benzofurans and Stroke

DL-3-n-butylphthalide (NBP) is widely used as a neuroprotective drug for ischemic stroke in China. There is, however, no established evidence on its efficacy and safety for patients with ischemic stroke. We, therefore, conducted a systematic review and meta-analysis. Major databases were searched to identify randomized controlled trials that assessed the efficacy and safety of NBP on ischemic stroke, reporting outcomes among patients treated with NBP alone or combined with standard anti-ischemic stroke drugs vs. standard anti-ischemic stroke drugs. Continuous data were validated, extracted and synthesized of standardized mean differences (SMDs) by random effects models, while dichotomous data were validated, extracted and synthesized of relative risk (RR) by random effects models. Twelve randomized controlled trials involving 1160 patients were identified. Results suggested that NBP monotherapy is not superior to standard anti-ischemic stroke drugs based on the Barthel Index (SMD, 0.25; 95% CI

Topics: Aged; Benzofurans; Brain Ischemia; Databases, Bibliographic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Phytotherapy; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome

Stroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.

Topics: Animals; Benzofurans; Brain Ischemia; Humans; Platelet Aggregation Inhibitors; Stroke

Discovering effective agents to slow or stop neurodegeneration is a challenging task. Over decades, only a few drugs were approved by Food and Drug Administration (FDA) and most ended in failure. The lessons learned have switched the strategy of drug discovery from designing highly selective ligands to a network pharmacology approach. This enables many natural products like butylphthalide (NBP) once again to be regarded as a valuable source of leads for drug discovery. In this review, we first start with the neuroprotective effects of NBPs on acute ischemic stroke, and later spread to their applications in major neurodegenerative diseases. The underlying mechanisms are also discussed in order to provide a direction for further study. Hopefully, this review could bring some new insights for drug development in this struggling field.

Topics: Animals; Benzofurans; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Stroke

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Topics: Abietanes; Angina Pectoris; Animals; Benzofurans; Drugs, Chinese Herbal; Fibrinolytic Agents; Herb-Drug Interactions; Humans; Hyperlipidemias; Lactates; Phenanthrenes; Phenanthrolines; Plant Extracts; Randomized Controlled Trials as Topic; Salvia miltiorrhiza; Stroke

To evaluate the neurological safety and clinical efficacy of darifenacin and mirabegron in patients with a history of cerebrovascular accident (CVA) who had overactive bladder (OAB) symptoms.. This prospective randomized study, approved by the institute's ethics committee, was carried out at a tertiary care center from December 2018 to June 2020. Treatment naïve adult patients with a past history of CVA with stable neurological status for atleast past 3 months with symptoms of OAB for 3 or more months were included. Eligible patients received either darifenacin or mirabegron for a period of 3 months and various parameters on the 3-day International Consultation on Incontinence Questionnaire (ICIQ) bladder diary, the Montreal Cognitive Assessment-Basic score (MoCA-B), and the adverse events at 3 months posttreatment were compared to that at the baseline.. A total of 60 patients were included, 30 in each arm. After 3 months of treatment with darifenacin or mirabegron, the majority of the ICIQ bladder diary parameters improved and there was no deterioration in the cognitive function as noted on the MoCA-B score in either of the arms. On intergroup comparison, the mean change in bladder diary parameters and the MoCA-B scores was similar between the two groups.. Darifenacin and mirabegron, in the short term, do not adversely affect the cognitive function in patients with a history of CVA with OAB symptoms. Both are safe and effective treatment options in patients with OAB post-CVA.

Topics: Acetanilides; Adult; Benzofurans; Humans; Prospective Studies; Pyrrolidines; Stroke; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive; Urological Agents

As a neuroprotective medication, butylphthalide (NBP) may help protect against cerebral ischaemic injury. However, evidence on whether NBP influences the outcomes of patients who had acute ischaemic stroke who are receiving revascularisation treatment is limited. This study aims to evaluate whether additional NBP therapy can improve the functional outcome of patients who receive intravenous recombinant tissue plasminogen activator and/or endovascular treatment (EVT).. The study will be a randomised, double-blind, placebo-controlled, multiple-centre, parallel group trial. The sample size is estimated at 1200 patients. Eligible patients will be randomised at a 1:1 ratio to receive either NBP or placebo daily for 90 days, which will include 14 days of injections and 76 days of capsules. The first use of NBP/placebo will be started within 6 hours of onset of ischaemic stroke. The primary outcome is the functional outcome as assessed by the 90-day modified Rankin Scale, adjusted for baseline scores on the National Institutes of Health Stroke Scale. The primary safety outcome is the percentage of serious adverse events during the 90 days of treatment. This trial will determine whether NBP medication benefits patients who had acute ischaemic stroke who receive intravenous thrombolysis or EVT.. The protocol was written according to the general ethical guidelines of the Declaration of Helsinki and approved by the Institutional Review Board/Ethics Committee of Beijing Tiantan Hospital, Capital Medical University with approval number KY 2018-003-02. Ethics committees of all participating sites have approved the study . Results of the study will be published in peer-reviewed scientific journals and shared in scientific presentations.. NCT03539445.

Topics: Benzofurans; Brain Ischemia; Double-Blind Method; Humans; Ischemic Stroke; Randomized Controlled Trials as Topic; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

The effectiveness of neuroprotective agents is still unclear. Here we analyzed the clinical outcomes of acute ischemic stroke (AIS) patients treated with human urinary kallidinogenase (HUK) or edaravone (Eda) combined with butylphthalide (NBP).. From January 2016 to December 2017, a total of 165 AIS patients were enrolled in this open-label, randomized controlled clinical study. Patients were randomly allocated into HUK group and Eda group in a ratio of 2:1. All the patients received basic treatments and NBP (200 mg p.o. qid) while HUK group received 0.15 PNA unit of HUK injection (ivgtt. qd) and Eda group received 30 mg Eda (ivgtt. bid) for 14 consecutive days. Independency rate [12-month modified Rankin Scale (mRS) score ≤ 1] and related factors were compared between the two groups.. Twelve-month mRS score of the HUK group (1, IQR 0~1) was significantly lower compared with Eda group (2, IQR 1~3, p < .0001). The HUK treatment achieved an independency rate of 79.1% while the Eda treatment only had 45.3% (p < .0001). Further binary logistic regression showed that recurrent stroke (RR: 0.1, 95% CI: 0.0~0.1, p = .038) and HUK treatment (RR: 4.2, 95% CI: 1.1~16.5, p = .041) could significantly affect patients' 12-month outcomes.. Human urinary kallidinogenase combined with NBP can enhance AIS patients' long-term independency rate, and the effectiveness of HUK combined therapy is better than Eda.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Brain Ischemia; Drug Therapy, Combination; Edaravone; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Stroke; Tissue Kallikreins; Treatment Outcome; Young Adult

In China, both human urinary kallindinogenase (HUK) and 3-n-butylphthalide (NBP) are recommended for clinical use to improve cerebral blood circulation during an acute ischemic stroke (AIS). The objective was to evaluate the economic value of HUK vs NBP for patients with AIS from a Chinese payer's perspective.. An economic evaluation based on data of patients who have been treated with either HUK (n = 488) or NBP (n = 885) from a prospective, phase IV, multi-center, clinical registry study (Chinese Acute Ischemic Stroke Treatment Outcome Registry, CASTOR) was conducted to analyze the cost and effectiveness of HUK vs NBP for AIS in China. Before the analysis, the patients were matched using propensity score. Both a cost-minimization analysis and a cost-effectiveness analysis were conducted to compare the matched pairs. A bootstrapping exercise was conducted for the matched arms to demonstrate the probability of one intervention being cost-effective over another for a given willingness-to-pay for an extra quality-adjusted life-year (QALY).. After propensity score matching, 463 pairs were matched. The overall medical cost in the HUK arm is USD 2,701.20, while the NBP arm is USD 3,436.83, indicating HUK is preferred with cost-minimization analysis. Although the QALY gained in the HUK arm (0.77176) compared with the NBP arm (0.76831) is statistically insignificant (p = .4862), the cost-effectiveness analysis as exploratory analysis found that, compared with NBP, HUK is a cost-saving strategy with the lower costs of USD 735.63 and greater QALYs gained of 0.00345. Among the 5,000 bootstrapping replications, 100% indicates that HUK is cost-effective compared with NBP under a 1-time-GDP threshold; and 97.12% indicates the same under a 3-time-GDP threshold.. This economic evaluation study indicates that administrating HUK is a cost-saving therapy compared with NBP for managing blood flow during AIS in the Chinese setting.

Topics: Benzofurans; Cerebrovascular Circulation; China; Cost-Benefit Analysis; Female; Health Services; Humans; Male; Models, Econometric; Prospective Studies; Quality-Adjusted Life Years; Stroke

To observe the curative effect of dl-3-n-Butylphthalide (NBP) on patients with acute cerebral infarction (ACI) and its effects on levels of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).. A total of 160 ACI patients treated in our hospital who met the criteria were selected and randomly divided into treatment group (n=80, including 42 males and 38 females) and control group (n=80, including 40 males and 40 females). The control group was treated with routine drug therapy, while the treatment group was treated with butylphthalide on this basis. The curative effect was evaluated using the National Institute of Health Stroke Scale (NIHSS) and the Activity of Daily Life Scale (ADL Scale). The levels of the two factors in serum were measured using enzyme-linked immunosorbent assay (ELISA), and the changes in the levels of the two factors in serum at different time points before and after treatment were compared between the two groups.. After treatment, the levels of the two factors in serum in both groups were significantly increased compared with those before treatment (p<0.05), and the increase in treatment group was more significant than that in control group (p<0.05). The scores of ADL scale in both groups were significantly increased after treatment compared with those before treatment, and the increase in treatment group was more significant than that in control group (p<0.05). The scores of NIHSS in both groups were significantly decreased compared with those before treatment, and the decrease in treatment group was more significant than that in control group (p<0.05).. NBP can improve the expressions of VEGF and bFGF in serum of ACI patients, and its effect is superior to that of conventional drugs.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Benzofurans; Cerebral Infarction; Female; Fibroblast Growth Factor 2; Humans; Male; Middle Aged; Neuroprotective Agents; Stroke; Vascular Endothelial Growth Factor A; Young Adult

Dl-3-n-butylphthalide (NBP), first isolated from the seeds of celery, showed efficacy in animal models of stroke. This study was a clinical trial to assess the efficacy and safety of NBP with a continuous dose regimen among patients with acute ischemic stroke.. A randomized, double-blind, double-dummy trial enrolled 573 patients within 48 hours of onset of ischemic stroke in China. Patients were randomly assigned to receive a 14-day infusion of NBP followed by an NBP capsule, a 14-day infusion of NBP followed by aspirin, or a 14-day infusion of ozagrel followed by aspirin. The efficacy measures were Barthel index score and the modified Rankin scale (mRS) at day 90. Differences among the three groups on mRS were compared using χ(2) test of proportions (with two-sided α = 0.05) and Logistic regression analysis was conducted to take the baseline National Institutes of Health Stroke Scale (NIHSS) score into consideration.. Among the 535 subjects included in the efficacy analysis, 90-day treatment with NBP was associated with a significantly favorable outcome than 14-day treatment with ozagrel as measured by mRS (P < 0.001). No significant difference was found among the three groups on Barthel index at day 90. The rate of adverse events was similar among the three groups.. The 90-day treatment with NBP could improve outcomes at the third month after stroke. The NBP treatment (both intravenous and oral) is safe (ChiCTR-TRC-09000483).

Topics: Adult; Aged; Benzofurans; Double-Blind Method; Female; Humans; Male; Middle Aged; Stroke; Treatment Outcome

To investigate the efficacy of butylphthalide combined with edaravone in the treatment of acute ischemic stroke and the effect on serum inflammatory factors.. One hundred and sixty patients with acute ischemic stroke who attended the neurovascular intervention department of our hospital from May 2020 to June 2022 were enrolled as study subjects for prospective analysis and were equally divided into a control group and an experimental group using the random number table method, with 80 cases in each group. The control group was treated with edaravone injection, while the experimental group was treated with butylphthalide combined with edaravone. The disease was recorded to compare the efficacy, erythrocyte sedimentation rate, homocysteine, serum inflammatory factors including tumor necrosis factor-. The total effective rate of treatment in the experimental group was 90.0% (72/80), while that of the control group was 62.5% (50/80), the total effective rate of the experimental group was significantly higher than that of the control group, and the difference was statistically significant (. The treatment of acute ischemic stroke with butylphthalide combined with edaravone has positive significance in improving blood circulation regulation and serum inflammatory factor levels and is reliable and worthy of clinical promotion.

Topics: Benzofurans; Edaravone; Humans; Inflammation; Interleukin-6; Ischemic Stroke; Stroke

Topics: Benzofurans; Brain; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Stroke; Structure-Activity Relationship

Cerebral venous disorder may have a harmful effect on ischaemic stroke; however, the underlying mechanism remains to be elucidated. Although Dl-3-n-butylphthalide is a multitarget agent for antiischaemic stroke, its neuroprotective role in brain ischaemia accompanied by brain venous disturbance remains unclear. In this study, we induced cerebral venous disturbance by the occlusion of bilateral external jugular veins (EJVs) to explore the potential mechanism of the adverse effects of cerebrovenous disorders in cerebral infarction and explore the protective effect of Dl-3-n-butylphthalide on cerebral infarction accompanied through cerebral venous disturbance.. Cerebral venous disturbance was induced in Sprague-Dawley rats through the permanent occlusion of bilateral EJVs, and cerebral ischaemic stroke was induced through the permanent occlusion of the right cortical branches of the middle cerebral artery. 2,3,5-triphenyltetrazolium chloride staining, MRI, Evans blue extravasation and behavioural test were performed to evaluate infarction volume, cerebral blood flow (CBF), blood-brain barrier (BBB) integrity and neurological function. Immunofluorescence staining and western blot analysis were performed to detect loss of neuron, endothelial cells, pericytes and tight junctions.. Bilateral EJVs occlusion did not cause cerebral infarction; however, it increased the infarction volume compared with the simple middle cerebral artery occlusion (MCAO) group, accompanied by severe neuron loss, worse neurological function, lower CBF, increased EJVs pressure, exacerbated Evans blue extravasation and brain oedema, as well as attenuated angiogenesis. Dl-3-n-butylphthalide displayed a neuroprotective effect in rats with MCAO accompanied by EJVs occlusion by reducing neuron loss, accelerating CBF restoration, promoting angiogenesis and relieving BBB damage.. Bilateral EJVs occlusion did not significantly affect normal rats but aggravated brain damage in the case of ischaemic stroke. Dl-3-n-butylphthalide treatment plays a neuroprotective role in rats with MCAO accompanied by EJVs occlusion, mainly due to the promotion of CBF restoration and BBB protection.

Topics: Animals; Benzofurans; Brain Injuries; Brain Ischemia; Drainage; Endothelial Cells; Evans Blue; Infarction, Middle Cerebral Artery; Ischemic Stroke; Rats; Rats, Sprague-Dawley; Stroke

Topics: Animals; Atherosclerosis; Benzofurans; Brain Ischemia; Endothelial Cells; Mice; Neuroprotective Agents; Oxidative Stress; Rats; Stroke

For investigating an influence on butylphthalide sodium chloride injection combined with edaravone dexborneol on neurological function and serum inflammatory factor levels in sufferers having acute ischemic stroke, 120 sufferers having acute ischemic stroke from September 2020 to September 2021 are chosen for the study subjects. In line with the diverse therapies, they took part in a control group and the study group, with 60 examples in each group. The control group is treated with edaravone dexborneol, and the study group is treated with butylphthalide sodium chloride injection, based on the control group. The posttreatment curative efficacy on the two groups is recorded, and treatment of both the two groups is compared. Before and after neurological function indexes (NIHSS and mRS), inflammatory factor indexes (IL-6, CRP, and TNF-

Topics: Benzofurans; Edaravone; Humans; Interleukin-6; Ischemic Stroke; Quality of Life; Sodium Chloride; Stroke; Treatment Outcome; Tumor Necrosis Factor-alpha

To assess cerebral hemodynamic changes by transcranial doppler ultrasound in patients with acute cerebral infarction before and after treatment with butylphthalide, A total of 90 patients with acute cerebral infarction admitted to our hospital from January 2019 to January 2020 were selected and equally divided into the control group and the experimental group according to the order of admission. The control group was treated with conventional treatment, while the experimental group was additionally given butylphthalide drug treatment. The experimental group obtained better hemodynamic indexes as compared with the control group (P<0.05). The experimental group yielded a notably higher total clinical effective rate after treatment in contrast with the control group (P<0.05). After treatment, the serum indexes of the experimental group were evidently lower than those of the control group (P<0.05). After treatment, a remarkably lower NIHSS score of the experimental group than the control group was observed (P<0.05). The BI index score of the experimental group after treatment was considerably higher than that of the control group (P<0.05). After treatment, the MMSE score in the experimental group was significantly higher than it was in the control group (P<0.05). The treatment of butylphthalide in patients with acute cerebral infarction can effectively improve the clinical symptoms of the patients and the cerebral hemodynamics of the patients tested by TCD found that this treatment yields an excellent therapeutic effect and is worthy of promotion and application.

Topics: Acute Disease; Benzofurans; Brain Ischemia; Cerebral Infarction; Hemodynamics; Humans; Stroke; Ultrasonography, Doppler, Transcranial

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Ischemia; Ischemic Stroke; Magnetic Resonance Spectroscopy; Neuroprotective Agents; Rats; Stroke

The treatment of acute ischemic stroke (AIS) remains a tough challenge in clinic. Here, we report the anti-AIS activity of R- and S-FMPB generated from hybridization of ring-opened R- and S-3-N-butylphthalide (R- and S-NBP) derivatives (R- and S-APB) with 4-fluro-edaravone (4-F-Eda), respectively. S-FMPB (10 mg/kg, iv) significantly improved the neurological score and alleviated cerebral infarction and edema of rats suffered from transient middle cerebral artery occlusion (tMCAO), superior to RS- and R-FMPB, as well as better than RS-FMPB by oral administration in previous studies. Importantly, S-FMPB is more active not only than the equimolar S-APB and 4-F-Eda alone or in combination but also than the clinical drugs NBP and edaravone (Eda) in combination at the equimolar doses. Furthermore, S-FMPB showed relative stability in plasma or liver microsome of rats but could be converted into two active metabolites (S-NBP and 4-F-Eda) in rats with good pharmacokinetic properties in terms of longer half-life period (t

Topics: Animals; Benzofurans; Edaravone; Ischemic Stroke; Neuroprotective Agents; Rats; Stroke

To investigate the effect of tetramethylpyrazine hydrochloride combined with butylphthalide on serum S100B, CRP, Hcy and NIHSS score in patients with acute cerebral infarction. 80 patients with acute cerebral infarction treated in our hospital from February 2019 to February 2021 were selected for retrospective analysis, and according to different treatment methods, the patients were equally divided into control group (conventional treatment) and experimental group (tetramethylpyrazine hydrochloride and butylphthalide). After treatment, the total effective rate of patients in the experimental group was significantly higher than that in the control group (P<0.05); the levels of serum S100B, CRP and Hcy, and NHISS scores in the two groups decreased, and the experimental group was significantly lower than the control group (P<0.05); the ADL scores of the two groups increased and the experimental group witnessed higher score (P<0.05); the number of patients in the experimental group with scores of 0-2 and 5 were significantly larger than that in the control group (P<0.05). The combination of tetramethylpyrazine hydrochloride and butylphthalide emanates a promising result in the treatment of patients with ACI. It reduces serum S100B, CRP and Hcy levels, protects nerve tissue, and improves nerve function, and thus merits clinical application.

Topics: Acute Disease; Benzofurans; Brain Ischemia; Cerebral Infarction; Humans; Pyrazines; Retrospective Studies; S100 Calcium Binding Protein beta Subunit; Stroke

To investigate the effects of DL-3-N-butylphthalide (NBP) via intranasal delivery after ischaemic stroke in mice.. C57BL/6 mice were divided into three groups: sham, stroke with vehicle and stroke with NBP treatment. Ischaemic stroke was induced by permanent ligation of right middle cerebral artery with 7 min common carotid artery occlusion. NBP (100 mg/kg) or vehicle was intranasally administered at 1 hour after stroke and repeated once a day until sacrifice. Bromodeoxyuridine (BrdU) (50 mg/kg/day) was given from the third day until sacrifice. Sensorimotor function was tested during 1-21 days after stroke. Local cerebral blood flow in the ischaemic and peri-infarct regions was measured using laser Doppler flowmetry before, during and 3 days after ischaemia. Expressions of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase as well as regenerative marker BrdU in the peri-infarct region were analysed by western blotting and immunohistochemical methods.. Compared with the vehicle group, NBP treatment significantly increased the VEGF expression in the poststroke brain. Stroke mice that received NBP showed significantly less vascular damage after stroke and more new neurons and blood vessels in the peri-infarct region at 21 days after stroke. In the adhesive removal test, the sensorimotor function of stroke mice treated with NBP performed significantly better at 1, 3 and 7 days after stroke compared with vehicle controls.. Daily intranasal NBP treatment provides protective and neurogenic/angiogenic effects in the poststroke brain, accompanied with functional improvements after a focal ischaemic stroke in mice.

Topics: Animals; Benzofurans; Brain Ischemia; Ischemic Stroke; Mice; Mice, Inbred C57BL; Stroke; Vascular Endothelial Growth Factor A

Currently, ischemic stroke is the leading cause of disability and death worldwide, and the performance of corresponding drugs is often unsatisfactory owing to the complex pathological processes and the impediment of the blood-brain barrier (BBB). Here, we employed various tertiary amino groups, including different linear, cyclic, and bimolecular drug structures, to modify 3-n-butylphthalide (NBP), a natural product used for ischemic stroke treatment, which has poor bioavailability, to generate a series of six prodrugs. These prodrugs showed significantly improved solubility and cellular uptake, which were primarily driven by putative pyrilamine cationic transporters. They also displayed more efficient brain delivery in vivo, reaching as high as 21.5-fold brain accumulation increase compared with NBP, leading to much higher bioavailability and stronger therapeutic effects. The toxicity of these molecules is also lower or similar to that of unmodified NBP. We showed that the tertiary amino group-modified NBP prodrugs are effective and safe for treating ischemic stroke with significantly enhanced druggability; hence, they have potential for further clinical development.

Topics: Benzofurans; Brain; Brain Ischemia; Humans; Ischemic Stroke; Neuroprotective Agents; Prodrugs; Stroke

This study will specifically investigate the effect of butylphthalide on hemodynamics in patients with watershed stroke (WS).. We will search the following databases from their inceptions to the March 1, 2020: Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All relevant randomized controlled trials on exploring the effect of butylphthalide on hemodynamics in patients with WS will be considered for inclusion. No language limitation will be imposed to this study. All study quality will be checked using Cochrane risk of bias tool. RevMan 5.3 software will be utilized for data analysis.. This study will summarize the latest evidence to investigate the effect of butylphthalide on hemodynamics in patients with WS.. Findings from this study will provide theoretical basis of butylphthalide on hemodynamics in patients with WS for clinician and future research.. This study is carried out based on the published data, thus, no ethical approval is required. We will submit this study to a peer-reviewed journal for publication.. INPLASY 202030006.

Topics: Benzofurans; China; Hemodynamics; Humans; Meta-Analysis as Topic; Neuroprotective Agents; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Systematic Review as Topic; Treatment Outcome

Cerebral stroke occurs following ischemic and hemorrhagic lesions in the brain. Survival and recovery of stroke patients depend on the severity of the initial injury but also the therapeutic approaches applied for emergent lifesaving and continuing post-stroke management. Dl-3-n-Butylphthalide (NBP), an active compound derived from Chinese celery seeds, has shown clinical efficacy in the treatment of ischemic cerebral stroke.. In the present study we explored the therapeutic effect of NBP in a rat model of intracerebral hemorrhage (ICH), focusing on its potential role in promoting neovascularization in the perihemorrhagic zone. ICH was induced in male Sprague-Dawley rats by unilateral injection of autologous blood into the globus pallidus, with sham-operated (Sham group), vehicle-treated (ICH) and NBP-treated (at 10 and 25 mg/kg/Bid, p.o., ICH + NBP10 and ICH + NBP25, respectively) groups examined behaviorally, macroscopically, histologically and biochemically at 1, 3, 7 and 15 days (d) post operation. Rats in the ICH + NBP10 and ICH + NBP25 groups showed reduced Longa's motor scores relative to the ICH groups at the 3 and 7d time points, while the hematoma volume was comparable in the two NBP relative to the ICH groups as measured at 7d and 15d. In the perihemorrhagic zone, the numeric density of blood vessels immunolabeled by CD34, an angiogenic marker, was greater in the ICH + NBP10 and ICH + NBP25 than ICH groups, more so in the higher dosage group, at 1, 3, 7 and 15d. Levels of the vascular endothelial growth factor (VEGF) and angiopoietins-2 (Ang-2) proteins were elevated in the NBP groups relative to the sham and vehicle controls in immunoblotting of tissue lysates from the injection region.. These results suggest that NBP can alleviate neurological defects following experimentally induced local brain hemorrhage, which is associated with a potential role of this drug in promoting neovascularization surrounding the bleeding loci.

Topics: Animals; Benzofurans; Brain; Cerebral Hemorrhage; Disease Models, Animal; Male; Nervous System Diseases; Rats, Sprague-Dawley; Stroke; Vascular Endothelial Growth Factor A

3-

Topics: Animals; Apium; Asthma; Benzofurans; Brain Ischemia; Humans; Neuroprotective Agents; Seeds; Stereoisomerism; Stroke

To evaluate the effect of dl-3-N-butylphthalide (NBP) on new cerebral microbleeds (CMBs) in patients with acute ischemic stroke (AIS).. We will prospectively enroll patients with AIS admitted to the stroke center of Jingjiang People's Hospital. Qualified participants will be randomly assigned to either the NBP group (NBP injection) or the control group (NBP injection placebo) in a ratio of 1:1. Patients will complete the brain magnetic resonance imaging within 48 hours and 14 days after stroke onset to observe the CMBs through susceptibility weighted imaging, and evaluate whether the use of NBP will affect the new CMBs in AIS patients. SPSS 20.0 will be used for statistical analyses.. We will provide practical and targeted results assessing the safety of NBP for AIS patients, to provide reference for clinical use of NBP.. The stronger evidence about the effect of NBP on new CMBs in AIS patients will be provided for clinicians.

Topics: Benzofurans; Cerebral Hemorrhage; Clinical Protocols; Humans; Ischemia; Magnetic Resonance Imaging; Platelet Aggregation Inhibitors; Prospective Studies; Stroke

The lack of inclusion of comorbidities in animal models of stroke may underlie the limited development of therapy in stroke. Previous studies in mice deficient of CD36, an immune receptor, indicated its contribution to stroke-induced inflammation and injury in hyperlipidemic conditions. The current study, therefore, tested whether pharmacological inhibition of CD36 provides neuroprotection in hyperlipidemic stroke. The hyperlipidemic mice subjected to stroke showed an exacerbation of infarct size and profound brain swelling. However, post-stroke treatment with CD36 inhibitors did not reduce, and in some cases worsened, acute stroke outcome, suggesting potential benefits of elevated CD36 in the post-stroke brain in a hyperlipidemic condition. On the other hand, chronic treatment of a CD36 inhibitor prior to stroke significantly reduced stroke-induced brain swelling. There was a trend toward infarct reduction, although it did not reach statistical significance. The observed benefit of preventative CD36 inhibition is in line with previously reported smaller infarct volume and swelling in CD36 KO mice. Thus, the current findings suggest that insights gained from the genetic models should be carefully considered before the implementation of pharmacological interventions, as a potential therapeutic strategy may depend on preventative treatment or a post-stroke acute treatment paradigm.

Topics: Animals; Apolipoproteins E; Benzofurans; Brain Edema; CD36 Antigens; Disease Models, Animal; Drug Administration Schedule; Drugs, Chinese Herbal; Hyperlipidemias; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Protective Agents; Stroke

Remyelination has been widely noticed as an important repair mechanism triggered after a stroke-induced white matter injury, but it often fails due to the lack of recruitment of the oligodendrocyte progenitor cells (OPCs) to the demyelinated area and the inadequate differentiation of OPCs. Racemic dl-3-n-butylphthalide (dl-NBP) has been reported to improve the functional recovery in animal models of vascular dementia, Alzheimer's disease (AD) and ischemic stroke. Dl-NBP (70 mg/kg) by oral gavage for two weeks from day 7 after a stroke was administered in the study, the treatment promoted differentiation and maturation of OPCs in perilesional white matter and enhanced the length of crossing corticospinal tract (CST) fibers into the denervated hemispheres. These effects could be linked to increased expression levels of brain-derived neurotrophic factor (BDNF) and the reduced expression of neurite outgrowth inhibitor (NogoA) in the perilesional area in dl-NBP group. However, dl-NBP did not increase the numbers of neuron/glia type 2 (NG2)-positive and oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells in the subventricular zone. Our data highlight the effects of dl-NBP in the remyelination process and reveal the therapeutic potential of this approach in cerebral ischemia.

Topics: Animals; Benzofurans; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cell Differentiation; Male; Myelin Sheath; Nogo Proteins; Oligodendrocyte Precursor Cells; Oligodendroglia; Rats; Rats, Wistar; Recovery of Function; Remyelination; Stroke; White Matter

Stroke is the third leading cause of death and disability in developing countries. The effective therapy for acute ischemic stroke is thrombolysis with recombinant tissue plasminogen activator (rt-PA) within 4.5 h of stroke onset. An effective post-ischemic neuroprotectant would extend the advantages of rt-PA, and protect against complications of thrombolysis. We previously reported that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a newly discovered ligand for high-affinity type 2 imidazoline receptor (I2R), provides neuroprotection against ischemic stroke in rats. Here we investigated the protective effects of 2-BFI in combination with delayed intravenous rt-PA after stroke induced by embolic middle cerebral artery occlusion (eMCAO) in rats. Infarct size was determined using 2,3,5-triphenyltrazolium chloride staining, while neurological deficit was assessed based on neurological score. Numbers of apoptotic cells in vivo were estimated using TUNEL stain, and expression of the pro-apoptotic protein BAX and anti-apoptotic protein BCL-2 were quantified by Western blotting. The results showed that 2-BFI (3 mg/kg) administered at 0.5 h after embolic MCAO combined with rt-PA (10 mg/kg) administered at 6 h reduced brain infarct size, mitigated neurological deficit, decreased the number of TUNEL-positive cells, down-regulated BAX expression, and up-regulated BCL-2 expression. These findings suggest that 2-BFI may extend the therapeutic window of rt-PA to 6 h after embolic stroke onset in rats.

Topics: Animals; Apoptosis; Benzofurans; Brain; Disease Models, Animal; Drug Therapy, Combination; Embolism; Imidazoles; Male; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Stroke; Tissue Plasminogen Activator

This study examined whether the neuroprotective drug, 3-. PC12 neuronal cells were pretreated for 24 hours with NBP (10 μmol/L), then exposed to oxygen and glucose deprivation (OGD) for 8 hours as an in vitro model of ischemic stroke. Indices of anti-oxidative response, mitochondrial function and mitochondrial dynamics were evaluated.. OGD suppressed cell viability, induced apoptosis and increased caspase-3 activity. NBP significantly reversed these effects. NBP prevented oxidative damage by increasing the activity of superoxide dismutase and lowering levels of malondialdehyde (MDA) and reactive oxygen species (ROS). At the same time, it increased expression of Nrf2, HO-1 and AMPK. NBP attenuated mitochondrial dysfunction by enhancing mitochondrial membrane potential and increasing the activity of mitochondrial respiratory chain complexes I-IV and ATPase. NBP altered the balance of proteins regulating mitochondrial fusion and division.. NBP exerts neuroprotective actions by enhancing anti-oxidation and attenuating mitochondrial dysfunction. Our findings provide insight into how NBP may exert neuroprotective effects in ischemic stroke and raise the possibility that it may function similarly against other neurodegenerative diseases involving mitochondrial dysfunction.

Topics: Animals; Antioxidants; Apoptosis; Benzofurans; Brain Ischemia; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Neurons; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Signal Transduction; Stroke

Racemic l-3-n-butylphthalide (dl-NBP), is able to achieve a functional recovery in animal models of cerebral ischemia, vascular dementia, and Alzheimer's disease. In this study, we investigated the effect of dl-NBP on axonal growth, neurogenesis and behavioral performances in rats with cerebral ischemia.. Focal cerebral ischemia in rats was produced by intracerebral injection of endothelin-1. Starting from postoperative day 7, the experimental rats were administered 70mg/kg dl-NBP by oral gavage for two weeks. Biotinylated dextran amine (BDA) was injected into the contralateral sensorimotor cortex on day 14 after ischemia to trace the sprouting of corticospinal tract (CST) fibers into the denervated cervical spinal cord. The expressions of Nogo-A, Nogo-R, Rho-A, and ROCK in the perilesional cortex, the expressions of BDA, PSD-95, and vGlut1 in the denervated spinal cord, 5-bromo-20-deoxyuridine (BrdU)/DCX-positive cells in the subventricular zone (SVZ) of the injured hemisphere were detected by immunofluorescence. The rats' behavioral abilities were measured on postoperative days 30-32 in the beam-walking, cylinder and sticky label tests.. dl-NBP treatment significantly increased the number and length of crossing CST fibers, enhanced significantly the expression levels of synapse-associated proteins including PSD95 and VGlut-1 in the denervated cervical spinal cord, elevated the number of BrdU+/DCX+ cells in SVZ, and reduced markedly those of Rho-A+, ROCK+, Nogo-A+ and Nogo-R+ cells in perilesional cortex. In addition, dl-NBP improved the behavioral performance of the ischemic rats.. dl-NBP enhanced the behavioral recovery after cerebral ischemia in rats, possibly by increasing axonal growth and neurogenesis.

Topics: Animals; Benzofurans; Biotin; Brain Infarction; Dextrans; Disease Models, Animal; Disks Large Homolog 4 Protein; Doublecortin Protein; Endothelin-1; Male; Motor Activity; Neuronal Plasticity; Nogo Proteins; Nogo Receptor 1; Platelet Aggregation Inhibitors; Psychomotor Performance; Rats; Rats, Wistar; Recovery of Function; Signal Transduction; Stroke; Vesicular Glutamate Transport Protein 1

The present study investigated the effects of dl-3-n-butylphthalide on cognitive function of patients with acute ischemic stroke (AIS).. A total of 104 patients with AIS admitted between October 2012 and June 2013 were assigned to either the Treatment (standardized treatment plus dl-3-n-butylphthalide) or Control (standardized treatment alone) groups. Cognitive function was assessed by the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) and Mini-Mental State Examination (MMSE) before and 1 month after treatment, when high-sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) were also detected. A multivariate logistic regression analysis was done for explore the independent risk factors for vascular dementia (VD).. The proportion of cognitive impairment was significantly lower after treatment than before in both the Treatment (88% vs. 64%, P = 0.023) and Control (87% vs. 70%, P = 0.047) groups. Vascular dementia dropped from 30 to 10% in the Treatment (P = 0.035) and from 25.9 to 16.7% in the Control (P = 0.027) groups. Total cognitive improvement was more significant in the Treatment Group (P = 0.018); naming, memory, attention, and linguistic abilities were significantly improved (all P < 0.05). Serum Hcy and hs-CRP levels were significantly lower in the Treatment Group than in the Control Group 1 month after treatment (P < 0.05).. Dl-3-n-butylphthalide could significantly improve the cognitive function of AIS patients 1 month after stroke. Hcy was involved in the incidence of VD 1 month after AIS. However, further studies are necessary because of differences between groups at baseline.

Topics: Benzofurans; Biomarkers; Brain Ischemia; C-Reactive Protein; Cognition; Dementia, Vascular; Female; Homocysteine; Humans; Logistic Models; Male; Mental Status Schedule; Middle Aged; Multivariate Analysis; Neuroprotective Agents; Neuropsychological Tests; Nootropic Agents; Prospective Studies; Risk Factors; Stroke; Treatment Outcome

The research aim was to investigate the effects of dl-3-n-butylphthalide (NBP) on the level of circulating endothelial progenitor cells (EPCs) and clinical outcome in patients with acute ischemic stroke (AIS).. A total of 170 patients were included and randomly assigned to NBP group and control group. All patients were administrated a basic antiplatelet and lipid-lowering therapy. Among the patients, 86 received additional NBP administration for 30 days, whereas 84 received only basic therapy (the control). The level of circulating EPCs (marked with CD34(+)/CD133(+)/KDR(+)) was determined by flow cytometry at baseline and days 7, 14, and 30 after therapy. Impairment of neurological function was evaluated by the National Institutes of Health Stroke Scale (NIHSS) on days 7, 14, 30, and 90 after therapy. The association between the increased level of circulating EPCs and improvement of NIHSS score was evaluated by Pearson analysis. The clinical outcome was evaluated by modified Rankin Scale (mRS) on day 90. During the observation period, any adverse events related to drugs were reported.. The levels of circulating EPCs on days 14 and 30 were significantly higher in the NBP group than in the control group. In contrast, NIHSS score was notably lower in NBP group on day 14, 30 and day 90. Pearson correlation analysis revealed a significant association between the increased level of EPCs and improvement of NIHSS score. Also, the mRS score in the NBP group was lower on day 90. Importantly, the reported adverse events in the 2 groups were comparable.. NBP significantly increases the circulating level and improves clinical outcome in patients with AIS.

Topics: Aged; Antigens, CD; Benzofurans; Brain Ischemia; Cell Movement; Diffusion Magnetic Resonance Imaging; Endothelial Progenitor Cells; Female; Follow-Up Studies; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Retrospective Studies; Severity of Illness Index; Statistics as Topic; Stroke; Time Factors; Vascular Endothelial Growth Factor Receptor-2

To search for novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of ring-opened derivatives of NBP bearing both nitric oxide (NO) and hydrogen sulfide (H2S)-donating moieties (NO/H2S-NBP) (8a-8o) were designed, synthesized, and biologically evaluated. The most active compound 8d was more potent than NBP and the corresponding H2S-NBP 10 or NO-NBP 13 in inhibition of the ADP-induced platelet aggregation in vitro. In addition, 8d produced moderate levels of NO and H2S, which could be beneficial for improving cardiovascular and cerebral circulation. More importantly, in a rat model of transient focal cerebral ischemia, oral treatment with 8d improved neurobehavioral function, reduced the infarct brain size and brain-water content, and enhanced the levels of brain antioxidant SOD, GSH and GSH-Px but diminished the level of oxidant MDA. These protective effects of 8d against the ischemia/reperfusion (I/R)-related brain damage were greater than that of NBP, suggesting that 8d may be a promising agent for further investigation.

Topics: Animals; Antioxidants; Benzofurans; Drug Discovery; Male; Rats; Stroke

Silent information regulator 1 (SIRT1), a histone deacetylase, has been suggested to be effective in ischemic brain diseases. Salvianolic acid B (SalB) is a polyphenolic and one of the active components of Salvia miltiorrhiza Bunge. Previous studies suggested that SalB is protective against ischemic stroke. However, the role of SIRT1 in the protective effect of SalB against cerebral ischemia has not been explored. In this study, the rat brain was subjected to middle cerebral artery occlusion (MCAO). Before this surgery, rats were intraperitoneally administrated SalB with or without EX527, a specific SIRT1 inhibitor. The infarct volume, neurological score and brain water content were assessed. In addition, levels of TNF-α and IL-1β in the brain tissues were detected by commercial ELISA kits. And the expression levels of SIRT, Ac-FOXO1, Bcl-2 and Bax were detected by Western blot. The results suggested that SalB exerted a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema and increased neurological scores. SalB also exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-1β levels in the brain tissue. Moreover, SalB upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FOXO1 and Bax. These effects of SalB were abolished by EX527 treatment. In summary, our results demonstrate that SalB treatment attenuates brain injury induced by ischemic stoke via reducing apoptosis and inflammation through the activation of SIRT1 signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Benzofurans; Brain; Brain Edema; Brain Ischemia; Carbazoles; Central Nervous System Agents; Disease Models, Animal; Infarction, Middle Cerebral Artery; Inflammation; Male; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Severity of Illness Index; Sirtuin 1; Stroke; Treatment Outcome

Fourteen hybrids (10a-g, 11a-g) of 3-n-butylphthalide (NBP) and edaravone (Eda) analogues have been designed and synthesized as potential anti-ischemic stroke agents. In vitro biological studies showed that compounds 10d and 10g exhibited more potent anti-platelet aggregation than ticlopidine (Ticlid), aspirin (ASP) and NBP. Compound 10g more significantly prevented H2O2-mediated neuronal cell (PC12) death than NBP, Eda or NBP together with Eda. Meanwhile, 10g also possessed potent radical scavenging effects on hydroxyl radical (˙OH) and superoxide anion radical (˙O2(-)). Our findings may provide new insights into the development of these hybrids, like 10g, for the intervention of ischemic stroke.

Topics: Animals; Antipyrine; Benzofurans; Cell Line; Drug Design; Edaravone; Free Radical Scavengers; Humans; Hydrogen Peroxide; Neurons; Neuroprotective Agents; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Stroke

To explore the effects of modulating autophagy on neuroamyloidogenesis in an ischemic stroke model of cultured neuroblastoma 2a (N2a)/Amyloid precursor protein (APP)695 cells.. The ischemic stroke model of N2a/APP695 cells was made by 6h oxygen-glucose deprivation/12h reperfusion (OGDR). Drug administration of 3-methyladenine (3-MA), rapamycin or dl-3-n-butylphthalide (NBP) was started at the beginning of the OGDR and lasted until the end of reperfusion, in order to explore their effects on N2a/APP695 cells under OGDR conditions. Then the cells were incubated in the drug-free and full culture medium under normoxic conditions for 12h. Cell viability and injury were investigated. The key proteins of nuclear factor kappa B (NF-κB) pathway and a key component of autophagy Beclin 1 were detected by Western blotting; immunofluorescence double-staining of amyloid-β (Aβ)1-42 with Beclin 1 was performed to investigate their cellular co-localization relationship; β-secretase and γ-secretase activity assay and Aβ1-42 enzyme-linked immunosorbent assay were performed to investigate the amyloidogenesis.. The results showed that, OGDR enhanced cell injury, autophagy activity, neuroinflammation and Aβ generation in N2a/APP695 cells; down-regulating autophagy by 3-MA and NBP increased cell viability, decreased lactate dehydrogenase (LDH) production, inhibited the activation of NF-κB pathway, suppressed β- and γ-secretase activities and Aβ generation; while up-regulating autophagy by rapamycin got the opposite results; immunofluorescence double-staining results showed elevated Aβ1-42(+) signal was co-localized with Beclin 1(+) signal.. Our data suggested that down-regulating autophagy may inhibit ischemia-induced neuroamyloidogenesis via suppressing the activation of NF-κB pathway. This study might help us to find a new therapeutic strategy to prevent brain ischemic damage and depress the risk of post-stroke dementia.

Topics: Adenine; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Autophagy; Benzofurans; Brain Ischemia; Cell Survival; Mice; Neuroblastoma; Sirolimus; Stroke; Tumor Cells, Cultured

In search of novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of hybrids ((S)- and (R)-5a-f) from optically active ring-opened NBP derivative and isosorbide were synthesized for evaluating their anti-ischemic stroke activity. Compound (S)-5e displayed the strongest activity in inhibiting the adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation in vitro, with 10.0- and 8.4-fold more effectiveness than (S)-NBP, respectively. Furthermore, (S)-5e was stable in artificial gastrointestinal fluids and could penetrate the blood-brain barrier (BBB) with an appreciate lipid/water partition coefficient relative to (S)-NBP. More importantly, oral treatment with (S)-5e protected from acute thrombosis and inhibited the ischemia/reperfusion-related brain injury in animals. Our findings suggest that (S)-5e may be promising for further evaluation for the intervention of ischemic stroke.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Isosorbide; Platelet Aggregation Inhibitors; Rats; Stereoisomerism; Stroke

Topics: Benzofurans; China; Fibrinolytic Agents; Humans; Stroke

With the failure of so many pre-clinical stroke studies to translate into the clinic, there is a need to find new therapeutics to minimize the extent of cellular damage and aid in functional recovery. Domain V (DV), the c-terminal protein fragment of the vascular basement membrane component, perlecan, was recently shown to afford significant protection in multiple transient middle cerebral artery occlusion stroke models. We sought here to determine whether DV might have similar therapeutic properties in a focal photothrombosis stroke model in both young and aged mice. Young (3-month old) and aged (24-month old) mice underwent photothrombotic stroke to the motor cortex and were then treated with DV or phosphate buffered saline vehicle at different initial time points up to 7 days. Stroke volume was analyzed histologically using cresyl violet and functional recovery assessed behaviorally on both the grid-walking and cylinder tasks. In young mice, DV administration resulted in a significant decrease in infarct volume when treatment started 3 or 6 h post-stroke. In aged mice, DV administration was only protective when started 3 h post-stroke. In addition to a decrease in the area of infarction, DV treatment was effective in significantly decreasing the number of foot-faults on the grid-walking task and improving use of the stroke-affected limb in the cylinder task in both young and aged. Previously, we have shown that DV can alter the expression profile of various astroglial markers. Consistent with our previous finding, treatment groups that showed therapeutic potential in both young and aged mice also showed an elevation in glial fibrillary acidic protein (GFAP) expression in peri-infarct regions. We conclude that DV is neuroprotective and affords significant improvements in functional recovery in both young and aged mice after focal ischemia. These data also highlight a therapeutic time-window shift that is narrower in aged compared with young mice and is associated with an elevation in GFAP expression and heightened astrogliosis.

Topics: Age Factors; Animals; Benzofurans; Disease Models, Animal; Heparan Sulfate Proteoglycans; Mice; Neuroprotective Agents; Quinolines; Stroke; Treatment Outcome

Stroke is caused by vascular dysfunction and currently there are no effective therapeutics to stroke induced brain damage. In contrast to an intense emphasis on neuroprotection, relatively few studies have addressed means of vascular protection in cerebral ischemia. Here we discovered that the ligand to immidazolin receptor, 2-BFI, not only provided potent neuroprotection during middle cerebral artery occlusion in rat, which confirmed our previous reports, but also protected the integrity of the cerebral vasculature. Treatment with 2-BFI twice daily after the occlusion of the middle cerebral artery for 14 d significantly improved the neurological deficits, reduced brain infarction, and importantly, protected the cerebral vasculature as evidenced by the increased expression of an endothelial marker, von Willebrand factor, and better preservation of the cerebral vasculature, as viewed under a confocal microscope on rat brain perfused with FITC-labeled dextran. These results indicated that 2-BFI contributes to protection of neurovasculature. Understanding the molecular mechanisms could eventually lead to development of more effective therapies for stroke.

Topics: Animals; Benzofurans; Brain Ischemia; Cerebrum; Imidazoles; Imidazoline Receptors; Infarction, Middle Cerebral Artery; Ligands; Male; Middle Cerebral Artery; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; von Willebrand Factor

The aim of this study was to investigate the protective effect of dl-3-n-butylphthalide (NBP) on chronic brain injury caused by diabetes.. A group of diabetic Sprague-Dawley rats was orally treated with NBP for 6 weeks. In this study, we examined glial reactivity in hippocampus of streptozotocin (STZ)-induced diabetic rats by determining the expression of glial fibrillary acidic protein (GFAP) and CD11b. We also examined anti-apoptosis protein, vascular endothelial growth factor (VEGF) and key apoptosis enzyme, caspase-3, expression by immunohistochemistry.. We found that GFAP, CD11b, VEGF (685.1 +/- 35.5 cells/mm(2) in diabetic rats versus 320.6 +/- 21.9 cells/mm(2) in control rats, p<0.05, n=5) and VEGF(+)-caspase-3(+) (393.4 +/- 24.2 cells/mm(2) versus 135.8 +/- 12.0 cells/mm(2) in control rats, p<0.05, n=5) immunostaining increased in the hippocampus of diabetic rats; However, treatment with NBP resulted in an obvious reduction of GFAP and CD11b-immunoreactive gliocytes in hippocampus. VEGF expression was up-regulated (837.2 +/- 20.1 cells/mm(2), n=5), while the caspase-3 expression was reduced (240.0 +/- 15.1 cells/mm(2), n=5) in the NBP-treated diabetes mellitus-NBP rats.. These results suggest that diabetes causes increased glial reactivity, apoptosis and compensatory VEGF expression, and NBP may have a protective effect for diabetic brain damage through enhancing VEGF expression to inhibit caspase-3 mediated apoptosis.

Topics: Animals; Apoptosis; Benzofurans; Cerebral Arteries; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Gliosis; Hippocampus; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Up-Regulation; Vascular Endothelial Growth Factor A

The purpose of the study is to establish a model of cold-induced stroke in hypertensive rats, and to study the preventive effect of dl-3n-butylphthalide ( NBP ) on stroke. Stroke-prone renovascular hypertension(RHRSP) was created in Sprague-Dawley rats. The animals were assigned randomly to NBP, aspirin treated and vehicle control group, with administration of the medications for 7 days, and then subjected to cold treatment in an environmentally controlled chamber for 3 days to induce the occurrence of stroke. The incidence of stroke, the volume of the brain lesion, patency of the microvessels by FITC-dextran perfusion and the number of microvessels by immunohisochemical detection of vwF were investigated. Cold induced different types of stroke in RHRSP. The incidence of ischemic stroke and the volume of the infarct were decreased, and the perfused microvessels were increased with NBP pretreatment. Our data suggest that NBP prevents cold-induced ischemic stroke via improvement of cerebral microvessels.

Topics: Animals; Aspirin; Benzofurans; Brain; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Cold Temperature; Dextrans; Disease Models, Animal; Fluorescein-5-isothiocyanate; Hypertension, Renal; Male; Microcirculation; Molecular Structure; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Treatment Outcome

To study the expressions of BDNF, BDNF mRNA, NGF and NGF mRNA in the permanent focal cerebral ischemia tissues of rats. METHHODS: Healthy male Sprague-Dawley rats were taken for this study project. According to the procedure of Zea-Longa, the rat model with permanent cerebral ischemia was established by rat middle cerebral artery obstructed (MCAO) with a nylon thread, and the model rats of neurobehavioral evaluation as 1-3 grade were randomly divided into two groups: butylphthalide group (A group) and control group (B group). A group was given with 25 mg/kg butylphthalide, B group was given with edible oil, two times every day. 3 days after occlusion, all rats were sacrificed after evaluated the neurobehavioral scores, and the samples of cerebrum were obtained after in situ perfusion and fixation with 40 g/L paraformaldehyde. 5 rats in each group were taken to tetrazolium chloride (TTC) staining for macroscopic observation of cerebral infarction area, the rest samples were processed by immunohistochemistry to evaluate effects of butylphthalide on BDNF and NGF expression, hybridization in situ to evaluate effects of butylphthalide on BDNF mRNA and NGF mRNA expression. SPSS12. 0 for statistical analysis, it was P<0. 05 as having statistical significance.. Comparing to control group (B group), butylphthalide group (A group) did not have significantly pathological difference, but the grade of behavior and infarction area were apparently reduced (P<0. 05). In butylphthalide group, there was a significant expression up-regulation to BDNF, NGF, BDNF mRNA and NGF mRNA in the peripheral around infarction and cornu ammonis or hippocampus area (P<0. 05). However in the infarction area, the expressions of BDNF, NGF, BDNF mRNA and NGF mRNA had no significantly statistical difference (P> 0. 05).. Comparing to control group, butylphthalide can significantly up-regulate the expressions of BDNF and NGF in genetic transcription level, and protect from the ischemia injury.

Topics: Animals; Benzofurans; Brain-Derived Neurotrophic Factor; Cerebrum; Gene Expression Regulation; Ischemia; Male; Nerve Growth Factor; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stroke

Topics: Animals; Antioxidants; Behavior, Animal; Benzofurans; Dogs; Dopamine Antagonists; Drugs, Investigational; Humans; Mice; Neuroprotective Agents; Rats; Stroke