ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Objective To investigate the effects of DL-3-n-Butylphthalide(NBP)on proliferation and apoptosis of 1-methyl-4-phenyl-pyridinium (MPP +)-induced SH-SY5Y cells, and mechanisms via mixed lineage kinase 3 (MLK3) signaling pathway. Methods The SH-SY5Y cells were divided into control group,MPP+group,NBP group and URMC-099 group,that cultured normally,with 1 mmol/L MPP+for 24 hours,with 10μmol/L NBP for 3 hours and then with MPP+for 24 hours,and with 200 nmol/L MLK3 inhibitor URMC-099 for 3 hours and then with MPP+for 24 hours,respectively.The morphology of SH-SY5Y cells was observed under inverted phase contrast mi-croscope and the survival rate was measured with 3-(4,5-Cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays.The apoptosis was quantified under flow cytometry with Annexin V/PI fluorescence staining,and the nuclear morphology was observed with Hoechst 33342 staining.The expression of phosphorylated protein of MLK3(p-MLK3),c-Jun N-terminal kinase(p-JNK),extra cellular regulated protein ki-nases(p-ERK1/2)were detected with Western blotting.Results Compared with the control group,the survival rate reduced and apoptosis in-creased in MPP+group(P<0.05),with the increase of p-MLK3 and p-JNK and decrease of p-ERK1/2 d(P<0.05).Compared with MPP+group,the survival rate increased and apoptosis reduced in both NBP and URMC-099 groups(P<0.05),with the decrease of p-MLK3 and p-JNK and increase of p-ERK1/2(P<0.05).Conclusion NBP can decrease the apoptosis and promote the proliferation of SH-SY5Y cells in-duced by MPP+,which may be associated with inhibiting MLK3 signaling pathway,and regulating the downstream p-JNK and p-ERK1/2.
ABSTRACT
Objective:To study the effect of 3-n-butylphthalide (NBP) on the expression of brain-derived neurotrophic factor (BDNF) in the hippocampal CA1 region of the vascular dementia (VD) rats,and to explore its protective effect on VD.Methods:Eighty healthy Wistar rats were equally and randomly assigned to sham operation group,NBP control group (sham operation + NBP injection),VD group (VD models),NBP treatment group (VD models + NBP injection) (n=20).Each group was divided into four subgroups (n =5):1,2,4,and 8 weeks after operation groups.The VD rat models were established by using permanent bilateral common carotid artery ligation.After consciousness,the rats in NBP treatment group and NBP control group were intraperitoneally injected with 5 mg · kg-1 · d-1 NBP for consecutive 7 d.The rats in VD and sham operation groups were intraperitoneally injected with 0.2 mL · d-1 saline for consecutive 7 d.At 1,2,4,and 8 weeks after operation,the rats in each group were decapitated.The brains were obtained,and then the hippoeampus tissues were isolated.The BDNF expression levels in the hippocampal CA1 region were determined using real-time quantitative PCR and immunohistochemistry methods.Results:At 2,4,and 8 weeks after s operation,the expression levels of BDNF mRNA in the hippocampus of the rats in VD group were significantly higher those in sham operation group (P＜ 0.05);at 4 and 8 weeks after operation,the expression levels of BDNF mRNA in the hippocampus of the rats in NBP treatment groups were significantly higher than that in VD group (P＜ 0.05).The immunohistochemistry results showed that the expression level of BDNF protein in the hippocampal CA1 region of the rats in VD group was higher than that in sham operation group at 4 weeks after operation (P＜ 0.05);the expression level of BDNF protein in the hippocampal CA1 region of the rats in NBP treatment group was higher than that in VD group at 8 weeks after operation (P＜0.05).Conclusion:The BDNF expression is increased in the hippocampal CA1 region of the rats with VD after the neurons were injured by ischemia.NBP can increase the BDNF expression level in the hippocampal CA1 region of the VD rats and protect the nerves.
ABSTRACT
Objective To investigate the effect of Dl-3-n-butylphthalide on acute cerebral infarction.Methods In Department of Neurology in the Fifth Hospital of Wuhan from March 2013 to June 2014,100 cases of patients with first onset of acute cerebral infarction were recruited.The participants were divided into 2 groups (control group and treatment group) randomly,with 50 participants in each group.Besides general treatment,the patients of treatment group received intravenous injection of Dl-3-n-butylphthalide in acute phase and orally took soft capsule of Dl-3-n-butylphthalide in recovery phase.All the patients were followed up for 24 weeks.Neurological function and general cognition were assessed separately by national institute of health stroke scale (NIHSS),and mini mental state examination (MMSE) was applied to assess overall cognitive function.Results NHISS score was gradually decreased and MMSE score was increased in both groups.As compared with the control group,NIHSS score and MMSE score were changed significantly in the treatment group.From first onset to 24 weeks after treatment,NHISS score was decreased by 30％ in the control group and 44％ in the treatment group;MMSE score was increased by 17％ in the control group and 32％ in the treatment group.Conclusion Sequential therapy with Dl-3-n-butylphthalide improves neurological function and general cognition faster and more significant for patients with acute cerebral infarction.
ABSTRACT
Objective To investigate the clinical efficacy of dl-3n-butylphthalide and its effect on NT-proBNP levels and inflammatory cytokines of patients with acute cerebral infarction.Methods Total 118 patients with acute cerebral infarction in Hengshui Fifth People's Hospital were randomly divided into control group and observation group.Sixty patients in control group were treated with conventional medication,and 58 patients in observation group were treated with dl-3n-butylphthalide injection based on conventional medication.The NT-proBNP levels,score of neurological deficits (NIHSS),inflammatory cytokines including hypersensitive C-reactive protein (hs-CRP),interleukin-6 (IL-6),and tumor necrosis factor-cα (TNF-α) before and after 7 and 14 d of treatment,and adverse reaction were observed and analyzed.Results Before treatment,differences in the NT-proBNP levels,NIHSS score,hs-CRP,IL-6,and TNF-α between two groups were not obvious.After 7 and 14 d of treatment,NT-proBNP levels in observation group were significantly lower than those in control group (P ＜ 0.05).And after treatment for 14 d,NIHSS score in observation group were conspicuously lower than those in control group (P ＜ 0.05).Additionally,the levels of hs-CRP,IL-6,and TNF-α in observation group were markedly lower than those in control group (P ＜ 0.05).Conclusion D1-3n-butylphthalide injection has a good ability in inhibiting NT-proBNP levels and inflammatory cytokines,and improves the neurological function of patients with acute cerebral infarction.
ABSTRACT
Objective Isolation , purification and structure identification of phthalides from A pium graveolens L . Methods Silica gel column and preparative TLC chromatography were used to isolate and purify the phthalide compounds .The structures of those compounds were determined through spectral analysis .Results Three pure compounds were identified as 3-n-butylphthalide ,sedanenolide and sedanolide .Conclusion Three pure phthalide compounds can be used as analytical reference standard for quantitative analysis of A .graveolens .
ABSTRACT
Objective:To probe the therapeutic effects of Butylphthalide Injection in the elderly patients with acute cerebral infarction (ACI) and its influence in cerebral hemodynamics and cerebral vascular reserve (CVR),and to clarify the pharmacological action mechanism of butylphthalide in treatment of ACI.Methods:A total of 100 cases of elderly patients with ACI were selected as the subjects and divided into observation group and control group according to the serial number on admission.Fifty cases were included in each group.The patients in control group were treated with the conventional treatment, while the patients in observation group were treated with Butylphthalide Injection on the basis of the conventional treatment.The National Institute of Health Stroke Scale (NIHSS) score, the brain hemodynamics indexes of the peak velocity (Vp), the mean velocity (Vm) and the differences of the velocity (DVp, DVm) as well as pulsatility index (PI), CVR of bilateral middle cerebral artery (MCA)of the patients in two groups were observed and compared.The therapeutic effects of the patients in two groups were evaluated and compared.Results:The NIHSS score of the patients in observation group after treatment was significantly lower than that in control group (t=15.420, P<0.05).The therapeutic effects and the clinical efficiency of the patients in observation group were significantly better than those in control group (U=2.225, χ2=5.005, P<0.05).The Vp and Vm of the patients in observation group after treatment were significantly higher than those in control group(t=10.819,t=7.259, P<0.05)and the DVp and DVm were significantly lower than those in control group (t=16.438,t=19.055, P<0.05).The CVR of the patients in observation group after treatment was significantly higher than that in control group(t=6.884, P<0.05)and the PI was significantly lower than that in control group (t=4.979, P<0.05).Conclusion:Butylphthalide Injection can effectively correct the abnormality of brain hemodynamics in the ACI patients, enhance the ability of body in maintaining the stability of cerebral vascular perfusion, improve the neurological symptoms in the patients with ACI, and improve the therapeutic effects.
ABSTRACT
Objective:To study the effect of 3-n-butylphthalide (NBP) on the expression of brain-derived neurotrophic factor (BDNF) in the hippocampal CA1 region of the vascular dementia (VD) rats,and to explore its protective effect on VD.Methods:Eighty healthy Wistar rats were equally and randomly assigned to sham operation group,NBP control group (sham operation + NBP injection),VD group (VD models),NBP treatment group (VD models + NBP injection) (n=20).Each group was divided into four subgroups (n =5):1,2,4,and 8 weeks after operation groups.The VD rat models were established by using permanent bilateral common carotid artery ligation.After consciousness,the rats in NBP treatment group and NBP control group were intraperitoneally injected with 5 mg · kg-1 · d-1 NBP for consecutive 7 d.The rats in VD and sham operation groups were intraperitoneally injected with 0.2 mL · d-1 saline for consecutive 7 d.At 1,2,4,and 8 weeks after operation,the rats in each group were decapitated.The brains were obtained,and then the hippoeampus tissues were isolated.The BDNF expression levels in the hippocampal CA1 region were determined using real-time quantitative PCR and immunohistochemistry methods.Results:At 2,4,and 8 weeks after s operation,the expression levels of BDNF mRNA in the hippocampus of the rats in VD group were significantly higher those in sham operation group (P＜ 0.05);at 4 and 8 weeks after operation,the expression levels of BDNF mRNA in the hippocampus of the rats in NBP treatment groups were significantly higher than that in VD group (P＜ 0.05).The immunohistochemistry results showed that the expression level of BDNF protein in the hippocampal CA1 region of the rats in VD group was higher than that in sham operation group at 4 weeks after operation (P＜ 0.05);the expression level of BDNF protein in the hippocampal CA1 region of the rats in NBP treatment group was higher than that in VD group at 8 weeks after operation (P＜0.05).Conclusion:The BDNF expression is increased in the hippocampal CA1 region of the rats with VD after the neurons were injured by ischemia.NBP can increase the BDNF expression level in the hippocampal CA1 region of the VD rats and protect the nerves.
ABSTRACT
@#A series of hydrogen sulfide-releasing derivatives of open ring 3-n-butylphthalide(5a-5f)were designed, synthesized, and their structures were confirmed by MS and 1H NMR. The inhibitory activity of the target compounds against adenosine diphosphate(ADP)and arachidonic acid(AA)-induced platelet aggregation was evaluated in vitro by Born′s turbidimetric assay. In comparison with 3-n-butylphthalide(NBP), compound 5e possessed better antiplatelet aggregation activity. Therefore, it may be utilized as a lead compound for further investigation.
ABSTRACT
In the present study, a series of novel nitric oxide-hydrogen sulfide releasing derivatives of (S)-3-n-butylphthalide ((S)-NBP) were designed, synthesized, and evaluated as potential antiplatelet agents. Compound NOSH-NBP-5 displayed the strongest activity in inhibiting the arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation in vitro, with 3.8- and 7.0-fold more effectiveness than (S)-NBP, respectively. Furthermore, NOSH-NBP-5 could release moderate levels of NO and HS, which would be beneficial in improving cardiovascular and cerebral circulation. Moreover, NOSH-NBP-5 could release (S)-NBP when incubated with rat brain homogenate. In conclusion, these findings may provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke.
Subject(s)
Animals , Humans , Male , Rabbits , Rats , Benzofurans , Chemistry , Hydrogen Sulfide , Chemistry , Molecular Structure , Nitric Oxide , Chemistry , Platelet Aggregation , Platelet Aggregation Inhibitors , Chemistry , Pharmacology , Rats, Sprague-Dawley , Thrombosis , Drug TherapyABSTRACT
Objective To compare the oil yield of celery seeds and the contents of 3-n-butylphthalide and the total phthalocyanine lactones of celery seed oil extracted by different methods. Methods Three routine extraction methods involving organic solvent extraction, Soxhlet extraction, steam distillation extraction, as well as subcritical extraction method and supercritical fluid extraction method were used to extract the celery seed oil. The contents of 3-n-butylphthalide and total phthalocyanine lactones were respectively detected by high performance liquid chromatography(HPLC) and ultraviolet visible spectrophotometry. Results The ranges of oil yield and the contents of 3-n-butylphthalide and total phthalocyanine lactones of celery seed oil extracted by different methods were 0.30%-20.02%, 1.40%-10.13%, 4.74%-17.65%, respectively, indicating obvious differences. Conclusion With R134a and butane as the solvents, the subcritical extraction method is better than other extraction methods for the extraction of 3-n-butylphthalide. With dimethyl ether as the solvent, the subcritical extraction method is the best for the extraction of total phthalocyanine lactones.
ABSTRACT
L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single- and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 1 h, and the mean t1/2 was approximately 13.76 h. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses.
L-3-n-butilftalida (L-NMP) é um antioxidante natural, que pode ser utilizado para o tratamento do acidente isquêmico agudo e demência vascular. Este estudo avaliou segurança, tolerância e farmacocinética de comprimidos de L-NBP em chineses voluntários sadios. Este foi um estudo monocêntrico, randomizado, duplo cego, com controle por placebo e doses única e múltipla. Os indivíduos receberam dose única de comprimido de L-NBP de 80, 160, 320 ou 480 mg (n=40) e doses múltiplas de 160 mg duas vezes ao dia, por sete dias (n=12). Amostras de plasma foram analisadas com LC-MS/MS. Os parâmetros farmacocinéticos do L-NBP foram calculados utilizando análise não compartimental, com o programa WinNonlin. A análise estatística foi realizada utilizando-se o programa SPSS. Todos os eventos adversos (EAs) foram moderados e de duração limitada. EAs nesse estudo ocorreram menos frequentemente e mais moderadamente do que os EAs relacionados para cápsulas moles de DL-NBP. Não se observaram eventos adversos graves (EAG), morte ou abandono do estudo. Com dose única, atingiu-se o Cmax em cerca de 1 hora e o t1/2 médio foi de, aproximadamente, 13,76 h. A área sob a curva (ASC) e o Cmax aumentaram com o aumento da dose, mas não se observou proporcionalidade na faixa acima de 160 a 480 mg. No estudo de dose múltipla, o equilíbrio foi alcançado em três dias, com pequeno acúmulo. Em resumo, o comprimido de L-NMP foi bem tolerado em indivíduos chineses saudáveis. O acúmulo pequeno apareceu após doses repetidas.
Subject(s)
Pharmacokinetics , Administration, Oral , Tablets/administration & dosage , AntioxidantsABSTRACT
Phthaloyl dichloride (1)was reacted with LiAlSeH2 to give benzo[c]selenophene-1;3-dione (2);which was treated with the Grignard reagents to generate hydroxyl compounds 3a-3h.These compounds were finally converted to target products 4a-4h by treatment with hydriodic acid.The structures of 4a-4h were confirmed by MS and 1 H NMR.Their inhibitory activity against adenosine diphosphate (ADP)-induced platelet aggregation was evaluated by Born′s turbidimetric assay;free radical scavenging activity was assayed by xanthine oxidasemethod and 1;10-phenanthroline spectrophotometric method.It was found that compound 4 f displayed more potent inhibi-tory effect on platelet aggregation than 3-n-butylphthalide and comparable hydroxyl free radical scavenging activity in vitro to that of edaravone.Therefore;compound 4 f might be the candidate for further investigation.
ABSTRACT
Objective To observe microvascular architecture and free radical metabolism in hippocampus after focal cerebral ischemia/reperfusion and to explore the effect of NBP (3-n-butylphthalide). Methods Fifty-four SD rats were ran?domly divided into NBP pretreatment group, ischemia/reperfusion group and sham operation group (n=18 in each group). The model of middle cerebral artery occlusion(MCAO)was established by suture method. The neurological scores were counted and the volume of infarction was measured;TA-Fe method was applied to observe the microvascular architecture of hippo?campus, Mivnt image analysis system was used to analyze the microvessel density(MVD)and the microvessel area density (MVA)of hippocampus quantitatively;The activity of SOD and content of MDA were measured by colorimetric method. Re?sults Compared to the ischemia reperfusion(IR)group, the neurological scores and the volume of infarction were decreased sharply in NBP group. What′s more, the activity of SOD, MVD and MVA were all enhanced but the content of MDA and the count of closed microvessels were both reduced(P < 0.01). Conclusion NBP can improve microvascular architecture of hippocampus and reduce the free radical injury. There is a protective effect on hippocampus of rats who suffered focal cere?bral ischemia reperfusion.
ABSTRACT
Objective To investigate the effect of butylphthalide on Nrf2 signaling pathway after cerebral ischemia-reperfusion in rats and neuroprotective effect.Methods A model of middle cerebral artery ischemia-reperfusion injury in rats was induced by suture method.The rats were randomly divided into 4 groups:a sham operation,an ischemia-reperfusion,a low-dose (100 mg/kg) butylphthalide,and a high-dose (400 mg/kg) butylphthalide.Neurological deficit score was performed at 24 h after referfusion.Western blotting was used to detect the Nrf2 expression,the superoxide dismutase activity and malondialdehydecontent in the ischemic brain tissue.TUNEL assay was used to detect the nerve cell apoptosis.Immunohistochemical staining was used to detect the expression of cleaved caspase-3.Results Butylphthalide significantly upregulated the Nrf2 protein expression with a dose-dependent manner (P ＜ 0.05),increased superoxide dismutase activity (P ＜ 0.05),decreased malondialdehyde content (P ＜ 0.05),decreased numbers of cleaved caspase-3 positive cells and apoptotic cells (P ＜ 0.05).Conclusions Butylphthalide may play a significant neuroprotective effect after cerebral ischemia-reperfusion injury in rats.Its role may be associated with the upreglation of Nrf2 signaling pathway and enhancing antioxidant activity