Dl-3-N-butylphthalide alleviates renal ischemia-reperfusion injury by down-regulating NF-κB signaling pathway and inhibiting cell pyroptosis in rat models / 器官移植

Objective To elucidate the mechanism of dl-3-N-butylphthalide (NBP) on renal ischemia-reperfusion injury (IRI) in rat models. Methods Forty SD rats were randomly divided into the sham operation group (Sham group), model group (IRI group), NF-κB inhibitor pyrrolidine dithiocarbamate group (PDTC group), low-dose NBP group (NBP-L group) and high-dose NBP group (NBP-H group), with 8 rats in each group. Serum creatinine (Scr), serum cystatin C(Cys-C), blood urea nitrogen (BUN) and serum interleukin (IL)-1β and IL-18 levels were detected in all groups. Pathological injury of renal tissues in each group was observed by Hematoxylin-eosin (HE) staining. The expression levels of inflammatory factors and nuclear factor (NF)-κB signaling pathway and cell pyroptosis-related proteins in renal tissues were measured by Western blot and immunohistochemical staining. Results Compared with the Sham group, renal tissue injury was more severe, and the levels of Scr, Cys-C, BUN and serum IL-1β and IL-18 were all up-regulated in the IRI group. Western blot showed that the relative expression levels of NOD-like receptor protein (NLRP3), Gasdermin D(GSDMD), cysteinyl aspartate specific proteinase (Caspase)-1, IL-18, IL-1β, NF-κB p65 and p-NF-κB p65 proteins were all up-regulated, and immunohistochemical staining revealed that the expression levels of NF-κB p65 and p-NF-κB p65, IL-1β, IL-18 and NLRP3 proteins were all up-regulated in the IRI group. Compared with the IRI group, renal tissue injury was alleviated, and the levels of Scr, Cys-C, BUN and serum IL-18 and IL-1β were down-regulated in the PDTC, NBP-L and NBP-H groups. Western blot showed that the expression levels of NLRP3, GSDMD, Caspase-1, IL-1β, IL-18, NF-κB p65 and p-NF-κB p65 proteins were down-regulated, and immunohistochemical staining indicated that the expression levels of NF-κB p65, p-NF-κB p65, IL-1β, IL-18 and NLRP3 proteins were down-regulated in the PDTC, NBP-L and NBP-H groups, respectively. Compared with the NBP-L group, renal tissue injury was mitigated, and the levels of Scr, Cys-C, BUN, serum IL-18 and IL-1β were all down-regulated in the NBP-H group. Western blot showed the expression levels of NLRP3, GSDMD, Caspase-1, IL-1β, IL-18, NF-κB p65 and p-NF-κB p65 proteins were down-regulated in the NBP-H group. Immunohistochemical staining indicated that the expression levels of NF-κB p65, p-NF-κB p65, IL-1β, IL-18 and NLRP3 proteins were down-regulated in the NBP-H group. Conclusions NBP may down-regulate the activity of NF-κB/NLRP3 signaling pathway and reduce the expression levels of cell pyroptosis-related proteins and inflammatory factors after renal IRI, thereby suppressing cell pyroptosis and alleviating renal IRI.

Effects of butylphthalide combined with hyperbaric oxygen therapy on post-stroke cognitive impairment / 中国基层医药

Objective:To investigate the clinical efficacy of butylphthalide combined with hyperbaric oxygen therapy on post-stroke cognitive impairment in patients with acute ischemic stroke.Methods:A total of 90 patients with post-stroke cognitive impairment who were hospitalized within 72 hours of onset in Suining County People's Hospital from December 2019 to November 2020 were included in this study. They were randomly divided into a control group and an observation group ( n = 45/group). The control group was given conventional treatment and the observation group was given butylphthalide combined with hyperbaric oxygen therapy in addition to conventional treatment. The National Institutes of Health Stroke Scale score, Montreal Cognitive Assessment score, and Activities of Daily Living score were compared between the two groups before and after treatment. Results:Before treatment, there were no significant differences in the National Institutes of Health Stroke Scale score, Montreal Cognitive Assessment score, and Activities of Daily Living score between the two groups (all P > 0.05). At 14 days and 1 month after surgery, the National Institutes of Health Stroke Scale scores in the observation group were (4.02 ± 2.18) points and (3.21 ± 2.03) points, which were significantly lower than (5.21 ± 2.24) points and (4.62 ± 2.68) points in the control group ( t =2.55, 2.81, both P < 0.05). At 1 and 3 months after treatment, the Montreal Cognitive Assessment score in the observation group were (19.79 ± 5.67) points and (23.69 ± 2.67) points, which were significantly higher than (16.88 ± 5.12) points and (19.74 ± 2.29) points in the control group ( t = 2.56, 7.53, both P < 0.05). At 1 and 3 months after treatment, Activities of Daily Living scores in the observation group were (54.85 ± 5.69) points and (74.38 ± 4.98) points, which were significantly higher than (46.78 ± 6.24) points and (63.21 ± 5.24) points in the control group ( t = 6.41, 9.76, both P < 0.05). Conclusion:Butylphthalide combined with hyperbaric oxygen therapy for the treatment of post-stroke cognitive impairment in patients with acute ischemic stroke can alleviate neurologic deficits, and improve cognitive function and the ability of daily life.

Effects of butylphthalide combined with ozagrel sodium on National Institutes of Health Stroke Scale score, activities of daily living score, and coagulation function in patients with acute cerebral infarction / 中国基层医药

Objective:To investigate the effects of butylphthalide combined with ozagrel sodium on the National Institutes of Health Stroke Scale (NIHSS) score, activities of daily living (ADL) score, and coagulation function in patients with acute cerebral infarction.Methods:Ninety-four patients with acute cerebral infarction who were admitted to Gujiao Medical Group Central Hospital from January 2019 to November 2021 were included in this study. They were randomly assigned to undergo treatment with either ozagrel sodium (control group, n = 47) or butylphthalide combined with ozagrel sodium (observation group, n = 47) for 14 consecutive days. Before and after treatment, NIHSS score, ADL score, coagulation function (thrombin time, prothrombin time, D-dimer, activated partial thrombin time), bilateral middle cerebral artery blood flow status (mean blood flow velocity (Vm), resistance index, pulsatility index), brain tissue damage factor (brain natriuretic peptide, neuron-specific enolase, S100 β protein) and the incidence of adverse drug reactions were compared between the two groups. Results:Before treatment, there were no significant differences in NIHSS and ADL scores between the two groups (both P > 0.05). After treatment, the NIHSS score was significantly lower in the observation group than that in the control group [(8.70 ± 1.62) points vs. (9.45 ± 1.2) points, t = 2.51, P < 0.05]; the ADL score was significantly higher in the observation group than that in the control group [(65.15 ± 7.41) points vs. (61.20 ± 6.32) points, t = 2.78, P < 0.05]. Before treatment, there were no significant differences in thrombin time, prothrombin time, D-dimer, and activated partial thrombin time between the two groups (all P > 0.05). After treatment, thrombin time, prothrombin time, and activated partial thrombin time were significantly higher in the observation group than those in the control group ( t = 4.34, 3.00, 2.63, all P < 0.05). After treatment, D-dimer level in the observation group was significantly lower than that in the control group ( t = 3.39, P < 0.05). Before treatment, mean blood flow velocity, resistance index, and pulsatility index were similar between the two groups (all P > 0.05). After treatment, the mean blood flow velocity in the observation group was significantly higher than that in the control group ( t = 3.23, P < 0.05). The pulsatility index and resistance index were significantly lower in the observation group than those in the control group ( t = 2.14, 3.16, both P < 0.05). Before treatment, there were no significant differences in brain natriuretic peptide, neuron-specific enolase, and S100 β protein levels between the two groups (all P > 0.05). After treatment, brain natriuretic peptide, neuron-specific enolase, and S100 β protein levels in the observation group were significantly lower than those in the control group ( t = 3.09, 2.18, 3.33, all P < 0.05). There was no significant difference in incidence of adverse reactions between the observation and control groups [6.38% (3/47) vs. 2.13% (1/47), P > 0.05]. Conclusion:Butylphthalide combined with ozagrel sodium for the treatment of acute cerebral infarction can reduce neurological dysfunction and brain tissue injury, and improve coagulation function, hemodynamic state of the middle cerebral artery, and activities of daily life, without increasing adverse reactions.

Improvement effect and mechanism of N-butylphthalide on inflammatory injury of bone marrow mesenchymal stem cells in rats / 中国药房

OBJECTIVE To study the improvement effect and possible mechanism of N-butylphthalide on inflammatory injury of bone marrow mesenchymal stem cells （BMSCs） in rats. METHODS BMSCs of rats were divided into control group， model group， N-butylphthalide low-concentration， medium-concentration and high-concentration groups （10， 20， 50 μmol/L）. BMSCs were cultured in vitro and lipopolysaccharide （the final concentration of 10 mg/L） was used to establish the inflammatory injury model. After the intervention of N-butylphthalide， the survival rate， apoptotic rate， the contents of tumor necrosis factor α （TNF- α）， interleukin 1β （IL-1β） and IL-6 in cell culture medium， the mRNA expression of nuclear factor-κB（NF-κB） p65， and the protein expressions of caspase-3， B-cell lymphoma 2 （Bcl-2）， Bcl-2 related X protein （Bax） and NF-κB p65 in cells were detected. RESULTS Compared with control group， the survival rate and protein expression of Bcl-2 were decreased significantly in model group （P＜0.05）； the apoptotic rate， contents of TNF-α， IL-1β and IL-6， the mRNA expression of NF-κB p65， and the protein expressions of caspase-3， Bax and NF-κB p65 were increased significantly （P＜0.05）. Compared with model group， above indexes were significantly reversed in all concentration groups of N-butylphthalide （P＜0.05）， in concentration-dependent manner. CONCLUSIONS N-butylphthalide can ameliorate the inflammatory injury of BMSCs induced by lipopolysaccharide， and its mechanism may be related to the inhibition of NF-κB signaling pathway.

Efficacy of dl-3-n-butylphthalide in the treatment of dysphagia after cerebral infarction in 35 patients / 中国基层医药

Objective:To investigate the therapeutic effect of dl-3-n-butylphthalide on dysphagia after cerebral infarction.Methods:Seventy acute cerebral infarction patients with dysphagia who received treatment in The First People's Hospital of Huzhou from December 2019 to December 2020 were included in this study. They were randomly assigned to receive either routine treatment combined with swallowing function training (routine treatment group, n = 35) or intravenous dl-3-n-butylphthalide, routine treatment, and swallowing function training in combination (dl-3-n-butylphthalide treatment group, n = 35). All patients received 2 weeks of treatment. Clinical efficacy and swallowing function training pre- and post-treatment were compared between the two groups. Results:Total response rate was significantly higher in the dl-3-n-butylphthalide treatment group than in the routine treatment group [100.0% (35/35) vs. 91.4% (32/35), χ2 = 1.39, P = 0.238]. Before treatment, there were no significant differences in the scores of the Water-Swallowing Test and the Standardized Swallowing Assessment between the two groups ( P = 0.898, 0.691). The scores of the Water-Swallowing Test and the Standardized Swallowing Assessment measured after treatment in the dl-3-n-butylphthalide treatment group were (0.68 ± 0.76) points and (21.60 ± 2.50) points, which were significantly lower than those in the routine treatment group [(1.15 ± 0.77) points, (27.62 ± 3.80) points, t = 2.57, 7.82, P = 0.012, < 0.001]. Conclusion:Dl-3-n-butylphthalide treatment is highly effective on dysphagia after acute cerebral infarction. It can effectively promote the recovery of a patient's swallowing function. The treatment method is worthy of clinical application.

Clinical efficacy and safety of Butylphthalide combined with Donepezil in the treatment of vascular dementia / 中华老年医学杂志

Objective:To investigate the clinical efficacy and safety of Butylphthalide combined with Donepezil in the treatment of vascular dementia.Methods:A total of 214 patients with vascular dementia admitted to our hospital from December 2018 to December 2020 were divided into control(n=107)treated with Donepezil tablets, and study group(n=107)treated with Butylphthalide capsule plus Donepezil tablets in a multicenter single-blind randomized control trial.Clinical efficacy, dementia degree, cognitive function, behavioral ability, homocysteine(Hcy), brain-derived neurotrophic factor(BDNF), glial fibrillary acidic protein(GFAP)and neuron-specific enolatase(NSE)expression were compared between the two groups before versus after 24 weeks of treatment.And their safety was also evaluated.Results:The total effective rate was statistically significantly higher in study group than in the control group(93.46% and 80.37%, χ2=8.054, P<0.05). The scores of Hasegawa Dementia Scale(HDS), mini mental state examination scale(MMSE)and blessed Behavior Scale(BBS)in the treatment group before treatment were(17.2±2.4)points, (19.0±2.2)points and(25.1±1.8)points respectively; After 24 weeks of treatment, the scores in the treatment group were(27.4±2.8)points, (26.8±1.9)points and(14.2±2.7)points respectively; Before treatment, the scores in control group were(17.4±2.0)points, (18.6±2.1)points and(25.4±1.7)points respectively; After 24 weeks of treatment, the scores in control group were(21.8±3.3)points, (22.3±1.6)points and(19.5±2.3)points respectively.Hcy, BDNF, GFAP and NSE in the treatment group before treatment were(34.5±4.3)μmol/L、(3.5±0.4)μg/L、(13.2±0.8)μg/L and(18.9±1.7)μg/L; After 24 weeks of treatment, the scores in treatment group were(15.9±2.9)μg/L respectively μmol/L、(5.3±0.3)μg/L、(9.7±0.6)μg/L and(18.9±1.7)μg/L; Before treatment, the scores in control group were(35.3±4.4)μmol/L、(3.4±0.4)μg/L、(13.1±0.9)μg/L and(19.2±1.3)μg/L; After 24 weeks of treatment, the scores in control group was(23.3±4.9)μmol/L、(4.5±0.4)μg/L、(10.8±0.7)μg/L and(14.3±2.1)μg/L respectively.Before treatment, there was no significant difference in the expression of HDS scale, MMSE score, BBS score, Hcy, BDNF, GFAP and NSE between the two groups of patients with vascular dementia( t=0.662, 1.360, 1.253, 1.345, 1.829, 0.859, 1.450, all P>0.05); After treatment 24 weeks, the ADAS-Cog score, BBS score, Hcy, GFAP and NSE expressions of the two groups of vascular dementia patients were lower than that before treatment, while the HDS scale score, MMSE score and BDNF expression were higher than that before treatment(in treatment group: t=34.746, 31.273, 36.204, 36.289, 28.610, 27.256, 37.239; in control group: t=21.339, 18.849, 20.866, 20.522, 11.795, 14.497, 20.115, all P<0.05), the differences were statistically significant; After treatment for 24 weeks, the BBS score, Hcy, GFAP and NSE expression in the treatment group were lower than in control group, while the HDS scale score, MMSE score and BDNF expression were higher than in control group( t=15.457, 11.623, 16.551, 12.342, 13.385, 18.740, 11.547, all P<0.05), the differences were statistically significant.In the control group, there were 2 cases of mild gastrointestinal reaction and 3 cases of dizziness, with the incidence of 4.67%; Slight gastrointestinal reaction occurred in 4 cases and dizziness in 5 cases in the treatment group, with an incidence of 8.41%.There was no significant difference in the incidence of adverse reactions between the two groups( χ2=1.223, P>0.05). Conclusions:Butylphthalide soft capsules combined with Donepezil hydrochloride tablets have significant clinical effects on patients with vascular dementia, effectively reduce the degree of dementia, and improve the cognitive function and behavioral ability of patients, with good security.Therefore, it is worthy of clinical promotion.

Mechanism of Huoxue Rongluo recipe in promoting angiogenesis after ischemic stroke based on correlation between miR-370-3p and JAK2/STAT3 pathway / 中国药理学通报

Aim To explore the mechanism of Huoxue Rongluo reeipe in promoting angiogenesis after ischemic stroke based on the correlation between mir-370-3p and JAK2/STAT3 pathway.Methods Hats were randomly divided into six groups.MCAO/R method was used to establish the model.After seven days of intragastrie administration,the expressions of CD31 ,vWF and vascular endothelial growth factor ( VEGF) in brain tissue were observed by immunofluorescence stai- ning; the expression of JAK2 ,p-jak2,STAT3 and p- STAT3 in brain tissue was detected by Western blot; J the expressions of JAK2,STAT3 mRNA and mir-370- 3p in brain tissue were detected by real-time PCR f RT-PCR) ; the correlation between mir-370-3p and JAK2/STAT3 pathway was analyzed by Pearson correlation ; the expressions of lncma-hl9 and mir-370-3p were detected by real-time quantitative PCR ( RT qPCR) ; the targeting relationship between lncrna-hl9 and mir-370-3p was detected by luciferase reporter assay.Results Huoxue Rongluo decoction could increase the microvessel density and average fluorescence intensity of VEGF,up-regulate JAK2 and STAT3 mR- NA,down-regulate the expression of mir-37()-3p,and promote the expressions of JAK2,p-jak2 ,STAT3 and p- STAT3.Mir-370-3p was highly negatively correlated with JAK2 and STAT3 mRNA respectively,which could be reversed by stattic,an inhibitor of STAT3 SH2 domain.Conclusions Huoxue Rongluo recipe may stimulate angiogenesis after ischemic stroke by down- regulating the expression of mir-370-3p,activating JAK2 / STAT3 pathway and promoting the expression of downstream VEGF,so as to improve the symptoms of neurolo.

Efficacy of Naoxintong capsule combined with butylphthalide injection on acute cerebral infarction and its effects on inflammatory factors, oxidative stress response and hemorheology / 中国基层医药

Objective:To investigate the effect of Naoxintong capsule combined with butylphthalide injection on inflammatory factors, oxidative stress response and hemorheology in patients with acute cerebral infarction. Methods:Eighty-six patients with acute cerebral infarction who received treatment in Zhuji Hospital of Traditional Chinese Medicine from December 2017 to December 2019 were included in this study. Thrombolysis and thrombectomy were contraindicated in these patients. They were randomly assigned to receive treatment either with butylphthalide injection (control group, n = 43) or butylphthalide injection and Naoxintong capsule (observation group, n = 43) for 2 weeks. Therapeutic effects, Barthel Index, inflammatory factors (C-reactive protein, intercellular adhesion molecule-1 and interleukin-6), oxidative stress response (malondialdehyde and superoxide dismutase) and hemorheology (whole blood viscosity at high and low shear rates, plasma viscosity and fibrinogen) were compared between the two groups. Results:Total effective rate in the observation group was significantly higher than that in the control group (93.02% vs. 72.09%, χ2 = 6.541, P < 0.05). After treatment, Barthel Index in the observation group was significantly higher than that in the control group [(61.51 ± 5.24) points vs. (50.43 ± 4.81) points, t = 10.215, P < 0.05). After treatment, serum levels of C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 in the observation group were (4.42 ± 1.03) mg/L, (84.23 ± 5.05) μg/L and (94.33 ± 10.22) μg/L, respectively, which were significantly lower than those in the control group [(8.32 ± 1.71) mg/L, (103.51 ± 6.35) μg/L, (118.92 ± 13.31) μg/L, t = 12.810, 15.583, 9.609, all P < 0.05]. After treatment, serum malondialdehyde level in the observation group was significantly lower than that in the control group [(3.76 ± 0.78) μmol/L vs. (4.94 ± 0.90) μmol/L, t = 6.497, P < 0.05]. Serum superoxide dismutase level in the observation group was significantly higher than that in the control group [(35.76 ± 2.65) U/L vs. (30.34 ± 2.11) U/L, t = 10.492, P < 0.05]. After treatment, whole blood viscosity at high and low shear rates, plasma viscosity and fibrinogen levels in the observation group were (4.10 ± 0.51) mPa · s, (9.31 ± 1.36) mPa · s, (1.24 ± 0.26) mPa · s and (2.71 ± 0.40) g/L respectively, which were significantly lower than those in the control group [(5.72 ± 0.76) mPa · s, (11.49 ± 1.59) mPa · s, (2.21 ± 0.32) mPa · s and (3.92 ± 0.54) g/L, t = 11.607, 6.832, 15.427 11.807, all P < 0.05). Conclusion:Naoxintong capsule combined with butylphthalide injection is highly effective in the treatment of acute cerebral infarction. It can reduce inflammatory reaction and improve oxidative stress response and hemorheological changes.

Analysis of serum S-100 beta protein,NSE and neurological deficits in patients with cerebral infarction and reperfusion treated with butylphthalide / 中国基层医药

Objective To investigate the effects of butylphthalide on serum S-100 beta protein,NSE and neurological deficits in patients with cerebral infarction and reperfusion.Methods From January 2016 to January 2018,104 patients with early cerebral infarction admitted to the People's Hospital of Feicheng were divided into two groups according to different treatment methods.The control group (n =52) was given routine treatment,while the observation group (n =52) was given butylphthalide treatment on the basis of the control group.The degree of neurological deficit,serum NSE and S-100 beta protein levels were compared between the two groups before and after thrombolysis.Results The NIHSS scores of the two groups before thrombolysis were (10.27 ± 1.32) points and(10.28 ± 1.30) points,respectively,the difference between the two groups was no statistically significant(t =0.038,P ＞ 0.05).The NIHSS scores of the two groups were decreased at 24h and 7d after thrombolysis,which of the observation group at 24h and 7d after thrombolysis were (8.32 ± 1.37)points and (4.25 ± 1.54)points,respectively,which were significantly lower than those of the control group [(9.24 ± 1.40) points and (9.50 ± 1.24) points],the differences were statistically significant (t =3.396,19.147,all P ＜ 0.05).The serum NSE levels of the two groups before thrombolysis were (22.56 ± 5.78) U/mL and (22.58 ± 5.77) U/mL,respectively,the difference between the two groups was no statistically significant (t =0.017,P ＞ 0.05).At 24h and 7d after thrombolysis,the serum NSE levels of the two groups were decreased.The serum NSE levels of the observation group at 24h and 7d after thrombolysis were (15.08 ± 9.35) U/mL and (13.25 ± 6.47) U/mL,respectively,which were significantly lower than those in the control group [(18.96 ± 10.14)U/mL and (16.98 ± 7.11) U/mL],the differences were statistically significant(t =2.028,2.79,all P ＜ 0.05).The serum S-100β protein levels in the two groups before thrombolysis were(1.26 ± 0.71)μg/L and (1.27 ± 0.70)μg/L,respectively,and the difference was not significant (t =0.0723,P ＞0.05).At 24h and 7d after thrombolysis,the serum S-100β protein levels were decreased in both two groups,which in the observation group were (1.13 ± 0.62) μg/L and (0.53 ± 0.48) μg/L,respectively,which were significantly lower than those in the control group [(1.40 ± 0.64) μg/L,(0.87 ± 0.32) μg/L],the differences were statistically significant (t =2.185,4.25,all P ＜ 0.05).Conclusion Butylphthalide injection for patients with cerebral infarction and reperfusion can effectively promote the recovery of neurological function,improve the levels of serum NSE and S-100 beta protein,and help patients recover as soon as possible.

Dissolution rule of Siwu Decoction by different decocting methods based on chemistry holography / 中草药

Objective: To study the content variation and chemical composition of Siwu Decoction between mixed decoction and single decoction comprehensively, and then explore variation rule of Siwu Decoction by different decocting methods based on material basis. Methods: Components of Siwu Decoction were identified by LC-MS/MS and an UPLC wavelength switching method for simultaneously determining the contents of multiple compounds in Siwu Decoction was established based on the idea of TCM chemistry holography. The mixed and single decoction samples were prepared and tested. Experimental data was compared to analyze material basis differences and variation rule of Siwu Decoction by different decocting methods. Results: A total of 72 compounds were identified and assigned, 18 compounds were quantitative detected and all of 18 analytes showed good linearity (R2 ≥ 0.999) within the test range. The relative standard deviations of the precision, repeatability and stability were not exceeding 2.0%, and the recoveries were in the range of 97%-105%. Analysis of Siwu Decoction samples showed dissolution of ligustilide, 3-n- butylphthalide, catechin, gallic acid and paeoniflorin was affected by the change of solvent volume and dissolution of aucubin, catechin, oxypaeoniflorin, paeoniflorin and acteoside were higher in mixed decoction than single decoction obviously. Compared to single decoction, the kinds of compounds in mixed decoction did not change significantly but the content showed notable variety. Conclusion: Through the study of chemistry holography, the composition and content of compounds in TCM mixed decoction and herbs single decoction can be compared and analyzed comprehensively to provide a new perspective for the study on the rule of TCM decoction and dissolution. TCM chemistry holography study may become a useful exploration of the TCM quality study.

Effects of butylphthalide on oxidative stress inflammatory pathway of cerebral ischemia-reperfusion injury in rats / 西安交通大学学报(医学版)

Objective: To observe the effects of butylphthalide on cerebral ischemia-reperfusion injury in rats. Methods: We divided 90 SD rats into sham-operation group, model group, low-dose butylphthalide group, medium-dose butylphthalide group, high-dose butylphthalide group, and ATRA group. Neurological impairment score (NDS) was used to evaluate neurological function. TTC staining was used to calculate the volume of ischemic brain tissue. The xanthine oxidase method was used to detect SOD. The thiobarbituric acid colorimetry was used to detect MDA. ELISA was used to detect IL-6 and TNF-α expressions. The Real-time PCR was used to detect HO-1 gene expression. Western blot was used to detect Nrf2 and HO-1 protein expressions. Results: In low-, medium-, and high-butylphthalide groups, the NDS; volume of ischemic brain tissue; expressions of MDA, IL-6 and TNF-α; 2-△△Ct value of HO-1; protein expressions of Nrf2 and HO-1 were lower than those in model group (P<0.05), but SOD expression was higher than that in model group (P<0.05). The NDS; volume of ischemic brain tissue; expressions of MDA, IL-6 and TNF-α; 2-△△Ct value of HO-1; protein expressions of Nrf2 and HO-1 decreased in a dose-depended manner in low-, medium-, and high-butylphthalide groups, and SOD expression was increased in a dose-depended manner (P<0.05). Conclusion: Butylphthalide can play an antioxidant role by up-regulating Nrf2/HO-1 pathway, which benefits neuroprotective function in cerebral ischemia-reperfusion rats.

Design, synthesis, and neuroprotective and anti-platelet aggregation research of 3-n-butylphthalide derivatives / 药学学报

Butylphthalide and ferulic acid exhibit excellent therapeutic effects in ischemic stroke. In this research, twelve 3-n-butylphthalide derivatives were designed by molecular hybridization strategy. The target compounds were obtained by nucleophilic substitution, reduction reaction, esterification reaction and elimination reaction, and the structure was confirmed by 1H NMR, 13C NMR and ESI-MS. All compounds were evaluated for neuroprotective activity against OGD/R-induced neurotoxicity in rat cortical neurons by MTT assay. The compounds with the best neuroprotective activity were biologically evaluated for their ability to inhibit platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP) via the Bron method．The results indicate that 7b exhibited potent neurocyte protective activity as well as prominent anti-platelet aggregation activity. Compound 7b has potential to be developed as a drug for ischemic stroke.

Advances in research on pharmacological and neuroprotective effects of traditional Chinese medicine after cerebral ischemia / 中国中药杂志

Cerebral ischemia is also known as ischemic stroke. In recent years, research on neuroprotection after ischemia has became a hot spot as stroke can result in symptoms of nerve damages such as hemiplegia, learning and memory disorders. The key factors that cause the death of cells include excitotoxicity, oxidative damage, nitrosative stress and inflammation. However, there is no effective preparation for the treatment of post-ischemic nerve defects at present, so it is urgent to find and develop effective drugs for the treatment of nerve damages after ischemia. Traditional Chinese medicine has advantages and potentials in the treatment of neurological diseases. Many scholars have carried out related researches on the active ingredients of traditional Chinese medicine and achieved some good results. In this context, the researches on the neuroprotective effects of traditional Chinese medicines such as tetramethylpyrazine, butylphthalide and total saponins of Panax notoginseng were reviewed. The author found that the neuroprotective researches of traditional Chinese medicine mostly focused on anti-apoptosis, anti-inflammatory and anti-oxidative stress, but those effects were not sounique to the nervous system. Furthermore, most ingredients of traditional Chinese medicine showed a poor water-soluble property. In view of the research status and existing problems of traditional Chinese medicine in nerve injury, the suggestions for the research and development of the potent neuroprotective agents were proposed in this study from the perspective of pharmacological mechanism research and preparation theory.

The effect of butylphthalide injection combined with interventional therapy on patients with acute anterior circulation large vessel occlusive stroke / 中华神经科杂志

Objective To investigate the effect of butylphthalide and sodium chloride injection on patients who received endovascular treatment for acute anterior circulation large vessel occlusive stroke.Methods A total of 173 patients were identified from February 2015 to December 2017 in the Department of Neurology of Jingling Hospital in this retrospective observational study.Propensity score-matching analysis was performed to balance differences in baseline characteristics between patients who received butylphthalide injection (butylphthalide group) and those who did not (control group).The modified Rankin Scale scores at 90 days were compared between the butylphthalide and control groups.Results A total of 144 patients who received endovascular treatment for acute anterior circulation large vessel occlusive stroke were finally analyzed,54 cases in the butylphthalide group and 90 cases in the control group.The proportion of good functional outcome at 90 days in the butylphthalide group was higher than that in the control group (63.0％ (34/54) vs 44.4％ (40/90);x2=4.633,P=0.031).Thirty-six pairs were matched successfully by the propensity score matching,36 patients in the butylphthalide group and 36 in the control group.There was no statistically significant difference in the 90-day functional outcome between the two groups (66.7％ (24/36) vs 44.4％ (16/36);x2=3.600,P=0.058).One hundred and fifteen patients were recanalized,47 cases in the butylphthalide group and 68 cases in the control group,and after the propensity score matching,30 pairs were analyzed.The proportion of good functional outcome at 90 days in the butylphthalide group was higher than that in the control group (73.3％ (22/30) vs 46.7％ (14/30);x2=4.444,P=0.035).Conclusion After propensity score-matching,butylphthalide and sodium chloride injection could improve 90-day functional outcome in patients with acute anterior circulation large vessel occlusive stroke and obtained recanalization by endovascular treatment while could not before propensity score-matching.

Clinical study of Xingnaojing combined with butylphthalide in treatment of vascular dementia / 中国中西医结合急救杂志

Objective To observe the clinical efficacy of Xingnaojing combined with butylphthalide in the treatment of vascular dementia (VD). Methods One hundred and twenty VD patients admitted to First People's Hospital of Tongxiang from August 1st 2014 to December 1st 2017 were enrolled, all the patients were given routine treatment according to their disease conditions, 53 cases were treated by intravenous drip of butylphthalide and sodium chloride injection (100 mL containing butylphthalide 25 mg and sodium chloride 0.9 g), 100 mL once, 2 times each day (single-use group); another 67 patients were treated with Xingnaojing 20 mL added into 200 mL glucose solution intravenous drip, once a day, on the basis of the treatment in the single-use group (combined group), and both groups were treated for 4 weeks. The changes of mini-mental state examination (MMSE) and activity of daily life (ADL) scores, clinical efficacy and adverse reactions were observed before and after treatment in the two groups. Results The MMSE and ADL scores in both groups were higher after treatment than those before treatment, and the MMSE and ADL scores in the combined group were significantly higher than those in the single-use group (MMSE scores: 26.77±1.30 vs. 25.64±2.81, ADL: 74.77±3.30 vs. 59.23±4.21, both P < 0.05); the clinical efficacy of the combined group was significantly higher than that of the single-use group [97.0% (65/67) vs. 81.1% (43/53), P < 0.05], however, there was no significant difference in the incidence of adverse reactions between the combined group and the single-use group [7.5% (5/67) vs. 7.6% (4/53), P > 0.05 ]. Conclusions After treatment of VD with the combination of Xingnaojing and butylphthalide, the cognitive function and daily living ability of the patients are improved to some extent, the combined treatment is more effective than the single application of butylphthalide, and no obvious adverse reaction occurs during the therapeutic course.

Clinical trial of nimodipine combine with butylphthalide in the treatment of patients with mild to moderate vascular cognitive impairment / 中国基层医药

Objective To evaluate the clinical efficacy and safety of nimodipine combine with butylphthalide in the treatment of patients with mild to moderate vascular cognitive impairment(VCI).Methods From January 2012 to December 2016,100 patients with mild to moderate VCI in Jinhua Municipal Central Hospital were randomly divided into control group(n =50) and treatment group(n =50) according to the random number table method.The control group received butylphthalide capsule,200 mg po tid.The treatment group received nimodipine tablets,40mg po tid,on the basis of the control group.The two groups of patients were treated for 24 weeks.Montreal cognitive assessment (MoCA),activities of daily living (ADL),serum hs-CRP,IL-6,TNF-α,clinical efficacy and adverse drug reactions were compared after treatment.Results After treatment,the scores of MoCA and ADL in the treatment group were (24.32 ± 2.87) points,(59.22 ± 6.17) points,respectively,which were significantly higher than those in the control group [(22.76 ± 2.67) points,(55.63 ± 6.3) points,t =2.814,2.870,all P ＜ 0.05].The effective rates in the treatment group and control group were 74.00％ (37/50),52.00％ (26/50),respectively,and there was statistically significant difference between the two groups (x2 =5.191,P ＜ 0.05).After treatment,the levels of hs-CRP [(189.51 ±23.27) mg/L vs.(211.51 ±25.51) mg/L],IL-6[(76.42 ±9.86) ng/L vs.(95.85 ± 10.23) ng/L],TNF-α[(0.24 ±0.08)ng/L vs.(0.32 ±0.10)ng/L] between the treatment group and the control group had statistically significant differences(t =4.505,9.670,4.417,all P ＜ 0.05).The adverse drug reactions were nausea and vomiting in 3 cases in the control group(6.00％),nausea and vomiting in 3 cases and hypotension in 1 case in the treatment group(8.00％),and there was no statistically significant difference between the two groups(P ＞0.05).Conclusion Nimodipine combined with butylphthalide in the treatment of mild to moderate VCI is effective and has high safety.

Influence of acupuncture combined butylphthalide soft capsule on cognitive function and MRI imaging in patients with vascular dementia / 心血管康复医学杂志

Objective :To explore influence of acupuncture combined butylphthalide soft capsule on cognitive function and head MRI imaging in patients with vascular dementia (VD).Methods : A total of 94 VD patients treated in our hospital were randomly and equally divided into butylphthalide group (received butylphthalide soft capsules ) and combined treatment group (received acupuncture pericardial acupoint treatment based on butylphthalide group ) ,both groups received controls of blood pressure and blood lipids ,anti—infection intervention ,and continuously treated for eight weeks .Mini—mental state ex—amination (MMSE) and clinical dementia rating scale (CDR) were used to assess cognitive function ,related head MRI in—dexes ,plasma levels of somatostatin (SS) and arginine vasopressin (AVP ) were measured.Results : Compared with bu—tylphthalide group after treatment ,there was significant rise in total effective rate (78.72% vs.93.62%) , P＝0.036 ;sig—nificant rise in MMSE score [ (19.18 ± 3.24) scores vs.(21.15 ± 4.11) scores] and significant reduction in CDR score [ (1.51 ± 0.26) scores vs.(1.37 ± 0.28) scores] , P＜0.05 both ;MRI indexes :significant reduction in width of three brain ventricles [(1.12 ± 0.13) cm vs.(1.03 ± 0.19) cm] ,and significant rise in anterior angle index [ (3.08 ± 0.96) vs. (3.54 ± 0.85)] and lateral brain ventricle body width index [ (3.19 ± 0.18) vs.(3.32 ± 0.21)] ,P＜0.05 or ＜0.01 ;sig—nificant rise in plasma levels of SS [ (133.59 ± 10.11) pg／ml vs.(139.14 ± 10.56) pg／ml] and AVP [ (35.37 ± 9.12) pg／ml vs.(40.25 ± 8.08) pg／ml] in combined treatment group , P＜0.05 or ＜0.01. There were no severe adverse reactions in either group .Conclusion : Acupuncture combined butylphthalide soft capsule can significantly improve cognitive function , plasma SS and AVP levels ,inhibit brain ventricle dilation ,promote brain function recovery in patients with vascular de—mentia ,and safety is high .

Therapeutic effect of butylphthalide on acute cerebral infarction and its influence on neurological func— tion and quality of life / 心血管康复医学杂志

Objective :To assess therapeutic effect of butylphthalide injection on acute cerebral infarction (ACI ) and its influence on neurological function and quality of life (QOL).Methods : A total of 106 ACI patients were enrolled from our hospital ,randomly and equally divided into routine treatment group and butylphthalide group (received bu—tylphthalide injection based on routine treatment ).After 14d treatment ,clinical therapeutic effect was assessed in two groups ;neurological function indexes were compared between two groups before and after treatment .Cognitive function and QOL were compared between two groups before and during follow—up .Results : Total effective rate of butylphthalide group was significantly higher than that of routine treatment group (88.68% vs.67.92%, P＝0.010).Compared with routine treatment group after 14d treatment ,there was significant reduction in score of U—nited States National Institutes of Health Stroke Score [NIHSS ,(9.47 ± 4. 24) scores vs .(6. 12 ± 3.81) scores] ,and significant rise in score of activity of daily living scale [Barthel index ,(45. 27 ± 6.78 ) scores vs .(63.19 ± 7.13 ) scores] in butylphthalide group , P＝0.001 both .Compared with routine treatment group during follow—up ,there were significant rise in scores of mini—mental state examination [MMSE ,(23.74 ± 4.82) scores vs.(27.56 ± 4.91) scores] ,Montreal Cognitive Assessment [MoCA , (24.07 ± 4. 98 ) scores vs .(27.96 ± 5.07 ) scores] and physical functioning ,social functioning ,mental health and general health dimension of the medical outcomes study 36—item short—form heath survey (SF—36) in butylphthalide group , P＝0. 001 all.Conclusion : Butylphthalide injection can significantly improve therapeutic effect ,neurological function ,cognitive function and quality of life in patients with acute cerebral infarction .

DL-3-n-butylphthalide protects the blood-brain barrier against ischemia/hypoxia injury via upregulation of tight junction proteins / 中华医学杂志(英文版)

Background@#The increased permeability of the blood-brain barrier (BBB) induced by ischemia/hypoxia is generally correlated with alteration of tight junctions (TJs). DL-3-n-butylphthalide (NBP) has been shown to exert neuroprotective effects after ischemic injury. However, few studies have assessed the correlation between NBP and TJs. This study aimed to investigate the potential effect of NBP on the TJ proteins claudin-5, zonula occludens-1 (ZO-1), and occludin during brain ischemia.@*Methods@#A chronic cerebral hypoperfusion (CCH) Sprague-Dawley rat model was established, and NBP (20, 40, or 80 mg/kg, gavage, once a day) treatment was performed for 14 days. NBP (0.1 or 1.0 μmol/L) pre-treatment was applied to an in vitro hypoxia microvascular endothelial cell model (1% O2, 24 h). BBB permeability was assessed by performing the Evans blue assay. The expressions and localization of claudin-5, ZO-1, occludin, phosphorylated/total protein kinase B (p-Akt/Akt), phosphorylated/total glycogen synthase kinase 3β (GSK-3β)/GSK-3β, and β-catenin/β-actin were evaluated by Western blotting or immunofluorescence. Reactive oxygen species (ROS) generation was measured by flow cytometry analysis. TJ ultrastructure was observed by transmission electron microscopy.@*Results@#In CCH rats, treatment with 40 and 80 mg/kg NBP decreased the Evans blue content in brain tissue (9.0 ± 0.9 μg/g vs. 12.3 ± 1.9 μg/g, P = 0.005; 6.7 ± 0.6 μg/g vs. 12.3 ± 1.9 μg/g, P < 0.01), increased the expression of claudin-5 (0.79 ± 0.08 vs. 0.41 ± 0.06, P < 0.01; 0.97 ± 0.07 vs. 0.41 ± 0.06, P < 0.01), and elevated the ZO-1 protein level (P < 0.05) in brain microvascular segments in a dose-dependent manner in comparison with the corresponding values in the model group. There was no significant difference in occludin expression (P > 0.05). In the hypoxia cell model, NBP pre-treatment improved TJ ultrastructure, decreased intracellular ROS level, and increased the expression of claudin-5 (P < 0.01) and ZO-1 (P < 0.01) in comparison with the corresponding values in the hypoxia group. NBP treatment also elevated the relative expression levels of p-Akt/Akt, p-GSK-3β/GSK-3β, and β-catenin/β-actin in comparison with the corresponding values in the hypoxia group (all P < 0.05).@*Conclusion@#NBP improves the barrier function of BBB against ischemic injury by upregulating the expression of TJ proteins, possibly by reducing oxidative stress and activating the Akt/GSK-3β/β-catenin signaling pathway.

Application and prospects of butylphthalide for the treatment of neurologic diseases / 中华医学杂志(英文版)

Objective@#The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized.@*Data sources@#Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis."@*Study selection@#Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors’ files.@*Results@#NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects.@*Conclusions@#The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.