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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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6-Bromo-3-n-butylphthalide was obtained by nitration, reduction and diazotization from carboxybenzaldehyde. Twenty hybrids from substituted styrene and 6-bromo-3-n-butylphthalide were synthesized 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 mechanism of neuroprotection was investigated by Western blot analyses. The results indicated that most of these compounds had a potent neuroprotective activity (All animal experiments were approved by the Experimental Animal Ethics Committee of Anhui University of Chinese Medicine), especially 10h and 10i showed significant effects, which may play a neuroprotective role by activating the PI3K/Akt signaling pathway.
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Objective To explore the protective effect and mechanism of butylphthalide on cerebral ischemia reperfusion injury in mice.Methods The cerebral ischemia reperfusion injury model was established by middle cerebral ischemia occlusion (MCAO).Thirty mice were divided into sham group,ischemia reperfusion group(I/R group) and butylphthalide group (NBP group) with 10 in each group.Neurological defect score and brain infarction volume were detected by TTC to evaluate the treatment effects of butylphthalide.Western blot was used to detect expression of RIP,RIP3 and AIF.Immunocoprecipitation (IP) was used to detect the interaction of AIF and RIP3.Immunofluorescence(IF) was used to detect the nuclear translocation and co-localization of AIF and RIP3.Results Compared with the I/R group,NBP treatment reduced the neurological defect score (I/R:(2.60 ± 0.22),NBP:(1.90 ± 0.23),t =2.18,P＜ 0.05) and brain infarction volume(I/R:(38.32±2.22) ％,NBP:(25.23±2.70) ％,t=3.74,P＜0.01).I/R elevated the expression of RIP1 and RIP3 whereas NBP significantly inhibited the expression of these two proteins (RIP1 (I/R:0.99±0.24,NBP:0.47±0.10,t=2.71,P＜0.05);RIP3 (I/R:0.52±0.17,NBP:0.15±0.04,t=2.87,P＜0.05)).I/R and NBP had no significant effects on the expression of AIF,but the IP results showed that I/R increased the interaction between AIF and RIP3 compared with the sham group.NBP alleviated the interaction between AIF and RIP3.IF results showed that the colocalization and nuclear expression of AIF and RIP3 increased after I/R whereas NBP treatment decreased the effect induced by I/R.Conclusion Butylphthalide alleviated cerebral ischemia reperfusion injury in mice through inhibiting the cell necroptosis.The mechanisms may correlate with decreasing the expression of RIP1 and RIP3 and alleviating the interaction and nuclear translocation of AIF and RIP3.
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Objective To investigate the effects of butylphthalide combined with edaravone on cerebral hemodynamics,vascular endothelial function and cytokines in elderly patients with acute cerebral infarction.Methods From May 2017 to May 2018,82 elderly patients with acute cerebral infarction admitted to the First People's Hospital of Wenling were selected and randomly divided into two groups according to the digital table,with 41 cases in each group.The patients in the control group were treated with edaravone,while the patients in the treatment group were treated with butylphthalide on the basis of the control group.The two groups were treated for 2 weeks.The neurological deficit scale (NIHSS),cerebral hemodynamics,vascular endothelial function and cytokines were compared between the two groups before and after treatment.Results The NIHSS score of the treatment group was (18.49 ±1.87)points,which was lower than (22.17 ± 1.32)points of the control group at 2 weeks after treatment (t =10.294,P＜0.05).The mean flow velocity [(31.70 ±3.25)cm/s],vascular resistance index (0.79 ±0.12) and maximum peak flow velocity [(54.21 ± 2.65)cm/s] in the treatment group were higher than those in the control group [(26.91 ± 4.39) cm/s,(0.61 ± 0.05) and (43.76 ± 3.10) cm/s] (t =5.615,8.866,16.407,all P ＜0.05).The contents of NO [(71.27 ± 6.58) μmol/L] and eNOS [(66.37 ± 3.65) U/mL] in the treatment group were higher than those in the control group [(62.30 ±2.71) μmol/L and (57.89 ±4.08) U/mL] (t =8.071,9.919,all P ＜ 0.05).After 2 weeks of treatment,the contents of IL-6 [(27.36 ± 2.71) pg/mL],CRP [(2.87 ±0.76) mg/L] and TNF-α[(98.24 ± 10.48) ng/mL] in the treatment group were lower than those in the control group [(43.25 ±4.10) pg/mL,(4.59 ±0.91) mg/L and (160.27 ± 15.42) ng/mL] (t =20.702,9.289,21.303,all P ＜ 0.05).The total effective rate of treatment group (90.24％) was higher than that of control group (68.29％)(x2 =6.011,P ＜ 0.05).Conclusion Butylphthalide combined with edaravone can improve cerebral hemodynamics,vascular endothelial function and alleviate cellular inflammatory reaction in elderly patients with acute cerebral infarction,and the curative effect is significant,which is worthy of clinical study.
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Objective To investigate the effects of butylphthalide soft capsules on cognitive function and daily living ability in patients with Parkinson's disease dementia(PDD). Methods From January 2016 to January 2017, 90 patients with PDD in the First People's Hospital of Wenling were divided into control group and study group by random number table method,with 45 cases in each group. The patients in the two groups were treated with conventional symptomatic treatment, and the control group was treated with donepezil, the study group was treated with butylphthalide soft capsules on this basis. The treatment time was 12 weeks. The clinical efficacies of the two groups were compared. Before treatment and 12 weeks after treatment,the cognitive functions of patients were assessed by Montreal cognitive assessment scale (MoCA) and mini - mental state examination (MMSE),and the daily living abilities of patients were assessed by Barthel index scale. Results The total effective rate of the study group was 93. 33％ ,which was higher than 75. 56％ of the control group (χ2 = 5. 414,P < 0. 05). 12 weeks after treatment,the scores of MoCA and MMSE scales in the two groups were (20. 54 ±2. 53)points,(18. 95 ± 2. 63)points,(23. 53 ± 2. 87)points,(22. 53 ± 2. 62)points,respectively,which were significantly higher than those before treatment[(16. 78 ±2. 34)points,(16. 03 ± 2. 24)points,(16. 23 ± 2. 78)points,(15. 23 ± 2. 34)points](t = 2. 863,2. 735,3. 062,3. 178,all P < 0. 05),and the scores of MoCA and MMSE scales in the study group were higher than those in the control group (t = 2. 798, 2. 753,all P < 0. 05). 12 weeks after treatment,the Barthel scores of the two groups were (64. 43 ± 5. 89) points, (76. 33 ± 5. 23 ) points, respectively, which were significantly higher than those before treatment [( 59. 34 ± 4. 83)points,(58. 26 ± 6. 65)points](t = 2. 916,3. 203,all P < 0. 05),and the Barthel score in the study group was higher than that in the control group (t = 2. 835,P < 0. 05). The incidence rate of adverse reaction in the control group was 6. 67％ ,which in the study group was 8. 89％ ,there was no statistically significant difference between the two groups (χ2 = 0. 155,P > 0. 05). Conclusion Butylphthalide soft capsules can significantly improve the cognitive function and daily living ability of patients with PDD,which is suitable for clinical application and promotion.
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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(χ2=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.
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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.
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Objective:To investigate the protective effect of butylphthalide on the brain of the rats with acute ischemic stroke, and to elucidate its mechanism in the treatment of acute ischemic stroke. Methods:Forty-eight rats were randomly divided into sham operation group, model group (focal cerebral ischemia rat model) and butylphthalide group (focal cerebral ischemia rat model + butylphthalide treatment), with 16 rats in each group.The nerve symptom scores of the rats in various groups were determined, and the brain tissue was stained by HE staining; triphenyl four azole nitrogen chloride (TTC) was used to detect the percentage of cerebral infarction area; Western blotting method and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression levels of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), and nuclear transcription factor inhibiting protein kappa B alpha(IκBα), nuclear transcription factor kappa B (NF-κB) p65(NF-κB p65) protein and mRNA in the brain tissue of the rats. Results:In sham operation group, there were no infarction and neurological defect in the brain tissue. Compared with model group, the percentage of cerebral infarction area and the neurological function score of the rats in butylphthalide group were significantly decreased(P<0.01). The structure and distribution of brain tissue cells of the rats in sham operation group were intact and uniform; most of the cells in model group were necrotic, cytoplasmic rupture, nucleus rupture and condensation; a small number of brain cells in butylphthalide group were swollen and necrotic. Compared with sham operation group, the expression levels of HGF, VEGF, MMP-2, MMP-9, and NF-κB p65 protein and mRNA in the brain tissue of the rats in model group were significantly decreased (P<0.01), and the expression levels of IκBα protein and mRNA were significantly increased (P<0.01). Compared with model group, the expression levels of HGF, VEGF, MMP-2, MMP-9, and NF-κB p65 protein and mRNA in the brain tissue of the rats in butylphthalide group were significantly increased (P<0.01),and the expression levels of IκBα protein and mRNA were significantly decreased (P<0.01). Conclusion:Butylphthalide can improve the nerve function of the rats with acute ischemic stroke and reduce the area of cerebral infarction;its mechanism may be related to increasing the HGF level in the brain tissue and promoting the cerebral angiogenesis.
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Objective: To investigate the effects of butylphthalide on the hippocampal neuron apoptosis and p38 mitogen-activated protein kinase (MAPK) signaling pathway in the rats with ischemic stroke, and to elucidate the mechanism of butylphthalide in ischemic stroke. Methods: A total of 102 male rats were randomly divided into sham operation group, model group and butylphthalide group; there were 34 rats in each group. The rats in model group and butylphthalide group were used to establish the focal cerebral ischemia models with modified Zea-Longa method. The rats in butylphthalide group were treated with butylphthalide (4. 5 mg · kg-1) after modeling. The rats in sham operation group were intraperitoneally injected with the same volume of normal saline at the same time points. The morphology of neurons was observed by HE staining. The apoptosis of hippocampal neurons was observed by in situ terminal transferase labeling (TUNED staining. The expression levels of activated caspase-3 (cleaved caspase-3), B lymphocyte tumor-2 (Bel-2), Bel-2 related X protein (Bax), p38, phosphorylation-p38 (p-P38) and MAPK proteins in hippocampus tissue of the rats in various groups were determined by Western blotting method. The expression levels of cleaved caspase-3, Bax, Bcl-2, p38, and MAPK mRNA in hippocampus tissue of the rats in various groups were determined by reverse transcription-polymerase chain reaction (RT-PCR). Results: The neurons in the hippocampal CA1 area of the rats in sham operation group were well aligned and the nuclei and cell membrane were normal. In model group, the neurons in the hippocampal CA1 area were disordered, the cells were swollen and burst, and the nuclei had pyknosis. In butylphthalide group, the structure of some neurons in the hippocampal CA1 area returned to normal. Compared with sham operation group, the number of neurons in the hippocampal CA1 area of the rats in model group was significantly reduced (P<0. 01), and the apoptotic index of neurons was significantly increased (P<0. 01). Compared with model group, the number of neurons in hippocampal CA1 area of the rats in butylphthalide group was significantly increased (P<0. 01), and the apoptotic index of neurons was significantly decreased (P<0. 01). Compared with sham operation group, the expression levels of cleaved caspase-3, Bax, p-p38 and MAPK proteins in hippocampal tissue of the rats in model group were significantly increased (P<0. 01), and the expression level of Bcl-2 protein in hippocampal tissue of the rats in model group was significantly decreased (P<0. 01); compared with model group, the expression levels of cleaved caspase-3, Bax, p-p38 and MAPK proteins in hippocampus tissue of the rats in butylphthalide group were significantly decreased (P<0. 01), and the expression level of Bcl-2 protein in hippocampus tissue of the rats in butylphthalide group was significantly increased (P<0. 01). Compared with sham operation group, the expression levels of cleaved caspase-3, Bax and MAPK mRNA in hippocampus tissue of the rats in model group were significantly increased (P<0. 01), and the expression level of Bcl-2 mRNA in hippocampal tissue of the rats in model group was significantly decreased (P<0. 01); compared with model group, the expression levels of cleaved caspase-3, Bax and MAPK mRNA in hippocampus tissue of the rats in butylphthalide group were significantly decreased (P<0. 01), and the expression level of Bcl-2 mRNA in hippocampus tissue of the rats in butylphthalide group was significantly increased (P<0. 01). Conclusion: Butylphthalide can inhibit the apoptosis of hippocampal neurons in the rats with ischemic stroke by inhibiting the p38 MAPK signaling pathway in the hippocampus tissue.
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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.