Pinocembrin Promotes OPC Differentiation and Remyelination via the mTOR Signaling Pathway / 神经科学通报·英文版

The exacerbation of progressive multiple sclerosis (MS) is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells (OPCs). To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs, we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds. One of the most effective drugs was pinocembrin, which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival. Based on these in vitro effects, we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases. We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis (EAE) and enhanced the repair of demyelination in lysolectin-induced lesions. Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin (mTOR). Taken together, our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway, and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.

Pinocembrin Promotes OPC Differentiation and Remyelination via the mTOR Signaling Pathway / 神经科学通报·英文版

The exacerbation of progressive multiple sclerosis (MS) is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells (OPCs). To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs, we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds. One of the most effective drugs was pinocembrin, which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival. Based on these in vitro effects, we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases. We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis (EAE) and enhanced the repair of demyelination in lysolectin-induced lesions. Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin (mTOR). Taken together, our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway, and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.

Advances in safety and efficacy of intravenous thrombolytic therapy for post-stroke stroke patients based on multi-modal MRI / 中国基层医药

Wake up ischemic stroke (WUIS),also known as awakening stroke,refers to patients with no new stroke symptoms during sleep,but after waking up,the patients or witness who found the acute cerebral infarction with stroke performance.The key to the treatment of acute ischernic stroke is to effectively restore reperfusion within the time window.The original intravenous recombinant tissue-type plasminogen activator (rt-PA) thrombolytic therapy,is widely recognized as an effective treatment method of choice for 4.5h onset of acute ischemic stroke reperfusion.Because the exact onset time of WUIS is unclear and limited by current scientific and technical levels,intravenous thrombolysis may lead to an increased risk of intracranial hemorrhage.Therefore,the American Heart Association and the American Stroke Association (AHA/ASA) were included in the "Intravenous Thrombolysis".Intravenous thrombolysis is not recommended in the Standard Scientific Statement.Patients who may be suitable for thrombolytic therapy are not able to obtain thrombolytic therapy,resulting in poor clinical prognosis.In recent years,with the further development of relevant clinical research and the rapid development of imaging technology,the latest research found that multi-mode imaging examination is safe and effective for intravenous thrombolytic therapy in patients with poststroke stroke.Multi-mode imaging studies help screening patients with acute reperfusion therapy,so that part of WUIS patients will benefit from the acute reperfusion therapy.This article reviews and summarizes the literature findings of WUIS in recent years.The pathophysiological changes,clinical features and imaging changes of patients with WUIS and non-WUIS are almost unanimously.Early CT and MRI examinations can help to extend acute stroke treatment to patients with WUIS.At present,for this type of patients,there are great research progress in the formulation and implementation of clinical treatment strategies.This article will briefly summarize the research progress and treatment status of WUIS.

Construction and application of information process management system in the treatment of acute ischemic stroke / 中国脑血管病杂志

Objective To investigate the construction and application in practice of information process management system in the treatment of acute ischemic stroke (AIS).Methods From August 2017 to November 2017,the clinical data of the 597 patients with suspected stroke received green channel treatment for stroke and incorporated into the information process management system at the Cerebrovascular Disease Center,Changhai Hospital,the Second Military Mcdical University were analyzed retrospectively.The operation status and operational efficiency of each link in the AIS treatment process were evaluated.The performance assessment indicators for stroke nurses and visiting doctors were developed.The accuracy and missed diagnosis of stroke determined by the stroke nurses were calculated.The operation ability of stroke nurses was evaluated by the doctor's arrival at triage desk to establishment of intravenous access time and signing of informed consent to rt-PA bolus time,with less than 10 min as the standard.The emergency response capability of consultation physicians was evaluated by calling consultation physician to arriving at the triage desk and establishing venous channel to transport to the CT room time,with less than 5 min as the standard.The standard-reaching rate was calculated.Results A total of 597 patients were prechecked as suspected stroke.Among them,549 patients with stroke were judged by doctors,430 established venous access,443 were transported to CT room,441 completed CT scan,and 52 were treated with venous thrombolysis.In the process,the median time of patients to hospital to doctor to triage desk,doctor to triage desk to establishment of venous channel,establishment of venous channel to transportion to CT room to completion of CT scan,completion of CT scan to rt-PA bolus,patients to hospital to completion of CT scan and patients to hospital to rt-PA bolus was 3 (1,5),8 (3,16),3 (2,5),3 (2,9),9 (3,22),20(10,30) and 27 (19,55) min,respectively.The stroke nurses determined the accuracy and misdiagnosis rate of stroke were 92.0％ (549/597) and 8.4％ (50/597) respectively.The standard-reaching rate of doctor to triage desk to establishment of venous channel,signing informed consent to rt-PA bolus time were 82.1％ (353/430) and 80.8％ (42/52) respectively.The standard-reaching rates of calling consultation doctor to doctor to triage desk,establishment of venous channel to transportion to CT room time were 94.5％ (564/597) and 91.4％ (405/443) respectively.Conclusion A process management system centered on "time management" may help analyze the efficiency of various links and personnel in the AIS treatment process,and optimize the process continuously.

Effects of quality supervision and continuous improvement on early management efficiency in patients with acute ischemic stroke / 中国脑血管病杂志

Objective To analyze the effects of quality supervision and continuous improvement system on optimizing in-hospital diagnosis and treatment process in patients with acute ischemic stroke (AIS).Methods From September 2013 to May 2016,424 consecutive patients with AIS treated with intravenous thrombolysis and/or endovascular therapy in Changhai Hospital,the Second Military Medical University were enrolled retrospectively.They were analyzed according to the annual running process (the first year[from September 2013 to August 2014],the second year[from September 2014 to August 2015],and the third year[from September 2015 to May 2016]).The spend time and delay (DTN>60 min,DTP>90 min) rate of each treatment process in the first,second,and third year (time from door-to-imaging[DTI],door-to-needle[DTN],imaging-to-needle (ITN),door-to-groin puncture (DTP) and imaging-to-groin puncture (ITP) were compared.Taking the time periods (>median) of having significant differences of the spend time of the treatment processes as the dependent variables in the first,second,and third year,the influence of the years and treatment modalities on delay was observed.The difference of constituent ratio of the reasons for delay in intravenous thrombolysis and endovascular therapy (objective reasons/other reasons) in different years were analyzed.Results (1) DTIs were 23.0 (11.0,42.0) min,22.0 (10.1,39.0) min,and 13.0 (6.0,27.0) min,respectively,and DTNs were 50.0 (30.0,77.1) min,45.0 (30.0,70.2) min,and 36.0 (24.0,57.0) min,respectively in the first,second,and third year.The spending time was shortened year by year.There were significant differences among the different years (all P0.05).(2) The DTN delay rates were 33.3% (40/120),20.7% (29/140),and 8.1% (9/111),respectively in the first,second,and third year.There were significant differences among the 3 years (x2=22.111,P0.05).(4) During the three years,the delay of intravenous thrombolysis was mainly due to objective reasons.The constituent ratio of other reasons caused delay of intravenous thrombolysis was decreased year by year.There was no other reasons for delay in the third year).There was no significant difference in the constituent ratio of the delay reasons in endovascular treatment (x2=3.622,P=0.164).Conclusion Under the existing process and resource allocation,setting the DTN target time and implementing continuous quality improvement are conducive to the effective implementation of brain CT scan and continuous optimization of intravenous thrombolysis in the processes in AIS patients with the first diagnosis.

Analysis of influencing factors of the prognosis of intravenous thrombolysis combined with endovascular interventional therapy in patients with acute moderate to severe cerebral infarction / 中国脑血管病杂志

Objective To study the prognostic influencing factors for intravenous thrombolysis combined with endovascular interventional therapy in patients with acute moderate to severe cerebral infarction. Methods From September 2013 to December 2015,the clinical data of 179 patients with moderate to severe acute cerebral infarction treated with intravenous thrombolysis combined with endovascular interventional therapy at the Cerebrovascular Disease Center,Shanghai Changhai Hospital were analyzed retrospectively. They were all treated with intravenous thrombolysis combined at least 1 endovascular interventional therapy (intra-arterial thrombolysis,mechanical thrombectomy or stenting)within 4. 5 h after onset. The patients with mRS ≤2 were divided into a good prognosis group (n = 71),those with 3≤mRS≤ 6 were divided into a poor prognosis group (n = 108)according to the modified Rankin Scale (mRS) scores after 3 months of treatment. The clinical data of both groups were analyzed,including age,sex,previous history,the National Institutes of Health Stroke Scale (NIHSS)score and Alberta stroke program early CT score (ASPECTS)immediately before and after treatment. The influencing factors of prognosis were further analyzed with multivariate Logistic regression analysis. Results The rate of good prognosis was 39. 7%(71 / 179). There were significant differences in age,history of transient ischemic attack at 1 week before the disease onset,the NIHSS score,and ASPECTS score before thrombolysis (62 ± 14 years vs. 71 ± 11 years,8. 4% (6 / 71)vs. 1. 9% (2 / 108),16 ± 6 vs. 19 ± 6,and 9. 5 ± 1. 0 vs. 8. 5 ± 1. 9,respectively;all P 0. 05). There were significant differences in the NIHSS score immediately after treatment,24 h intracranial hemorrhage transformation,and intraparenchymal hemorrhage between the good prognosis group and the poor prognosis group (10 ± 3 vs. 15 ± 7,7. 0%[5 / 71]vs. 28. 7%[31 / 108],and 0 vs. 12. 0%[13 / 108];all P < 0. 01). Multivariate Logistic regression analysis showed that the age (OR,1. 047,95% CI 1. 014 -1. 081;P = 0. 005),NIHSS score immediately after treatment (OR,1. 121,95% CI 1. 050 -1. 196;P =0. 001)were the prognostic risk factors for intravenous thrombolysis combined with endovascular interven-tional therapy for moderate to severe cerebral infarction. The ASPECTS on admission (OR,0. 382,95% CI 0. 233 -0. 627;P < 0. 01)was the protective factor. Conclusions The age and the NIHSS score immediately after treatment are the prognostic risk factors for intravenous thrombolysis combined with endovascular inter-ventional therapy for moderate to severe cerebral infarction. With the increase of age and the NIHSS score after treatment,the prognosis of patients is even worse. With the increase of ASPECTS score at admission,the prognosis is better.

Numerical study of hemodynamic factors in computational fluid dynamic modeling of intracranial artery atherosclerotic stenosis / 中华神经科杂志

Objective To study the role of risk factors associated with hemodynamics in patients with intracranial artery stenosis.Methods Eighteen patients with local stenosis of middle cerebral artery were recruited in this study retrospectively.According to patients′clinical symptoms and magnetic resonance imaging findings, they were divided into the symptomatic group (n=13) and the asymptomatic group (n=5).Wall shear stress ( WSS) , oscillatory shear index ( OSI) , velocity and pressure of the stenotic artery wall were compared between the two groups after reconstructing 3-dimentional model of hemodynamics.Then related risk factors of hemodynamics were analyzed in symptomatic intracranial atherosclerotic stenosis.Results There were no statistically significant differences between the two groups in the parameters such as age, sex, degree of artery stenosis, mean arterial pressure and some medical histories of hypertension and diabetes.The results showed obvious changes of hemodynamics in local artery stenosis.The WSS(78.69(68.15,117.65) Pa vs 39.34(22.76,60.54) Pa,U=4,P=0.003), pressure of the stenotic artery wall (1 815.14(1 242.44,4 398.84) Pa vs 735.55(361.17,1 528.78) Pa,U =7,P=0.010)and velocity of the local stenosis(3.87(2.58, 4.52) m/s vs 2.31(1.38,3.12) m/s,U=12,P=0.046) in the symptomatic group were much higher than those in the asymptomatic group; however, there were no significant differences between the two groups in OSI.Conclusions Hemodynamic features do exist in local intracranial atherosclerotic stenosis.The WSS, wall pressure and velocity of the local stenosis may be vital risk factors associated with symptomatic intracranial atherosclerotic stenosis.

Effect of the changes of hospital diagnosis and treatment mode on the treatment time in patients with acute ischemic stroke / 中国脑血管病杂志

Objective To analyze the effect of the changes of hospital diagnosis and treatment mode on the treatment time in patients with acute ischemic stroke before and after the establishment of Cerebrovascular Disease Center. Methods A total of 103 consecutive patients with acute ischemic stroke admitted to the Department of Neurology,Changhai Hospital,the Second Military Medical University between June 2008 and December 2012 were enrolled retrospectively. Thirty-one of them were excluded because of incomplete medical records. Finally,72 patients were enrolled as a control group and received series diagnosis and treatment mode. A total of 210 consecutive patients with acute ischemic stroke admitted to the Cerebrovascular Disease Center,Changhai Hospital,the Second Military Medical University from September 2013 to February 2015 were enrolled retrospectively. Thirteen patients were excluded (4 patients with recurrent transient ischemic attack were treated with recombinant tissue-type plasminogen activator,9 without complete data were treated with intravenous thrombolysis),197 were enrolled as an observation group finally,and they were received series diagnosis and treatment mode. The patients of both groups were visited within 4. 5 h after onset and received rt-PA treatment. The time-consuming changes of each time period from onset-to-door,door-to-imaging,imaging-to-needle,door-to-needle,and onset-to-needle time between the control group and the observation group were compared and analyzed. Results Compared with the control group,the door-to-imaging,imaging-to-needle,door-to-needle and onset-to-needle time were significantly shorter in the observation group. There were significant difference between the 2 groups (24 ± 12 min vs. 60 ± 20 min,27 ± 12 min vs. 62 ± 31 min,51 ± 17 min vs. 122 ± 52 min,and 153 ± 69 min vs. 230 ± 81 min,all P 0. 05). Conclusion The establishment of cerebral vascular disease center and the improvement of the processes have shortened the treatment time in patients with acute ischemic stroke within time window. The time from onset-to-door is still longer,and the propaganda and education of stroke should be strengthened.

Flavonoids of puerarin versus tanshinone II A for ischemic stroke: a randomized controlled trial / 中西医结合学报

Flavonoids are widely used today in the treatment of ischemic stroke. The therapeutic effects and functions of flavonoids are, therefore, generating more and more interest.

The roles of CD40-CD40L in carotid atherosclerotic plaque stability and their correlation with matrix metalloproteinase 9 / 中华神经科杂志

Objective To investigate the expression of CD40,CD40L and MMP9 in carotid atherosclerotic plaques and evaluate their roles in carotid atherosclerotic plaque stability.Methods Carotid atherosclerotic plaques were isolated in carotid eversion endarterectomy (GEE) in 37 patients with high-grade stenosis (>70%) including 20 stroke (A group) and 17 non-stroke patients (B group).The control group included samples of normal carotid artery from 11 normal individuals,The RNA expression levels of CD40,CD40 L and MMP9 in all A,B and control groups were quantitatively detected by real-time quantification polymerase chain reaction (PCR) and the protein expression levels were detected by Western blotting analysis.The expression and distribution of CD40,CD40L and MMP9 in carotid atherosclerotic plaques were detected by immunohistochemistry staining.Then correlations between CD40-CD40L and MMP9 were statistically analyzed.Results The relative CD40 mRNA level in high-grade stenosis of A group,B group and normal control were 2.41±0.43,1.03±0.38 and 0.31±0.12,respectively,and MMP9 mRNA 6.88±1.57,1.90±0.44 and 0.39±0.12,respectively.The levels of CD40 and MMP9 mRNA in A group were significantly higher than those in B group (P=0.000),the levels of CD40 and MMP9 in B group were significantly higher than those in controls (P=0.000).There was a linear correlation between CD40 and MMP9 mRNA (r=0.929,P=0.000).However,there were no significantly difference in mRNA levels of CD40L between carotid atherosclerosis and controls.The protein expression levels of CD40,CD40L and MMP9 in A group were significantly higher than those in B group (FCD40=104.100,P=0.000;FCD40L=129.932,P=0.000;FMMP9=13.565,P=0.021) and B group higher than normal controls (FCD40=115.848,P = 0.000;FCD40L= 30.482,P=0.005;FMMP9=35.557,P=0.004).The areas of positive staining of CD40,CD40L and MMP9 in immunochemistry study in A group were significantly higher than those in B group and B group was significantly higher than controls.There were linear correlations between positive staining areas Of CD40 and CD40L,CD40 and MMP9,CD40L and MMP9 (r=0.963,0.959,0.929,P=0.000).Expressions of CD40,CD40L and MMP9 were significantly higher in the shoulder areas of the atherosclerotic plaques than in other areas.Conclusions The CD40-CD40L has an important role in the formation of carotid atherosclerosis and plaque instability,probably by up-regulating MMP9.The expression of CD40L may be regulated by post-transcriptional modification to exert biological effects.

Contents of amino acid neurotransmitters and expression of GABAA receptor subunits' mRNA in subareas of basal ganglia in unilateral rat model of Parkinson's disease / 中华神经科杂志

Objective To explore contents of amino acid neurotransmitters and expression of GABAAreceptor subunits'mRNA in subareas of basal ganglia in unilateral rat model of Parkinson's disease (PD).Methods The rat model of PD was established through right unilateral intranigral microinjection of 6-hydroxydopamine(6-OHDA)in this study.Thawed samples were taken form neostriatum(Str).globus pallidus internus(Gpi),globus pallidus externum(Gpe)and subthalamic nucleus(STN).then contents of amino acid neurotransmitters were analyzed by established high performance liquid chromatography (HPLC)-electrochemical detection methods.The subunits α1,α2,β2/3 and γ2 of GABAA receptor in Str,Gpi,Gpe and STN wre examined with Northern Enzyme linked immunosorbent assay(ELISA).Results The content of GABA in Str,Gpi,Gpe and STN of diseased side were significantly increased as compared with undiseasedside.The level of glutamic acid(Glu)in Str,Gpe and STN and contents of aspartic acid (Asp)and glycine(Gly)in STN of the diseased side were significantly increased.In Str.there was a significant decrease of mRNA expression either in the subunit α1(105.3±24.5)or in the subunit β2/3(113.7 ±15.3)of GABAA receptor in the diseased side as compared with the undiseased 8ide(186.7 ±37.2,157.4±32.4,t=5.16,3.45;P<0.01).In Gpi,there was a significant increase of mRNA expression in the subunit α1(P<0.05)and α2,β2/3(P<0.01)of GABAA receptor in lesion side.In Gpe,there was a significant decrease of mRNA expression in the subunit α2(179.1±26.8)andβ2/3(154.7 ±37.8)of GABAA receptor in the diseased side(219.3.±19.7,231.1±55.8,t=3.42,3.21:P<0.01).In STN of right unilateral 6-0HDA lesion rat.there was a significant decrease of mRNA expression both in the subunitα1,α2 and β2/3(P<0.01)of GABAA receptor and in the subunit γ2(P<0.05)of GABAA receptor in the diseased side.Conclusions Changes of amino acid neurotransmitter contents and GABAA receptor subunits'mRNA expressional level in subareas of basal ganglia may be involved in PD.