Effects and Mechanisms of Xueshuantong on the Cognitive Function and Abnormal Neural Excitability in Mice with Alzheimer’ s Disease
-
摘要:
目的 探究血栓通[主要有效成分为三七皂苷(panax notoginseng,PNS)]对阿尔茨海默症(Alzheimer’s disease,AD)模型小鼠认知功能及神经兴奋性的影响,并探讨其潜在分子机制。 方法 用APP/PS1小鼠作为AD研究动物模型,在小鼠淀粉样蛋白尚未检测到阶段(2月龄)开始每日以60 mg/kg对血栓通组(APP/PS1+PNS)行灌胃给药,每日1次,连续给药6个月(给药至8月龄);对照组小鼠予同等体积的0.9%氯化钠(APP/PS1+vehicle)灌胃处理,同月龄野生型小鼠予0.9%氯化钠灌胃处理作为正常对照组(WT+ vehicle),每组各15只。6个月后,新物体识别实验、Morris水迷宫实验检测小鼠的认知功能;EEG脑电检测、Western blot、细胞表面生物素化试验以检测各组小鼠皮质与海马中BACE1的活性、Nav1.1α的分布、表达以及Navβ2的表达与酶解情况(Navβ2的酶解片段Navβ2 full length及Navβ2-CTF表达检测)。 结果 新物体识别实验显示,与对照组APP/PS1小鼠相比,血栓通用药后APP/PS1小鼠的辨别指数(discrimination index,DI)上升(P < 0.05);Morris水迷宫检测结果发现,血栓通灌胃6个月后小鼠在探索实验中逃避潜伏期缩短(P < 0.05),撤除平台后在目标象限停留时间增加(P < 0.05)、穿梭平台次数增加(P < 0.05);EEG脑电检测结果发现,血栓通给药后减少了APP/PS1小鼠棘波放电出现的频率(P < 0.05)。血栓通给药后显著降低了BACE1蛋白水平的表达(P < 0.05),而全长片段Navβ2的蛋白水平显著上升(P < 0.05),并纠正了Nav1.1α在神经元内外的异常分布(P < 0.05)。 结论 血栓通可以改善AD模型小鼠的学习记忆能力、纠正大脑异常兴奋性,其作用机制可能与抑制BACE1的活性从而减少Navβ2由 APP/PS1诱导的过度酶解,纠正皮质、海马神经元Nav1.1α的异常表达与分布,调节神经元的兴奋性有关。 Abstract:Objective To explore the possible effects and the underlying molecular mechanisms of xueshuantong [The main active component is panax notoginseng (PNS)] on the cognitive function and neural excitability of mice with Alzheimer’ s disease (AD). Methods The APP/PS1 mice were used as an animal model for AD research, at the stage when amyloid protein was not detected in mice (2 months of age). Mice in the xueshuantong group (APP/PS1+PNS) were administered by gavage once a day at a dose of 60 mg/kg for six months (for 8 months of age). The mice of the control group were given 0.9% sodium chloride (APP/PS1+Vehicle) intragastric treatment of the same volume, while the wild-type mice of the same age were given 0.9% sodium chloride intragastric treatment as the normal control group (WT+Vehicle) (15 mice in each group, n=15). After six months, the cognitive function of the mice was evaluated by the Novel Object Recognition (NOR) task and Morris Water Maze (MWM) test. The activity of BACE1, the distribution and expression of Nav1.1α, as well as the expression and enzymatic hydrolysis of Navβ2 (Navβ2 full-length and Navβ2-CTF fragments) in cortex and hippocampus were detected by EEG, Western blot and cell surface biotinylation assay, respectively. Results The NOR task showed that compared with the mice in the APP/PS1+Vehicle group, the Discrimination index (DI) of mice in the APP/PS1 group was significantly increased after xueshuantong administration (P < 0.05). The MWM test found that, the escape latency of the mice in the xueshuantong group was shortened followed six months in gastric administration (P < 0.05), while the stay time in the target quadrant and the number of platforms significantly increased (P < 0.05) after the removal of the platform. The results of EEG recording showed that xueshuantong reduced the frequency of spike-wave discharges in APP/PS1 mice (P < 0.05). Furthermore, xueshuantong significantly reduced the expression of BACE1 (P < 0.05). In the APP+PNS group, the expression of Navβ2 full-length was increased (P < 0.05), as well as corrected the abnormal distribution of Nav1.1α inside and outside of neurons (P<0.05). Conclusion Treatment with xueshuantong can significantly improve the learning and memory ability and correct the abnormal excitability of the brain in AD model mice. The mechanism may be related to the inhibition of BACE1 activity, the reduction of APP/PS1-induced excessive enzyme digestion of Navβ2, the correction of the abnormal expression and distribution of Nav1.1α in cortical and hippocampal neurons, as well as the subsequent regulation of neuronal excitability. -
Key words:
- Xueshuantong /
- Alzheimer’ s disease /
- Cognition /
- BACE1 /
- The enzymolysis of Navβ2 /
- The distribution of Nav1.1α
-
手足口病(hand,foot and mouth disease ,HFMD)是由多种肠道病毒引起,以婴幼儿发病为主,危害儿童健康的一类急性传染性疾病,其重症病例多由EV71型感染导致。接种EV71疫苗能减少手足口病重症患儿数量,降低其致死率、致残率。2017至2021年全国适龄儿童估算EV71疫苗累计接种率24.96%,而云南省20.58%,低于全国平均水平[1]。通过分析EV71阳性手足口病患儿疾病临床特征并结合其EV71疫苗接种情况,将有助于评估接种EV71疫苗的对重症发生的预防效果。同时,本研究结果将有助于进一步加大宣传接种EV71疫苗力度提供参考依据,对提高我国儿童健康生活质量具有一定意义。
1. 资料与方法
1.1 研究对象
2020年1月1日至2022年12月31日,在昆明市儿童医院就诊,临床确诊为“手足口病”,且粪便做肠道病毒核酸检测,检验结果通用型阳性并且EV71阳性的手足口病患儿共计131例,收集其病例临床资料及其EV71疫苗接种情况,回顾总结EV71阳性患儿临床表现并对EV71疫苗接种的预防效果进行分析。
1.2 检测方法
取患儿粪便置于密封的带螺旋盖的塑料管,塑料袋密封,4 ℃ 暂存 12 h内送达实验室,或者-20 ℃ 以下低温冷冻保存,做病原体核酸检测。所用试剂盒采用一步法实时荧光PCR技术。
1.3 统计学处理
采用SPSS 22.0软件进行统计学分析,计数资料用率(%)表示,采用χ2检验,P < 0.05为差异有统计学意义。
2. 结果
肠道病毒核酸检测结果通用型阳性并且EV71阳性手足口病的患儿共计131例,其分析结果如下。
2.1 2020至2022年EV71阳性病例检出例数
2020年阳性检出率低于2021年及2022年,两两比较后差异有统计学意义(χ2 = 136.055,P = 0.000),见表1。
表 1 2020至2022年EV71阳性手足口病患儿检出例数分布情况Table 1. Distribution detected cases of HFMD children with EV71 positive from 2020 to 2022年份 检测数(n) 阳性数(n) 阳性率(%) χ2 P 2020 6462 3 0.046 136.055 0.000* 2021 3006 77 2.562 2022 3638 51 1.402 合计 13106 131 1.000 *P < 0.05。 2.2 2020至2022年各月份EV71阳性病例检出例数
按月划分阳性检测例数分布情况,其中4~9月为高峰期,两两比较后差异有统计学意义,(χ2 = 125.705,P = 0.000),见表2。
表 2 2020~2022年各月份EV71阳性手足口病患儿检出例数分布情况Table 2. Distribution detected cases of HFMD children with EV71 positive in different months from 2020 to 2022月份 检测数
(n)阳性数
(n)阳性率
(%)χ2 P 1月 714 2 0.280 125.705 <0.001* 2月 151 1 0.662 3月 145 0 0.000 4月 267 9 3.371 5月 620 25 4.032 6月 1549 30 1.937 7月 1722 22 1.278 8月 655 9 1.374 9月 1128 16 1.418 10月 2373 11 0.464 11月 2467 4 0.162 12月 1315 2 0.152 合计 13106 131 1.000 *P < 0.05。 2.3 2020至2022年EV71阳性手足口病患儿年龄分布特点
小于1岁及大于5岁患儿阳性检出率高于1~5岁年龄段患儿。各年龄段手足口病患儿阳性检出例数两两比较,差异有统计学意义(χ2 = 8.765,P = 0.033),见表3。
表 3 2020至2022年EV71阳性手足口病患儿年龄分布情况Table 3. Age distribution of HFMD children with EV71 positive from 2020 to 2022年龄(岁) 检测数(n) 阳性数(n) 阳性率(%) χ2 P <1 824 12 1.456 8.765 0.033* 1~3 8657 77 0.889 4~5 2605 24 0.921 6~17 1020 18 1.765 合计 13106 131 1.000 *P < 0.05。 2.4 2020至2022年不同性别EV71阳性手足口病患儿分布特点
男女性EV71阳性手足口病患儿的阳性检出率差异无统计学意义,(χ2 = 1.221,P = 0.269),见表4。
表 4 2020至2022年EV71阳性手足口病患儿性别分布情况Table 4. Sex distribution of HFMD children with EV71 positive from 2020 to 2022性别 检测数(n) 阳性数(n) 阳性率(%) χ2 P 男 7827 72 0.920 1.221 0.269 女 5279 59 1.118 合计 13106 131 1.000 2.5 临床表现
2.5.1 EV71阳性手足口病患儿的临床表现及特点
临床上以“手、足及其他部位皮疹,口腔疱疹”为主诉来就诊的患儿为主,仅1例以“发热原因待查”为主诉就诊患儿。这些EV71阳性手足口病例中116例轻症,15例重症,临床表现见表5。
表 5 131例EV71阳性手足口病患儿临床表现Table 5. Clinical manifestations of 131 HFMD children with EV71 positive临床表现 阳性数(n) 发生率(%) 皮疹 130 99.237 发热 50 38.168 易惊 15 11.450 四肢抖动 10 7.634 呕吐(非喷射性) 9 6.870 嗜睡 2 1.527 心率增快 32 24.427 高血压 5 3.817 2.5.2 131例阳性患儿血液细胞常规分析
131例患儿中,有10例轻症患儿未做血液细胞常规分析,其余121例患儿均做血液细胞常规分析,结果显示白细胞升高21例;白细胞降低2例;血红蛋白降低1例;血小板降低1例;其余均正常。
2.5.3 15例重症患儿临床特征
15例重症患儿中,呼吸系统受损14例;神经系统受损13例;心血管系统损伤7例。经积极治疗,均治愈或好转出院,无死亡病例。
2.6 80例接受电话咨询是否接种EV71疫苗的患儿临床特征
80例EV71阳性手足口病患儿家长接受笔者电话咨询其患儿EV71疫苗接种情况,随后分析其临床特征。研究结果显示80例患儿中17例接种疫苗,63例未接种疫苗,见表6至表8。
表 6 EV71阳性手足口病患儿是否接种EV71疫苗的情况分析Table 6. Analysis of whether HFMD children with EV71 positive have been vaccinated with EV71 vaccine是否接种EV71疫苗 患儿人数(n) 构成比(%) 接种 17 21.250 未接种 63 78.750 合计 80 100 本研究通过分别对是否接种EV71疫苗的患儿按皮疹部位、神经系统、心血管系统等临床表现特征进行分析比较,研究结果显示其差异均无统计学意义(P = 0.939,P = 0.724,P = 1.000),见表7。
表 7 EV71阳性手足口病患儿临床表现与是否接种EV71疫苗的比较分析[n(%)]Table 7. Comparative analysis of clinical manifestations and whether EV71 vaccine is administered in HFMD children with EV71 positive [n(%)]临床表现 接种疫苗 未接种疫苗 χ2 P 皮疹部位 手皮疹 16(94.118) 56(88.889) 0.406 0.939 足皮疹 11(64.706) 40(63.492) 口皮疹 11(64.706) 47(74.603) 其他部位皮疹 1(5.882) 6(9.524) 神经系统 易惊 1(5.882) 8(12.698) 2.046 0.724 四肢抖动 1(5.882) 6(9.524) 发热 7(41.176) 21(33.333) 呕吐(非喷射性) 2(11.765) 5(7.937) 嗜睡 1(5.882) 1(1.587) 心血管系统 高血压 0(0.000) 5(7.937) 0.691 1.000 心率增快 2(11.765) 14(22.222) 本研究结果显示,EV71阳性手足口病患儿病情与是否接种EV71疫苗的差异无统计学意义(χ2 = 1.750,P = 0.333),见表8。
表 8 EV71阳性手足口病患儿病情与是否接种EV71疫苗的比较分析Table 8. Comparative analysis between clinical condition of HFMD children with EV71 positive with the vaccination of EV71 vaccine临床病情 接种(n) 未接种(n) χ2 P 轻症病例 17 57 1.750 0.333 重症病例 0 6 合计 17 63 3. 讨论
手足口病是一种儿童常见的急性肠道传染病,诊断标准参照手足口病诊疗指南(2010版)[2]。以发热和手、足、口等部位出现皮疹为主要临床表现。其发病率居儿童青少年法定传染病前列[3-4]。重症病例起病急,死亡率高,多由 EV71型导致[5]。
2020至2022年由于新型冠状病毒疫情管控需要,人员流动受限制,到昆明市儿童医院就诊患儿多为昆明地区常住人口,故本研究收集的131例患儿临床数据能体现疫情 2020至2022年昆明地区仅EV71阳性手足口病患儿的病情情况。2020年仅检出3例,考虑疫情初期人员流动严格受限,成年人居家办公为主,儿童也多在家活动,与外界几乎处于隔离状态,受感染机率极低。2021至2022年疫情管控较2020年有所松动,全市人员流动相对增加,故儿童被感染概率变大,阳性率也就增加。
发病高峰由每年4月开始至9月结束,流行时段与疫情前云南省昆明市、国内其他地区报道基本一致[6-8]。1~5岁患儿阳性检出率低于小于1岁及大于5岁的患儿;男性与女性阳性检出率差异不大,均与相关报道有差异[9-12]。
笔者收集的131例患儿中,116例轻症,15例重症。这些患儿大多数具有典型临床表现,诊断明确者占多数,但仍有少数患儿病情相对隐匿,需要结合肠道病毒核酸检测结果来明确诊断。15例重症患儿中,以高热、皮疹、呼吸系统及中枢神经系统、循环系统损害为主要临床表现,经甘露醇控制颅内压、酌情使用糖皮质激素、静脉注射免疫球蛋白、抗炎等对症支持治疗,均好转或治愈出院。值得注意,本研究结果显示是否接种EV71疫苗的患儿按皮疹部位、神经系统、心血管系统等临床表现特征进行分析比较,研究结果显示其差异均无统计学意义(P = 0.939,P = 0.724,P = 1.000),笔者推测主要原因是接种EV71疫苗后仍然感染EV71的手足口病患儿病例数过少有关,故提示笔者需要继续深入开展研究以收集更多类似患儿病例再分析以期望得到更客观研究结果。
自2017年我国开展EV71疫苗接种以来,重症手足口病病例(尤其是EV71感染的患儿)呈持续下降态势,死亡患儿也不断减少[13-14],昆明地区与之前对比也成效显著[15]。但是,在接受笔者电话咨询的80例患儿中,仅17例接种EV71疫苗(均为轻症病例),63例未接种EV71疫苗(其中有6例为重症手足口病病例),说明很多家长对该疫苗的重要性认知不足[16-17]。另外值得注意的是,虽然本研究结果显示,EV71阳性手足口病患儿病情与是否接种EV71疫苗的差异无统计学意义(χ2 = 1.750,P = 0.333),但是推测是由于本研究中收集到的接种EV71疫苗后仍然感染EV71导致手足口病患儿病例数过少有关,与此同时本研究发现未接种EV71疫苗的患儿之中出现较多重症病例,从一定程度上也能初步反映出该疫苗具有预防重症手足口病的良好效果。上述研究结果提示临床医师在未来日常诊疗工作中,要重点加强EV71疫苗的安全性、预防范围等方面的宣传,提高家长对该疫苗的知晓率,从而达到提高EV71疫苗接种率,降低手足口病患儿(尤其是重症患儿)的发病率。
-
图 1 Morris水迷宫任务显示血栓通对APP/PS1小鼠空间学习记忆变化的影响
A:各组小鼠在训练期间从第1天到第6天的逃避潜伏期;B:探针实验测试期间在目标象限所花费的时间;C:探针实验中在目标平台的穿梭次数;D:探针实验中APP/PS1小鼠的游泳路径。($ \bar x \pm s $,n=15),*P < 0.05 vs. WT+Vehicle,#P<0.05 vs. APP/PS1+PNS。
Figure 1. Morris water maze task shows the effect of xueshuantong on spatial learning and memory changes in APP/PS1 mice
图 4 血栓通改变APP/PS1小鼠中Nav1.1α的分布和Navβ2的裂解
A:各组小鼠额叶皮层和海马中BACE1、Navβ2全长、Navβ2-CTF的蛋白电泳图;B:各组小鼠额叶皮层和海马中BACE1的蛋白表达比较;C:各组小鼠额叶皮层和海马中Navβ2全长的蛋白表达比较;D:各组小鼠额叶皮层和海马中Navβ2-CTF的蛋白表达比较;E:各组小鼠额叶皮层和海马中的Nav1.1α的总量、细胞外Nav1.1α和细胞内Nav1.1α的蛋白电泳图;F:各组小鼠额叶皮层和海马中Nav1.1α总量的蛋白表达比较;G:各组小鼠额叶皮层和海马中细胞外Nav1.1α的蛋白表达比较;H:各组小鼠额叶皮层和海马中细胞外Nav1.1α的蛋白表达比较。($ \bar x \pm s $,n=15),*P<0.05 vs. WT+ Vehicle,#P<0.05 vs. APP/PS1 + PNS。
Figure 4. Xueshuantong alters Nav1.1α distribution and Navβ2 cleavage in APP/PS1 mice
-
[1] Grossberg G T, Tong G, Burke A D, et al. Present Algorithms and future treatments for Alzheimer's disease. [J] Journal of Alzheimer's Disease, 2019, 67(4): 1157-1171. [2] 王高瑞,陈姿羽,吴辉,等. 基于网络药理学和实验验证的血栓通改善缺血性脑微循环障碍作用机制研究[J]. 药学学报,2022,57(7):2077-2086. [3] Liu L,Zhang Q,Xiao S,et al. Inhibition of shear-induced platelet aggregation by xueshuantong via targeting piezo1 channel-mediated Ca2+ signaling pathway[J]. Frontiers in Pharmacology,2021,12:606245. doi: 10.3389/fphar.2021.606245 [4] Han S,Chen Y,Wang J,et al. Anti-thrombosis effects and mechanisms by xueshuantong capsule under different flow conditions[J]. Frontiers in Pharmacology,2019,10(FEB):35. doi: 10.3389/fphar.2019.00035 [5] Zhang J,Guo F,Zhou R,et al. Proteomics and transcriptome reveal the key transcription factors mediating the protection of Panax notoginseng saponins (PNS) against cerebral ischemia/reperfusion injury[J]. Phytomedicine,2021,92:153613. doi: 10.1016/j.phymed.2021.153613 [6] Peiran L,Ying L,Mingzhuo Z,et al. The development of a Panax notoginseng medicinal liquor processing technology using the response surface method and a study of its antioxidant activity and its effects on mouse melanoma B16 cells[J]. Food & Function,2017,8(11):4251-4264. [7] Han J Y,Li Q,Ma Z Z,et al. Effects and mechanisms of compound Chinese medicine and major ingredients on microcirculatory dysfunction and organ injury induced by ischemia/reperfusion[J]. Pharmacology & Therapeutics,2017,177:146-173. [8] Zhong L,Zhou X L,Liu Y S,et al. Estrogen receptor α mediates the effects of notoginsenoside R1 on endotoxin-induced inflammatory and apoptotic responses in H9c2 cardiomyocytes[J]. Molecular Medicine Reports,2015,12(1):119-126. doi: 10.3892/mmr.2015.3394 [9] Lee C Y,Hsieh S L,Hsieh S,et al. Inhibition of human colorectal cancer metastasis by notoginsenoside R1,an important compound from Panax notoginseng[J]. Oncol Rep,2017,37(1):399-407. doi: 10.3892/or.2016.5222 [10] Li W,Wu Y,Wan M,et al. Simultaneous determination of three saponins in human plasma after oral administration of compound danshen dripping pills by LC-MS/MS and its application in a pharmacokinetic study[J]. J Pharm Biomed Anal,2019,169:254-259. doi: 10.1016/j.jpba.2019.03.008 [11] Jian W,Yu S,Tang M,et al. A combination of the main constituents of Fufang Xueshuantong Capsules shows protective effects against streptozotocin-induced retinal lesions in rats[J]. Journal of Ethnopharmacology,2016,182:50-56. doi: 10.1016/j.jep.2015.11.021 [12] Gao L,Zhao H,Liu Q,et al. Improvement of hematoma absorption and neurological function in patients with acute intracerebral hemorrhage treated with Xueshuantong[J]. Journal of the Neurological Sciences,2012,323(1-2):236-240. doi: 10.1016/j.jns.2012.09.028 [13] Li Z,Li H,Zhao C H,et al. Protective effect of notoginsenoside R1 on an APP/PS1 mouse model of Alzheimer & aposs disease by up-regulating insulin degrading enzyme and inhibiting Aβ accumulation[J]. CNS & Neurological Disorders-Drug Targets,2015,14(3):360-369. [14] Huang J L,Xin J,Xin T,et al. Neuroprotective properties of panax notoginseng saponins via preventing oxidative stress injury in SAMP8 mice[J]. Evidence-Based Complementray and Alternative Medicine,2017,2017:8713561. [15] Huang J,Wu D,Wang J,et al. Effects of Panax notoginseng saponin on α,β,and γ secretase involved in Aβ deposition in SAMP8 mice[J]. Neuroreport,2014,25(2):89-93. doi: 10.1097/WNR.0000000000000048 [16] Xi Y,Yan B,Wang Y C,et al. Sodium channel voltage-gated beta 2 plays a vital role in brain aging associated with synaptic plasticity and expression of COX5A and FGF-2[J]. Mol Neurobiol,2016,53(2):955-967. doi: 10.1007/s12035-014-9048-3 [17] Tao H,Xiao Z,Rui M,et al. Navβ2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing[J]. Oncotarget,2017,8(59):99284-99295. doi: 10.18632/oncotarget.21849 [18] Hu T,Li S S,Lu M N,et al. Neuroprotection induced by Nav beta 2-knockdown in APP/PS1 transgenic neurons is associated with NEP regulation[J]. Nature Reviews Neuroscience,2019,20(2):2002-2011. [19] Lee M,Kim D,Shin H S,et al. High-density EEG recordings of the freely moving mice using polyimide-based microelectrode[J]. Journal of Visualized Experiments Jove,2011(47):2562. [20] Corbett B F,Leiser S C,Ling H,et al. Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer's disease[J]. Journal of Neuroscience,2013,33(16):7020-7026. doi: 10.1523/JNEUROSCI.2325-12.2013 [21] Sheena LP,Regan,Phil G,et al. Growth hormone during in vitro fertilization in older women modulates the density of receptors in granulosa cells,with improved pregnancy outcomes[J]. Fertility and Sterility,2018,110(7):1298-1310. doi: 10.1016/j.fertnstert.2018.08.018 [22] Huang Y,Guo B,Shi B,et al. Chinese herbal medicine xueshuantong enhances cerebral blood flow and improves neural functions in Alzheimer's disease mice[J]. Journal of Alzheimers Disease,2018,63(3):1089-1107. doi: 10.3233/JAD-170763 [23] Liu H,Liang J P,Li P B,et al. Core bioactive components promoting blood circulation in the traditional chinese medicine compound xueshuantong capsule (CXC) based on the relevance analysis between chemical HPLC fingerprint and in vivo biological effects[J]. Plos One,2014,9(11):e112675. doi: 10.1371/journal.pone.0112675 [24] Cheret C,Willem M,Fricker F R,et al. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles[J]. Embo Journal,2013,32(14):2015-2028. doi: 10.1038/emboj.2013.146 [25] Filser S,Ovsepian S V,Masana M,et al. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions[J]. Biological Psychiatry,2015,77(8):729-739. doi: 10.1016/j.biopsych.2014.10.013 [26] Zhu K,Xiang X,Filser S,et al. Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6[J]. Biological Psychiatry,2016,83(5):428-437. [27] Wong H K,Sakurai T,Oyama F,et al. Beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase[J]. Journal of Biological Chemistry,2005,280(24):23009-23017. doi: 10.1074/jbc.M414648200 期刊类型引用(1)
1. 丁震环,赵松伟. 通腑化痰醒神汤联合西医治疗中青年脑卒中后认知障碍痰瘀阻滞型的研究. 中医研究. 2024(10): 51-55 . 百度学术
其他类型引用(0)
-