Inactivity, SBP, BMI, Smoking, FBG, and Triglyceride(TG) are positively correlated to the risk of getting stroke. High-density Lipoprotein (HDL) is negatively correlated to the risk of getting stroke. Combining with the data of 2000 hospitalized stroke patients, the logistic regression model shows that the average probabilities of getting stroke are 7.20%±0.55%44Confidence Interval with confidence level 95%. for the low-risk level patients, 19.02%±0.94% for the medium-risk level patients and 83.89%±0.97% for the high-risk level patients. Conclusion:Based on the census data from Shanxi Province, we investigate stroke risk factors and their ranking. It shows that Hypertension, Physical Inactivity, and Overweight are ranked as the top three high stroke risk factors in Shanxi. The probability of getting a stroke is also estimated through our interpretable machine learning methods.

PCV21 COST-EFFECTIVENESS ANALYSIS OF PLUS ASPIRIN VS PLACEBO PLUS ASPIRIN IN THE TREATMENT OF ISCHEMIC STROKE BASED ON A RANDOMIZED CLINICAL TRIAL

Stroke is the leading cause of death and long-term disability in China with high-incidence, high-mortality and heavy-disease-burden. In addition to the chemical drugs, Chinese guidelines for diagnosis and treatment of acute ischemic stroke recommends the application of Chinese patent medicines. Ginkgolide injection is commonly used in the clinical treatment of stroke in China for its effect in promoting blood circulation and removing blood stasis, clearing channels and activating collaterals. A GISAA RCT study evaluated the efficacy and safety between Ginkgolide plus Aspirin and Placebo plus Aspirin. This study intends to evaluate the long-term cost-effectiveness of Ginkgolide plus Aspirin compared with placebo plus Aspirin based on the RCT results and literature. A Markov model is constructed consisting 4 states: No significant disability, Disability, Stroke recurrence and Death. Therapeutic data is from GISAA study. Utilities, transition probabilities are extracted from literatures. Costs data is from China Health Statistics Yearbook and hospital record survey. Expected costs and QALYs of 13 years’ circles (Calculated by average age of subjects and Chinese life expectancy) are calculated through TreeagePro11 software. The WTP threshold is the Chinese per capita GDP in 2018, ￥64644/QALY. The results are analyzed by single factor and probability sensitivity analysis. Ginkgolide plus Aspirin is found to have higher expected per-patient cost than placebo plus Aspirin, but also higher QALYs. Compared to placebo plus Aspirin, Ginkgolide plus Aspirin produces an incremental cost effectiveness ratio of ￥14920.17/QALY, which is below the WTP threshold. Probabilistic sensitivity analysis suggests that the acceptability of Ginkgolide plus Aspirin is higher than that of placebo plus Aspirin. The cost-effectiveness analysis based on RCT shows that the addition of ginkgolides to conventional treatment is cost-effective at the threshold of Chinese per capita GDP.

Validation and Evaluation of the Core Nursing Outcomes Evaluation System for Inpatients with Stroke.

To evaluate the reliability, validity, responsiveness, importance, and application level of the Core Nursing Outcomes Evaluation System for inpatients with stroke. The reliability, validity, responsiveness, importance, and application level were evaluated by expert scoring, clinical measurement, and questionnaire survey. The scale-level content validity index (S-CVI) and item-level content validity index (I-CVI) were >0.8. The scoring of intraclass coefficient of all indicators was >0.600 (p<.001). There were significant differences in the total scores among patients with different severities (p<.001). Compared with total scores at admission, the total scores at discharge were significantly improved (p<.01). The importance and application level scores of all indexes are >4.5 points. The system has higher reliability, validity, responsiveness, and importance, but the application of each dimension is disproportionate. Stroke is an acute cerebrovascular disease characterized by cerebral ischemia and hemorrhagic injury. Epidemiological findings revealed that stroke is the second leading cause of death and the leading cause of disability in the world (Feigin etal., 2014). Epidemiological survey of 600,000 people in China showed that the prevalence of stroke has been increasing over the past 30 years (Sun & Wang, 2018). At present, stroke has become the first cause of death among Chinese residents (Wang, 2018; Zhou etal., 2016). In surviving patients with stroke, more than 60% of patients had different degrees of neurological dysfunction (Wang, Liu, Yang, Peng, & Wang, 2018), about 40% of them had severe disabilities (You & Wu, 2016). About 60% of first onset stroke patients were associated with higher risk of recurrence (Wang etal., 2018). With increasing age, the global burden of stroke is becoming heavier and heavier (Johnston, Mendis & Mathers, 2009). In 2015, the cost of stroke treatment in China reached about 29.2 billion RMB, bringing heavy economic burden to families as well as society (Ma, 2018). From the above data, we deduced that stroke has characteristics of high prevalence rate, high disability rate, high mortality rate, and high recurrence rate. It is one of the important causes of death and disability, seriously threatening human health and has become an important public health problem faced by Chinese society currently.

Xingnaojing injection improves Aβ1-42-induced memory deficit in mice by altering of excitatory amino acid toxicity and synaptic plasticity

Alzheimer’s disease (AD), the widespread type of dementia, is characterized by depositions of senile plaques composed of insoluble amyloid β (Aβ) peptides, and neurofibrillary tangles. It causes progressive degeneration of synaptic plasticity and leads to memory loss and cognition impairment. Abnormal changes in synaptic structure and excitatory amino acid toxicity occurred in early stage in AD and are associated with decreased cognitive function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for treatment of stroke in China. In this research, mice were randomly divided into 4 groups: control, Aβ1-42 injected (Aβ) and Aβ1-42 injected with two doses of XNJ (low-dose, high-dose) administration groups. We performed bilateral intra-CA1 injection of Aβ1-42 except control group. Behavioral results showed that the mice treatment with high-dose of XNJ group has a longer exploration time for New object recognition (NOR) and more crossing platform times for Morris water maze (MWM) compared with Aβ group. The expression of MAP-2 was increased by administration of XNJ in immunofluorescence results. Golgi staining showed that XNJ can improve dendritic spine density of damaged neurons. It also increased the protein levels of GAP-43, PSD-95, NR2b, p-AKT/AKT and p-mTOR/mTOR in the brain tissues compared with Aβ group in the Western blot (WB). Our results indicated that XNJ exhibited a protective effect against excitatory amino acid toxicity and synaptic plasticity via AKT/mTOR signal pathway in mice with Aβ1-42-induced memory deficit. These results provided evidences for the novel and potential application of XNJ for the treatment of AD.

Systems pharmacology dissection of the anti-stroke mechanism for the Chinese traditional medicine Xing-Nao-Jing

Xing-Nao-Jing (XNJ) is a well-known injection that has been extensively applied in clinical treatment of stroke in China. However, the underlying mechanism of clinical administration of XNJ in stroke remains unclear. In this study, a systems pharmacology strategy based on pharmacokinetic and pharmacodynamics data was applied to analyze the pharmacological effect of XNJ on stroke. Sixteen active compounds were filtered from XNJ through Drug-likeness (DL) and Brain-blood-barrier (BBB) evaluations. Ninety-four potential targets of these active components were identified by SysDT and SEA. Biological process and pathway enrichment analyses of these targets demonstrated that XNJ exerted anti-stroke effects by biological processes and pathways, such as the response to oxidative stress, regulation of blood pressure, calcium signaling pathway, and apoptosis. Integrating the compound-target network and stroke-related PPI network, we found that Akt1, HIF-1α and ITGB2 may play key roles in the treatment of stroke. The experiments demonstrated that oxycurcumenol may prevent PC12 cells from oxidative stress-induced cell damage. Our study indicates that XNJ has an effect on stroke by protecting neuro cells from oxidative stress-induced cell damage via HIF1α, and the research strategy at the systems pharmacology level is feasible to reveal the mechanisms of novel lead compounds from natural products.

Xingnaojing for Moderate-to-severe Acute ischemic Stroke (XMAS): study protocol for a randomized controlled trial

BackgroundXingnaojing injection (XNJ) is widely used for the treatment of stroke in China. However, there is currently a lack of high-quality evidence of its efficacy for acute ischemic stroke. The main objective of this study is to determine whether the addition of XNJ to standard care improves the 3-month functional outcome in patients with acute ischemic stroke (AIS).Methods/designThe XMAS study is a multicenter, prospective, randomized controlled, open-label trial with a blinded endpoints design. A total of 720 patients will be randomly allocated to either the intervention or the control group in a 1:1 ratio. The intervention group receives XNJ combined with standard care, and the control group receives standard care alone. XNJ will be administered intravenously every 12 h for 10 days. The primary outcome is the proportion of patients who are independent at 3 months after stroke onset defined as a modified Rankin Scale score of 0 to 2. Secondary outcomes include early neurological deterioration at 48 h, the change in National Institutes of Health Stroke Scale score, patient-reported outcome, symptomatic intracranial hemorrhage at 10 days, the Barthel Index score, deaths from any cause and cardiovascular events at 3 months.DiscussionThe results of this trial will provide critical evidence for XNJ in the treatment of AIS as a complementary approach that can be initiated after reperfusion therapy or when the AIS is not eligible for thrombolytic treatment.Trial registrationClinical Trials.gov, ID: NCT02728180. Registered on 28 March 2016.

Chinese acute ischemic stroke treatment outcome registry (CASTOR): protocol for a prospective registry study on patterns of real-world treatment of acute ischemic stroke in China

RationaleStroke presents a serious health problem in China. Despite progresses made in recent years, there is still a lack of effective treatments for acute ischemic stroke (AIS) in clinical practices.AimsThe Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR) is designed to evaluate the patterns and cost-effectiveness of current treatments for AIS in real-world settings in China.DesignCASTOR is a prospective, multi-center study registered with ClinicalTrials.gov (NCT02470624) with a target sample size of 10,000 patients who are experiencing AIS. The patients are treated for AIS following the Chinese stroke guideline and local practice. Real-world data on treatment regimens, outcomes and costs are collected at baseline (Visit 1) and during subsequent visits (Visit 2 to Visit 5) after medication treatments.OutcomeThe primary objective of the present study is to analyze the current treatment status of AIS in real world settings. The secondary objectives include: 1) to compare the effectiveness of common treatment regimens, 2) to analyze the cost-effectiveness of different treatment regimens for AIS, 3) to analyze the incidence of adverse events and complications in enrolled patients with AIS, 4) to analyze the effect of Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification on the specific therapies during acute phase treatment period.DiscussionIn face of changing treatment patterns and increasing demand from medical insurers for cost-effectiveness data in China, a large-scale registry study examining the real-world patterns of AIS in hospitals is needed. The CASTOR study will help to find favorable cost-utility treatment regimens for AIS and improve the overall treatment outcome of Chinese patients with AIS.

Electroacupuncture improves neurobehavioral function and brain injury in rat model of intracerebral hemorrhage.

Acupuncture has been widely used as a treatment for stroke in China for a long time. Recently, studies have demonstrated that electroacupuncture (EA) can accelerate intracerebral hemorrhage (ICH)-induced angiogenesis in rats. In the present study, we investigated the effect of EA on neurobehavioral function and brain injury in ICH rats. ICH was induced by stereotactic injection of collagenase type I and heparin into the right caudate putamen. Adult ICH rats were randomly divided into the following three groups: model control group (MC), EA at non-acupoint points group (non-acupoint EA) and EA at Baihui and Dazhui acupoints group (EA). The neurobehavioral deficits of ICH rats were assessed by modified neurological severity score (mNSS) and gait analysis. The hemorrhage volume and glucose metabolism of hemorrhagic foci were detected by PET/CT. The expression levels of MBP, NSE and S100-B proteins in serum were tested by ELISA. The histopathological features were examined by haematoxylin-eosin (H&E) staining. Apoptosis-associated proteins in the perihematomal region were observed by immunohistochemistry. EA treatment significantly promoted the recovery of neurobehavioral function in ICH rats. Hemorrhage volume reduced in EA group at day 14 when compared with MC and non-acupoint EA groups. ELISA showed that the levels of MBP, NSE and S100-B in serum were all down-regulated by EA treatment. The brain tissue of ICH rat in the EA group was more intact and compact than that in the MC and non-acupoint groups. In the perihematomal regions, the expression of Bcl-2 protein increased and expressions of Caspase-3 and Bax proteins decreased in the EA group vs MC and non-acupoint EA groups. Our data suggest that EA treatment can improve neurobehavioral function and brain injury, which were likely connected with the absorption of hematoma and regulation of apoptosis-related proteins.

Toxicokinetics and toxicity of potassium 2-(1-hydroxypentyl)-benzoate in beagle dogs

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a prodrug of 3-n-butylphthalide (dl-NBP) for treatment of cerebral ischemic stroke in China, which undergoes lactonization to form dl-NBP in plasma. And, the phase II–III clinical trial of dl-PHPB has been approved by China Food and Drug Administration (CFDA) in 2013. In this study, a toxicity and toxicokinetics evaluation of dl-PHPB was performed using beagle dogs at specially high-dose 108 mg/kg/day (65-fold higher than humans at MHRD) for 4 weeks by intravenous administration, with a 3-week recovery period. And the plasma concentrations of dl-PHPB along with its metabolite dl-NBP were determined by HPLC-UV method. The results showed that dl-PHPB was quickly metabolized into dl-NBP, and no significant accumulation was observed. A slight to moderate behavior-associated toxicity was revealed in the process of delivery; and recovered to normal at the end of administration. Changes in the blood hematological profiles included significantly increased NEUT levels and lower LYM% content. Meanwhile, a notable increase in TG content was also observed in the serum biochemical parameters at 4-week post-exposure. These findings were reversible during the recovery period. The information from these studies would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.

XingNaoJing, prescription of traditional Chinese medicine, prevents autophagy in experimental stroke by repressing p53-DRAM pathway

BackgroundXingnaojing (XNJ), a well known prescription in traditional Chinese medicine, has been used for treatment of stroke in China. However, the effects and mechanisms of XNJ on autophagy are not clear. Here, we used the cell models of autophagy induced by serum-free condition and ischemia stroke in rats to further investigate whether the p53-DRAM pathway is involved in the effects of XNJ on autophagy.MethodsWe used the cell model of autophagy induced by serum-free condition and the rat model of ischemia caused by a middle cerebral artery occlusion (MCAO). The effects of XNJ on p53 transcriptional activity of PC12 cells were evaluated by the luciferase activity assay. The mRNA levels and the expression of p53 and its target autophagy gene DRAM (damage-regulated autophagy modulator) were analyzed respectively by Quantitative-RTPCR and Western blot assay. The activation of autophagy was detected by the levels of autophagy markers, microtubule associated protein light chain 3 (LC3) and p62 by Immunofluorescence and Western blot. p53 inhibitor was used to determine whether p53 is responsible for the effects of XNJ on preventing autophagy.ResultsThe assay for luciferase activity of p53 promoter indicated that XNJ inhibited p53 transcriptional activity. XNJ reduced the expression of p53 and its target autophagy gene DRAM (damage-regulated autophagy modulator) in serum-free condition PC12 cells and the cortex in MCAO rats. XNJ reduced autophagy of PC12 cells induced by serum-free condition and the cortex in MCAO rats. Furthermore, suppression of p53 by p53 inhibitor significantly reduced the effects of XNJ on the autophagy of PC12 cells in serum-free condition.ConclusionXNJ prevents autophagy in experimental stroke by repressing p53/DRAM pathway. Our findings are therefore of considerable therapeutic significance and provide the novel and potential application of XNJ for the treatment of brain diseases.

Acupuncture for acute stroke: study protocol for a multicenter, randomized, controlled trial.

BackgroundAcupuncture has been widely used as a treatment for stroke in China for more than 3,000 years. However, previous research has not yet shown that acupuncture is effective as a stroke treatment. We report a protocol for a multicenter, randomized, controlled, and outcome assessor-blind trial to evaluate the efficacy and safety of acupuncture on acute ischemic stroke.Methods/DesignIn a prospective trial involving three hospitals in the Zhejiang Province (China) 250 patients with a recent (less than 1 week previous) episode of ischemic stroke will be included. Patients will be randomized into two groups: an acupuncture group given scalp acupuncture and electroacupuncture, and a control group given no acupuncture. Eighteen treatment sessions will be performed over a three-week period. The primary outcome will be measured by changes in the National Institutes of Health Stroke Scale score at the one, three, and four-week follow-up. Secondary outcome measures will be: 1) the Fugl-Meyer assessment scale for motor function; 2) the mini-mental state examination and Montreal cognitive assessment for cognitive function; 3) the video-fluoroscopic swallowing study for swallowing ability; and 4) the incidence of adverse events.DiscussionThis trial is expected to clarify whether or not acupuncture is effective for acute stroke. It will also show if acupuncture can improve motor, cognitive, or swallowing function.Trial registrationChinese Clinical Trial Registry ChiCTR-TRC-12001971.

Bioavailability and Brain-Targeting of Geniposide in Gardenia-Borneol Co-Compound by Different Administration Routes in Mice

Both geniposide (Ge) and borneol (Bo) are bioactive substances derived from traditional Chinese medicine. Injections containing co-compound of Gardenia-Borneol are widely used for stroke treatment in China, such as “Xingnaojing” multi-component injection. As more and more adverse reactions (especially drug allergy) were reported, it is urgent to find more effective and safer routes of administration for such kinds of medicines. In this paper, bioavailabilities and brain-target effects of geniposide in Gardenia-Borneol co-compound through different administration routes in mice were investigated. Geniposide concentrations in plasma and in brain of mice were determined by reversed-phase high-performance liquid chromatography. The pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of Ge were 85.38% and 28.76% for i.n. and i.g. while Tmax were 1 min and 30 min. Cmax were 21.881 ± 5.398, 1.914 ± 0.327 and 42.410 ± 6.268 μg/mL for i.n., i.g. and i.v., respectively. The AUC of Ge in brain were 32413.6 ± 4573.9, 6440.1 ± 863.7 and 37270.5 ± 4160.6 ng/g·min for i.n., i.g. and i.v., respectively. The drug target indexes (DTI) were 1.02 and 0.60 for i.n. and i.g. The results demonstrated that geniposide could be absorbed promptly and thoroughly by i.n. administration in mice and basically transported into the brain though blood vessel passways.

Dl-3-n-Butylphthalide protects rat bone marrow stem cells against hydrogen peroxide-induced cell death through antioxidation and activation of PI3K-Akt pathway

Bone marrow stem cells (BMSCs) have been one of the most important cell sources for cell replacement therapy (CRT) in cerebral infarction. However, long-lasting oxidative stress during stroke, which plays an important role in neuron damage, deteriorates the microenvironment for cell survival, differentiation and removal. Thus the outcome of CRT in ischemic diseases was poor. dl-3-n-Butylphthalide (NBP) has protective effects on ischemic brain tissue through multiple mechanisms and has been used for stroke treatment in China for several years. In this study, hydrogen peroxide (H2O2) was used to induce oxidative stress injury to rat bone marrow stem cells (rBMSCs), imitating the microenvironment surrounding transplanted cells in the ischemic brain in vitro. The protective effects of NBP on rBMSCs against apoptosis induced by oxidative stress were investigated. Our results indicated that NBP could protect rBMSCs against apoptosis due to antioxidative properties and modulation of PI3K/Akt pathway. NBP could be used in combination with BMSCs for the treatment of cerebral infarction by improving the oxidative stress microenvironments and cell survival, however, further studies remain warranted.

Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats

EGb761 is a standard extract of Ginkgo biloba, which is a kind of traditional Chinese herbs that has widely used in clinic treatment of stroke in China. However, its effects against ischemic stroke have not been evaluated comprehensively and its neuroprotective mechanism has not really been explored. In the present study, magnetic resonance diffusion-weighted imaging (DWI), neurological behavior and TTC staining were used to evaluate the therapeutic effect of EGb761 in rat ischemic models. Additionally, Western blot and immunohistochemistry were performed to measure the phosphorylations of cAMP response element binding protein (CREB) and Akt as well as the expression of brain-derived neurotrophic factor (BDNF) in rat brains. The results showed that Ginkgo biloba extract injection significantly increased the apparent diffusion coefficient (ADC) value and average diffusion coefficient (DCavg) value both in the peripheral zone and central zone, improved behavior scores, as well as enhanced the phosphorylations of AKT, CREB and the expression of BDNF in the brains. All these data demonstrate that EGb761 had significant therapeutic effects on ischemic stroke and it perhaps worked through activating the Akt-CREB-BDNF pathway.