Safety Evaluation of Tianzhi Granules in Treating Mild-to-moderate Vascular Dementia / 中国实验方剂学杂志

ObjectiveTo systematically evaluate the safety of Tianzhi granules used in the treatment of mild-to-moderate vascular dementia. MethodA randomized， double-blind， double-simulated， positive drug/placebo parallel controlled multi-center phase Ⅳ clinical trial and an open multi-center phase Ⅳ clinical trial of Tianzhi granules in the treatment of mild-to-moderate vascular dementia were conducted. Safety data of 1 492 patients were included and analyzed according to inclusion and exclusion criteria. The main evaluation measures were the incidence rate of adverse events/adverse reactions， laboratory indicators， vital signs， and electrocardiogram （ECG） results. ResultA total of six adverse events possibly related to the test drug occurred in 520 patients of the double-blind trial， and the symptoms were all mild and recovered. The incidence of adverse events was not statistically different among Tianzhi granules， donepezil， and placebo groups. Nine adverse events possibly related to the test drug were observed in 972 patients of the open trial， and the symptoms were mild and recovered. Laboratory tests （blood routine， urine routine， liver function， kidney function， and coagulation） and vital signs were compared before treatment （baseline） and after treatment of 12 and 24 weeks， respectively. There was no statistical significance in the main indicators before and after treatment. In the double-blinded trial， there was no significant difference in safety indicators between different groups before and after treatment. The most frequent adverse reaction was gastrointestinal discomfort， with an incidence rate of 6.64‰. ConclusionAdverse reactions occasionally occur in patients using Tianzhi granules， and it is safe to use Tianzhi granules to treat mild-to-moderate vascular dementia clinically.

Pathogenesis and Treatment of Vascular Dementia Based on Integrated Traditional Chinese and Western Medicine： A Review / 中国实验方剂学杂志

Vascular dementia （VaD） is a common disease that affects the health of the elderly. Due to the aging of the social population， the incidence of VaD is increasing year by year. There have been no officially approved treatments for this disease， mainly because its pathogenesis is complex， and the mechanism of action of effective drugs is not yet clear， which hinders drug research for the treatment of VaD. Therefore， by reviewing the available literature related to VaD， this study sorted out the pathogenesis of VaD from traditional Chinese medicine （TCM） and western medicine， and concluded that in TCM， VaD was characterized by the deficiency of the spleen and kidney （deficiency） and combination of phlegm and blood stasis （excess）， while in western medicine， the pathogenesis of VaD is mainly inflammatory response， oxidative stress， abnormal expression of related proteins， and dysfunction of signaling pathways. On this basis， this study also summarized the research on the mechanism of action of commonly used single Chinese herbal medicine and Chinese herbal medicine compound， western medicine， and the combination of Chinese herbal medicine and western medicine in the treatment of VaD in recent years. The commonly used single Chinese herbal medicine Ginkgo Folium and Chinese herbal medicine compound Dihuang Yinzi have the multi-component and multi-target characteristics and few adverse reactions in the treatment of VaD， while the commonly used western medicines such as donepezil and memantine have the characteristics of the clear target and quick onset. The combination of Chinese herbal medicine and western medicines can achieve a better effect. This study summarized the research on the pathogenesis and treatment of VaD， aiming to link the pathogenesis of VaD with the mechanism of effective drug therapy， and provide an important reference for future drug development for the treatment of VaD.

Effect of Modified Shuyuwan on Hippocampal Myelin Sheath Injury in Vascular Dementia Rats Through Cx43/Glu/AMPAR Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of modified Shuyuwan （SYW） on hippocampal myelin sheath injury in vascular dementia （VD） model rats. MethodSixty male SD rats of SPF grade were randomly divided into sham operation group， model group， and high-， medium- and low-dose modified SYW groups， with 12 rats in each group. The VD model was induced by bilateral carotid artery ligation in rats of the groups except for those of the sham operation group. After modeling， rats were screened by the water maze test， followed by drug treatment by gavage. Specifically， rats in the modified SYW groups were treated with modified SYW at 10， 5， 2.5 g·kg-1·d-1， accordingly， and those in other groups were administered with the same amount of normal saline. After intragastric administration for 28 days， the spatial learning and memory abilities of rats were detected by the water maze test. The hippocampal neuron structure was observed by hematoxylin-eosin （HE） staining. The content of hippocampal tumor necrosis factor （TNF）-α， interleukin-6 （IL-6）， and glutamate （Glu） was observed by biochemical detection. The hippocampal expression of myelin basic protein （MBP）， astrocyte activation marker glial fibrillary acidic protein （GFAP）， and connexin 43 （Cx43） was detected by immunofluorescence detection. The myelin sheath structure in the hippocampus was observed by the electron microscope. The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor （AMPAR） and Cx43 protein expression was detected by Western blot. ResultCompared with the sham operation group， the model group showed prolonged escape latency （P<0.01）， decreased times of crossing the original platform and percentage of target quadrant detention time （P<0.01）， disordered neuron structure in the hippocampal CA1 region， loose myelin sheath lamella with blurry edge， up-regulated expression levels of TNF-α， IL-6， and Glu in the hippocampal CA1 region， especially Glu （P<0.01）， reduced expression of AMPAR （P<0.01）， increased protein expression of p-AMPAR and Cx43 （P<0.01）， significantly dwindled protein expression of MBP in the myelin sheath， and enhanced fluorescence co-labeled by GFAP and Cx43. Compared with the model group， the modified SYW groups showed shortened escape latency （P<0.05）， increased times of crossing the original platform and percentage of target quadrant detention time （P<0.05）， closely arranged hippocampal neuron structure， denser myelin sheath lamella with clear edge， down-regulated expression levels of TNF-α， IL-6， and Glu in the hippocampal CA1 region， especially Glu （P<0.01）， up-regulated AMPAR （P<0.01）， reduced protein expression of p-AMPAR and Cx43， especially in the high-dose group （P<0.01）， significantly elevated protein expression of MBP in the myelin sheath， and weakened fluorescence co-labeled by GFAP and Cx43， especially in the high-dose group. ConclusionModified SYW can improve the learning and memory abilities of VD rats， and the mechanism may be related to the inhibition of Cx43 expression， reduction of the release of Glu， inhibition of AMPAR-mediated inflammatory response to reduce the production of astrocyte marker GFAP， and promotion of the expression of MBP protein to alleviate myelin injury.

Association, pathological mechanisms, prevention and control strategies of diabetes and vascular dementia: a review / 预防医学

@#The incidence rate of vascular dementia is increasing year by year, and there is still no effective treatment at present, so it is very important to reduce the risk of developing vascular dementia. Research shows that diabetes is associated with vascular dementia. Based on the research literature related to diabetes and vascular dementia from January 1995 to April 2023, This article reviews the relationship between diabetes and vascular dementia, pathological mechanism and prevention and control strategies. It is found that diabetes can promote the occurrence and development of vascular dementia by inducing cerebrovascular disease, oxidative stress and inflammatory reaction, using hypoglycemic drugs, removing the incentives of cerebrovascular disease, maintaining the stability of blood-brain barrier and adhering to a healthy lifestyle are the main measures for the prevention and control of vascular dementia at this stage. Future research needs to further explore the mechanism of vascular dementia induced by diabetes, and seek economic and effective prevention targets.

Puerarin reduces intracellular Ca2+ concentration and upregulates BDNF to protect hippocampal neurons in vascular dementia rats / 西安交通大学学报(医学版)

【Objective】 To observe the effect of puerarin on the concentration of Ca2+ and the expression of brain derived neurotrophic factor (BDNF) in hippocampal neurons of vascular dementia (VD) rats so as to explore the mechanism of puerarin in protecting nerve cells. 【Methods】 Male SD rats were randomly divided into sham operation group, model group, and puerarin intervention group. The vascular dementia model was established by ligating bilateral common carotid arteries at intervals of 3 days. Two weeks after the operation, the learning and memory abilities of the rats were evaluated by Morris water maze, and the expression of BDNF in the hippocampus of the rats was detected by immunohistochemistry and Western blotting. The mean fluorescence intensity was measured by flow cytometry to represent the intracellular free Ca2+ concentration. 【Results】 In the puerarin intervention group, the rats’ escape latency in Morris water maze was significantly shortened, the expression of BDNF in the hippocampus was significantly increased, and the concentration of Ca2+ in hippocampal neurons was decreased. Compared with the model group, the difference was statistically significant (all P<0.05). 【Conclusion】 Puerarin has neuroprotective effect on VD rats, and its mechanism may be related to the decrease of Ca2+ concentration in hippocampal neurons and the up-regulation of BDNF expression.

Improvement effect of diterpene ginkgolides on acute tMCAO rats and chronic tMCAO rats / 药学学报

To study the cognitive effects of diterpene ginkgolides (DG), transient middle cerebral artery occlusion (tMCAO)-induced rats were established. tMCAO-rats induced by suture method were divided into sham operation group, solvent control group, NBP group, DG group. The animal experiments in the present study were performed in accordance with the Ethical Guidelines of the Laboratory Animal Welfare Ethical Committee of Peking Union Medical College (00000646, 00000635). The effects of DG on tMCAO rats were evaluated by neurological severity score, cerebral infarction volume measurement, step-down and Morris water maze test. In the acute tMCAO rat model, 100 mg·kg-1 DG improved the neural score and infarction volume. In the chronic tMCAO rat model, DG 100 mg·kg-1 significantly improved the survival rate of tMCAO-induced rats. The Morris water maze results showed 100 mg·kg-1 DG decreased the latency of tMCAO-induced rats to find the platform, while the effect was weaker than the NBP. However, DG 30 mg·kg-1 did not show a significant effect. In conclusion, DG exerted a therapeutic effect on transient middle cerebral artery occlusion.

Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease and vascular dementia / 中国药理学与毒理学杂志

OBJECTIVE Alzheimer's disease(AD)and vascular dementia(VD)are the primary causes of dementia in elderly individuals,and therapeutic options for both conditions are limited.Overactivation of N-methyl-D-aspartate(NMDA)receptors,decreased cerebral blood flow,and subsequent pathological events,play signifi-cant roles in the progression of AD and VD.METHODS In this study,we investigated the therapeutic effects and underlying mechanisms of MN-08,a novel memantine nitrate,in mouse models of AD and rats with VD.RESULTS MN-08 was found to inhibit Aβ accumulation,prevent neuronal and dendritic spine loss,and attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice(following a 6-month preventative course)and in 8-month-old triple-transgenic(3×Tg-AD)mice(following a 4-month therapeutic course),as well as in rat models of VD with preventive and therapeutic treatments.In vitro,MN-08 was shown to bind to and antagonize NMDA receptors,inhibit calcium influx,and reverse dysregula-tions of the ERK and PI3K/Akt/GSK3β pathway,subse-quently preventing glutamate-induced neuronal loss.Additionally,MN-08 exhibited favorable pharmacokinet-ics,blood-brain barrier penetration,and safety profiles in rats and beagle dogs.CONCLUSION These findings suggest that the novel memantine nitrate MN-08 may be a useful therapeutic agent for AD and VD.

Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-κB transcription regulation and activating cAMP/CREB axis

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC50 value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

Avaliação dos subtipos de transtorno neurocognitivo (demência) em ambulatório de referência do Distrito Federal, Brasil de 2010 a 2018 / Evaluation of subtypes of neurocognitive disorder (dementia) in a reference outpatient clinic in the Federal District, Brazil from 2010 to 2018

Objetivos: estabelecer diagnóstico diferencial das demências em ambulatório de geriatria no Distrito Federal, calculando-se sua prevalência por meio de exame clínico e avaliação multifuncional. Método: estudo longitudinal, retrospectivo, com amostra de pessoas com 60 anos ou mais residentes no Distrito Federal-Brasil, com déficit cognitivo caracterizado por Transtorno Neurocognitivo (TNC) Maior (demência), cadastradas durante os anos de 2010 a 2018. A coleta de dados foi realizada em prontuários para selecionar e avaliar o perfil do idoso com diagnóstico de TNC seguida de avaliação geriátrica ampla e avaliação multifuncional. A análise de dados foi realizada com o cálculo da prevalência, estatística descritiva e índice V de Cramer. Resultados: 158 indivíduos conseguiram concluir todas as avalições. 52,5% possuem de 80 a 89 anos, 62,5% são mulheres e 62,7% caucasianos, 50,6% viúvos e 47,5% analfabetos. A prevalência inicial de Doença de Alzheimer (DA) foi de 45,6%, reduzindo-se para 35,4% após um período de acompanhamento e a demência vascular (DV) foi de 34,2%, inicialmente, e 45,6% ao final. Utilizou-se o Coeficiente V de Cramer, em que se encontrou uma relação fraca de fatores de risco com os diagnósticos das demências apresentados. Conclusão: DV foi a mais prevalente na área estudada. Entende-se ser a maior frequência de DA esteja relacionada à avaliação superficial uma vez que esse tipo de demência é mundialmente mais frequente

Objetivos: estabelecer diagnóstico diferencial das demências em ambulatório de geriatria no Distrito Federal, calculando-se sua prevalência por meio de exame clínico e avaliação multifuncional. Método: estudo longitudinal, retrospectivo, com amostra de pessoas com 60 anos ou mais residentes no Distrito Federal-Brasil, com déficit cognitivo caracterizado por Transtorno Neurocognitivo (TNC) Maior (demência), cadastradas durante os anos de 2010 a 2018. A coleta de dados foi realizada em prontuários para selecionar e avaliar o perfil do idoso com diagnóstico de TNC seguida de avaliação geriátrica ampla e avaliação multifuncional. A análise de dados foi realizada com o cálculo da prevalência, estatística descritiva e índice V de Cramer. Resultados: 158 indivíduos conseguiram concluir todas as avalições. 52,5% possuem de 80 a 89 anos, 62,5% são mulheres e 62,7% caucasianos, 50,6% viúvos e 47,5% analfabetos. A prevalência inicial de Doença de Alzheimer (DA) foi de 45,6%, reduzindo-se para 35,4% após um período de acompanhamento e a demência vascular (DV) foi de 34,2%, inicialmente, e 45,6% ao final. Utilizou-se o Coeficiente V de Cramer, em que se encontrou uma relação fraca de fatores de risco com os diagnósticos das demências apresentados. Conclusão: DV foi a mais prevalente na área estudada. Entende-se ser a maior frequência de DA esteja relacionada à avaliação superficial uma vez que esse tipo de demência é mundialmente mais frequente

Deterioro cognitivo de origen vascular y demencia vascular esporádica: revisión narrativa de tema basada en la evidencia / Cognitive impairment of vascular origin and sporadic vascular dementia: an evidence-based narrative topic review

RESUMEN INTRODUCCIÓN: La enfermedad cerebrovascular y las demencias están unidas por el deterioro cognitivo y la demencia vascular. Se trata de condiciones de salud potencialmente prevenibles, capaces de generar discapacidad, especialmente en la población adulta mayor. METODOLOGÍA: El propósito de este trabajo es caracterizar el deterioro cognitivo vascular y el espectro de la demencia vascular esporádica, mediante una revisión de tema con énfasis neurocognitivo. RESULTADOS: Entre el 30 % y el 40 % de las personas con enfermedad cerebrovascular experimentan algún grado de compromiso cognitivo. Después de los tres meses de haber presentado una enfermedad cerebro-vascular, alrededor del 20 % al 30 % de los pacientes serán diagnosticados con demencia, y entre un 10 % y un 35 %, con deterioro cognitivo. El deterioro cognitivo vascular y la demencia vascular tienen una serie de factores comunes a la enfermedad cerebrovascular y a la enfermedad de Alzheimer. La demencia vascular presenta subtipos: la demencia multiinfarto, caracterizada por varios infartos cerebrales que se acumulan en el tiempo; la demencia por infarto estratégico, en la que hay infartos localizados en zonas cortico-subcorticales con gran conectividad; y la demencia por enfermedad isquémica de pequeñas arterias, producida por infartos lacunares o lesiones difusas de sustancia blanca, que afecta principalmente la velocidad de procesamiento y las funciones ejecutivas. CONCLUSIONES: El deterioro cognitivo en personas con enfermedad cerebrovascular involucra pérdidas en el rendimiento de una o varias funciones mentales superiores, situación que puede evolucionar hasta la demencia, en la que un déficit permanente en las funciones mentales afecta de manera importante el desempeño y el funcionamiento. Sin embargo, es un tema que permite hablar y promover activamente el control o la modificación de factores de riesgo cardiovascular.

ABSTRACT INTRODUCTION: Cerebrovascular disease and dementias are linked by cognitive impairment and dementia of vascular origin. Potentially preventable health conditions capable of generating disability, especially in the older adult population. METHODOLOGY: The purpose is to characterize the cognitive impairment of vascular origin and the spectrum of sporadic vascular dementia, through a review of the topic with a neurocognitive emphasis. RESULTS: Between 30 % to 40 % of people with cerebrovascular disease acquire some degree of cognitive impairment. After three months of having experienced a cerebrovascular disease, about 20 % to 30 % of patients will be diagnosed with dementia and between 10 % and 35 % with cognitive impairment. Vascular cognitive impairment and vascular dementia have several factors common to cerebrovascular disease and Alzheimer's disease. Vascular dementia has subtypes: multi-infarct dementia characterized by several cerebral infarcts that accumulate over time; dementia due to strategic infarction, where there are infarcts located in cortico-subcortical areas with great connectivity; and dementia due to ischemic disease of the small arteries, produced by lacunar infarcts or diffuse lesions of the white matter, which mainly affect processing speed and executive functions. CONCLUSIONS: Cognitive impairment in people with cerebrovascular disease involves losses in the performance of one or several higher mental functions, a situation that can evolve to dementia, where a permanent deficit in mental functions significantly affects performance and functioning. However, it is a topic that allows to speak and actively promote the control and / or modification of cardiovascular risk factors.

Effect of Danggui Shaoyao San on cognitive function of vascular dementia model rats and its mechanisms / 中华行为医学与脑科学杂志

Objective:To investigate the effects of Danggui Shaoyao San(DSS) on cognitive function and neuronal apoptosis in vascular dementia (VD) rats.Methods:Fifty SPF grade male SD rats aged 6-7 weeks were randomly divided into sham operation group, model group, positive drug group (nimodipine group, 9.45 mg·kg -1), DSS low-dose group (1.6 g·kg -1), DSS high-dose group (6.4 g·kg -1) according to random number table, with 10 rats in each group. The VD rat model was established by permanent ligation of bilateral common carotid arteries. Seven days after modeling, the rats in different groups were administrated by gavage according to corresponding interventions, once a day, for 28 days. Morris water maze test was used to evaluate the learning and memory ability of rats.The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) in hippocampal area of rat brain were detected by ELISA.The protein expressions of apoptosis-related proteins Bcl-2, Bax, cleaved Caspase-3 and leptin receptor/glycogen synthase kinase 3β microtubule-associated protein tau(LEP-R/GSK-3β/tau) signaling pathway were detected by Western blot. GraphPad Prism 9 software was used for statistical analysis of data, repeated measure ANOVA and one-way ANOVA were used for comparison between multiple groups, and SNK- q test was used for further pairwise comparison. Results:The results of water maze experiment showed that the time and group interaction of escape latency of the five groups were not significant ( F=1.223, P>0.05), the main effect of group and time were significant ( F=74.65, 18.32, both P<0.05). On the 5th day, the escape latency of nimodipine group, DSS low-dose group and DSS high-dose group were lower than that of model group ( q=14.425, 7.477, 21.392, all P<0.05), and that of DSS high-dose group was lower than that of nimodipine group ((15.28±2.46)s, (22.78±3.31)s, q=6.966, P<0.05). There was statistically significant difference in the number of crossing platforms of rats in 5 groups ( F=17.331, P<0.05). The numbers of platform crossing in nimodipine group and DSS high-dose group were higher than that in model group ( q=6.789, 10.635, 5.270, all P<0.05), and the number of platform crossing in DSS high-dose group was higher than that in nimodipine group ((6.84±1.63), (5.22±1.75), q=3.846, P<0.05). ELISA results showed that the levels of MDA, ROS and SOD in hippocampal tissues of rats in 5 groups were significantly different ( F=49.338, 38.518, 15.440, all P<0.05). The levels of MDA and ROS in hippocampus of DSS high-dose group were lower than those of model group ( q=16.061, 13.541, both P<0.05) and nimodipine group ( q=4.317, 5.162, both P<0.05), SOD level of DSS high-dose group was higher than those of model group ( q=8.179, P<0.05) and nimodipine group ( q=4.135, P<0.05). Western blot results showed that the levels of apoptosis-related proteins Bcl-2/Bax and Caspase-3 were significantly different in the 5 groups ( F=30.692, 43.384, both P<0.01). The level of Bcl-2/Bax in DSS high-dose group was higher than that in model group ( q=10.562, P<0.05) and nimodipine group ( q=3.820, P<0.05), the level of Caspase-3 was lower than those of model group ( q=12.139, P<0.05) and nimodipine group ( q=7.734, P<0.05). The levels of LEP-R, p-GSK-3β, p-S404 tau and p-S202 tau expression level in hippocampal tissues of the 5 group were significantly different ( F=80.927, 59.230, 159.784, 105.923, all P<0.01). The levels of LEP-R and p-GSK-3β protein in nimodpine group and DSS high-dose group were higher than those in model group ( q=16.275, 20.104, both P<0.05; q=12.942, 17.257, both P<0.05), the levels of p-S404 Tau and p-S202 Tau in the two groups were lower than those in model group ( q=19.121, 27.456, both P<0.05; q=17.559, 22.780, both P<0.05). The levels of LEP-R(0.98±0.15), (0.86±0.14)) and p-GSK-3β((0.95±0.16)s, (0.82±0.13)) in DSS high-dose group were higher than those in nimodipine group ( q=3.829, 4.314, both P<0.05), the levels of p-S404 Tau((0.41±0.03)s, (0.58±0.07)) and p-S202 Tau((0.48±0.05)s, (0.59±0.06)) in DSS high-dose group were lower than those of nimodipine group ( q=8.335, 5.220, both P<0.05). Conclusion:DSS can improve the cognitive function of VD rats, and the mechanism may be related with reducing oxidative stress level, inhibiting neuronal apoptosis, and upregulating LEP-R/GSK-3β/Tau signaling pathway.

Effect of Zishen Huoxue Prescription on Regulation of Mitophagy and Neurogenesis in Hippocampal CA1 Region of Vascular Dementia Rats / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Zishen Huoxue prescription on promoting neurogenesis in hippocampal CA1 region of vascular dementia （VD） rats by regulating mitophagy. MethodThe 2-VO method was used to establish the VD rat model and 60 SD rats were randomly divided into sham operation group， model group， donepezil hydrochloride group， and Zishen Huoxue prescription low-dose（8.9 g·kg-1）， medium-dose（17.8 g·kg-1） and high-dose（35.6 g·kg-1） groups. Morris water maze test was performed to detect the escape latency and the number of crossing platform in each group. The expression of phosphatase and tensin homology-induced kinase 1 （PINK1） and Parkinson protein （Parkin） mRNA in hippocampal CA1 region was detected by Real-time fluorescent quantitative polymerase chain reaction（Real-time PCR）. Western blot was used to determine the expression of mitochondrial autophagy signaling pathway-related proteins Parkin， prohibitin 2 （PHB2）， mitofusin 2 （Mfn2） and dynamin-related protein 1 （Drp1） in hippocampal CA1 region. The neurogenesis in hippocampal CA1 region was tested by Brdu method. ResultCompared with the conditions in the sham operation group， the learning and spatial memory abilities of the model group were decreased （P<0.05）， with damaged mitochondrial structure and autolysosome formation in the hippocampal CA1 region. The expressions of Parkin， Pink1 mRNA and Parkin， PHB2， and Drp1 proteins were up-regulated （P<0.05）， while the expression of Mfn2 protein and the neuronal regeneration in hippocampal CA1 region were reduced （P<0.05， P<0.05）. Compared with the conditions in the model group， Zishen Huoxue prescription enhanced the learning and spatial memory abilities of VD rats （P<0.05）， increased the number of autophagosomes in hippocampal CA1 region and improved the mitochondrial structure. The expression of Parkin， Pink1 mRNA and Parkin， PHB2， and Drp1 proteins in hippocampal CA1 region was up-regulated （P<0.05， P<0.01）while the expression of Mfn2 protein was down-regulated（P<0.05， P<0.01）. The number of new neurons in hippocampal CA1 region was also increased（P<0.05， P<0.01）. ConclusionThe promoting effect of Zishen Huoxue prescription on the neurogenesis in hippocampal CA1 region of VD rats was related to the mitophagy mediated by Pink1/Parkin signaling pathway.

Expression of serum soluble triggering receptor expressed on myeloid cells 2 in patients with vascular dementia and its relationship with β-amyloid 1-42 and lipoprotein-associated phospholipase 2 / 中华老年医学杂志

Objective:To investigate the expression levels of serum soluble triggering receptor expressed on myeloid cells 2(sTREM2)in patients with vascular dementia(VD)and its relationship with β-amyloid 1-42(Aβ1-42)and lipoprotein-associated phospholipase 2(Lp-PLA2), as well as its value in diagnosis and differential diagnosis.Methods:A total of 152 patients with ischemic stroke receiving routine treatment in our hospital from January 2018 to January 2020 were included and divided into a VD group(n=76)and a non-VD group(n=76)according to evaluation from subsequent visits at 3 months.General data, Mini-Mental State Examination Scale(MMSE), Hachinski Ischemic Scale(HIS)scores, and the levels of biochemical indicators were compared and analyzed for the two groups.Results:There were statistically significant differences in lesion size between the VD group and the non-VD group( P<0.05). The MMSE score in the VD group was significantly lower than that in the non-VD group.The HIS score, serum levels of sTREM2[(3.34±1.18)μg/L and(2.78±1.25)μg/L, t=2.121, P=0.036], Aβ1-42[(93.69±14.45)ng/L and(81.24±14.21)ng/L, t=4.003, P<0.001]and Lp-PLA2 levels[(58.67±14.15)μg/L and(43.18±13.86)μg/L, t=5.096, P<0.001]were significantly higher in patients with VD than in patients without VD( P<0.05). Serum sTREM2 was positively correlated with Aβ1-42( r=0.723, P<0.001)and Lp-PLA2( r=0.714, P<0.001), and Aβ1-42 was positively correlated with Lp-PLA2( r=0.698, P<0.001)in VD patients.The cut-off value, sensitivity, specificity, and area under the curve of serum sTREM2 for differentiating VD from non-VD were 3.96 μg/L, 81.30%, 78.40%, and 0.838, respectively. Conclusions:Serum sTREM2 is abnormally elevated in VD patients, and is significantly correlated with Aβ1-42 and LP-PLA2, thus STREM2 may be an indicator in the differential diagnosis of VD and non-VD.

Pharmacodynamic study of chiral oxiracetam on neuroprotection and anti-dementia / 药学学报

To compare the neuroprotective and anti-dementia pharmacological effects of chiral oxiracetam, glutamate and calcium ions were used to establish neuronal injury models in vitro, and the protective effects of chiral oxiracetam on primary neurons were assayed by MTT. Permanent bilateral common carotid artery occlusion (2-VO)-induced rats were randomly divided into sham group, model group, galantamine 3 mg‧kg-1 group, oxiracetam groups (30, 100 and 200 mg‧kg-1), S-oxiracetam groups (30, 100 and 200 mg‧kg-1) and R-oxiracetam 200 mg‧kg-1 group. The animal experiments in the present study were performed in accordance with the Ethical Guidelines of the Laboratory Animal Welfare Ethical Committee of Peking Union Medical College. Morris water maze and step-down test were applied to evaluate the cognitive dysfunction induced by cerebral hypoperfusion in rats. Oxiracetam, S-oxiracetam and R-oxiracetam exerted protective effects on primary neuronal damage caused by various stimuli, and oxiracetam and S-oxiracetam showed better neuro-protective effects. Morris water maze and step-down results showed that oxiracetam, S-oxiracetam and R-oxiracetam improved the cognition of 2-VO rats. In summary, S-oxiracetam exerted a better neuro-protective effect than oxiracetam and R-oxiracetam.

Longshengzhi Capsules Improves Cognitive Function of Vascular Dementia Model Rats / 中国实验方剂学杂志

ObjectiveTo study the effect of Longshengzhi capsules on the cognitive function of vascular dementia （VD） rats and reveal the underlying mechanism. MethodA VD rat model was established by permanent ligation of bilateral common carotid arteries. The model rats were randomly assigned into the model group （normal saline for gavage）， Hydergine （0.54 mg·kg-1） group， and high-， medium-， and low-dose （2.16， 1.08， and 0.54 g·kg-1， respectively） Longshengzhi capsules groups， with 15 rats each group. Additionally， a sham group （normal saline for gavage） was designed in this study. Morris water maze test was conducted in the last week. Hematoxylin-eosin （HE） staining was employed for observation of the pathological changes in the hippocampal area of rat brain. Serum oxidative stress indicators including superoxide dismutase （SOD）， malondialdehyde （MDA）， and glutathione peroxidase （GSH-Px） were examined. The levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-1β （IL-1β） were determined by enzyme-linked immunosorbent assay （ELISA）. The expression levels of B cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， protein kinase B （Akt）， p-Akt， nuclear factor-κB （NF-κB）， intercellular cell adhesion molecule-1 （ICAM-1）， and matrix metallopeptidase-9 （MMP-9） were determined by Western blot. ResultMorris water maze results showed that compared with sham operation group， the escape latency of rats in model group was significantly prolonged， and the number of crossing platform was significantly reduced. Compared with model group， the time of escape latency in Longshengzhi capsules high- and medium-dose groups was significantly shortened， and the number of crossing platform was significantly increased. Compared with sham operation group， SOD and GSH-Px levels in model group were significantly decreased （P<0.05， P<0.01）， MDA levels were significantly increased （P<0.05）， TNF-α， IL-6 and IL-1β levels were significantly increased （P<0.01）. Compared with model group， the level of SOD in serum of Longshengzhi capsules high-dose group was significantly increased （P<0.05）， the level of GSH-Px in serum of Longshengzhi capsules high-， medium- and low-dose groups was significantly increased （P<0.05， P<0.01）， and the level of MDA was significantly decreased （P<0.05）. TNF-α， IL-6 and IL-1β levels were significantly decreased （P<0.05， P<0.01）. HE staining showed that Longshengzhi capsules could improve pathological damage in hippocampus of VD rats. Western blot results showed that compared with sham operation group， the protein expressions of Bax， NF-κB， MMP-9 and ICAM-1 in model group were significantly increased （P<0.01）， and the protein expressions of Bcl-2， Akt and p-Akt were significantly decreased （P<0.05， P<0.01）. The protein expression of Bax， NF-κB， MMP-9 and ICAM-1 in Longshengzhi capsules high-， medium- and low-dose groups was significantly decreased （P<0.05， P<0.01）， and the protein expression of Bcl-2 was significantly increased （P<0.05， P<0.01）. The protein expression of Akt in Longshengzhi capsules high- and medium-dose groups was significantly increased （P<0.05）. The expression of p-Akt protein in Longshengzhi capsules high-dose group was significantly increased （P<0.01）. ConclusionLongshengzhi capsules can improve the cognitive function of VD rats， and its mechanism may be related to the inhibition of oxidative stress， inflammatory response and apoptosis. ConclusionLongshengzhi capsules can improve the cognitive function of VD rats by inhibiting oxidative stress， inflammatory reaction， and neuronal apoptosis.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Effects of Longshengzhi capsule on learning and memory ability of vascular dementia model rats and study on its metabolomics / 中国药房

OBJECTIVE To study the effect of Longsheng zhi capsule on lear ning and memory ability of vascular dementia model rats and explore its mechanism based on metabonomics. METHODS Totally 90 SD rats were randomly divided into sham operation group ，model group ，Dihydroergotoxin mesylate tablet group （positive control ，0.54 mg/kg），Longshengzhi capsule high-dose，medium-dose and low-dose groups （2.16，1.08 and 0.54 g/kg），with 15 rats in each group. In addition to sham operation group （only threading without ligation ），the vascular dementia model was prepared by permanent ligation of bilateral common carotid arteries in each group ，which was administered by gavage for 28 d. Morris water maze test was used to determine the learning and memory ability of rats ；hematoxylin eosin （HE）staining was used to observe the histopathological changes of hippocampus；the serum levels of superoxide dismutase （SOD），malondialdehyde（MDA）and glutathione peroxidase （GSH-Px） were detected ；the serum metabolic map was analyzed by ultra high performance liquid chromatography quadrupole time of flight tandem mass spectrometry （UPLC-Q-TOF/MS），the specific metabolites were screened by multivariate statistical analysis ，and the metabolic pathway was enriched and analyzed. RESULTS Morris water maze test showed that compared with model group ，the escape latency of rats in each administration group was significantly shortened ，the number of crossing the platform was significantly increased ，and the residence time in the target quadrant was significantly prolonged （P＜0.01 or P＜ 0.05）. The results of serum biochemical indexes showed that compared with model group ， the s erum level of SOD increased significantly in Dihydroergotoxine mesylate tablet group and Longshengzhi capsule high-dose group ，the serum level of GSH-Px increased significantly while the MDA level decreased significantly in each administration group （P＜0.05 or P＜0.01）. HE staining showed that Longshengzhi capsule could improve the histopathological damage of hippocampus in vascular dementia model rats. A total of 14 differential metabolites were screened and identified by UPLC-Q/TOF-MS and orthogonal partial least squares discriminant analysis model （VIP＞1 and P＜0.05）. The results of metabolic pathway enrichment analysis showed that the metabolic pathways involved in vascular dementia in rats mainly included vitamin B 6 metabolism，fatty acid metabolism and steroid hormone biosynthesis. CONCLUSIONS Longshengzhi capsule can improve the learning and memory ability of rats caused by vascular dementia. Its effect may be related to improving the oxidative stress injury caused by lipid accumulation in the process of vascular dementia. The metabolic pathways involved mainly include vitamin B 6 metabolism，fatty acid metabolism and steroid hormone biosynthesis.

Electroacupuncture Attenuates Immune-Inflammatory Response in Hippocampus of Rats with Vascular Dementia by Inhibiting TLR4/MyD88 Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate whether electroacupuncture (EA) alleviates cognitive impairment by suppressing the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway, which triggers immune-inflammatory responses in the hippocampus of rats with vascular dementia (VaD).@*METHODS@#The experiments were conducted in 3 parts and in total the Sprague-Dawley rats were randomly divided into 8 groups by a random number table, including sham, four-vessel occlusion (4-VO), 4-VO+EA, 4-VO+non-EA, sham+EA, 4-VO+lipopolysaccharide (LPS), 4-VO+LPS+EA, and 4-VO+TAK-242 groups. The VaD model was established by the 4-VO method. Seven days later, rats were treated with EA at 5 acupoints of Baihui (DV 20), Danzhong (RN 17), Geshu (BL 17), Qihai (RN 6) and Sanyinjiao (SP 6), once per day for 3 consecutive weeks. Lymphocyte subsets, lymphocyte transformation rates, and inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor α(TNF-α) were measured to assess immune function and inflammation in VaD rats. Transmission electron microscopy was used to observe the ultrastructure of nerve cells in the hippocampus. The levels of TLR4, MyD88, IL-6, and TNF-α were detected after EA treatment. TLR4/MyD88 signaling and cognitive function were also assessed after intracerebroventricular injection of TLR4 antagonist TAK-242 or TLR4 agonist LPS with or without EA.@*RESULTS@#Compared with the 4-VO group, EA notably improved immune function of rats in the 4-VO+EA group, inhibited the protein and mRNA expressions of TLR4 and MyD88 in the hippocampus of rats, reduced the expressions of serum IL-6 and TNF-α (all P0.05).@*CONCLUSIONS@#EA attenuated cognitive impairment associated with immune inflammation by inhibition of the TLR4/MyD88 signaling pathway. Thus, EA may be a promising alternative therapy for the treatment of VaD.

Acupuncture for improving neuroinflammation in vascular dementia rats by regulating Th1/Th2 cells balance in peripheral blood / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture on the balance of T helper (Th) 1/Th2 cells in peripheral blood, inflammatory reaction and intracerebral neuroinflammation in vascular dementia (VD) rats, and to explore the mechanism of acupuncture for improving cognitive function in VD.@*METHODS@#A total of 60 SPF Wistar rats were randomized into a normal group (n=12), a sham operation group (n=12) and an operation group (n=36). Bilateral common carotid artery occlusion was adopted to establish the VD model in rats of the operation group. The rats of successful modeling were randomized into a model group and an acupuncture group, 12 rats in each one. In the acupuncture group, Sanjiao acupuncture was applied at "Danzhong" (CV 17), "Zhongwan" (CV 12), "Qihai" (CV 6), "Xuehai" (SP 10) and "Zusanli" (ST 36), the needles were manipulated for 30 s at each acupoint, without retaining. The intervention was given once a day for 15 days, and there was 1-day rest on day 8. Morris water maze test was adopted to observe the ethology, flow cytometry was used to detect the ratio of Th1/Th2 in peripheral blood, and Luminex liquid chip technology was used to detect the levels of interleukin (IL)-4, IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in serum and hippocampus.@*RESULTS@#There were no significant differences in various indexes between the normal group and the sham operation group (P>0.05). Compared with the sham operation group, in the model group, the escape latency of hidden platform test and reversal platform test was prolonged (P<0.01), the residence time of the original platform quadrant was shortened and the number of crossing the original platform was reduced in probe test (P<0.01, P<0.05), the proportion of Th1 cells was increased, the proportion of Th2 cells was decreased and the ratio of Th1/Th2 cells was increased in peripheral blood (P<0.01), the levels of TNF-α and IFN-γ were increased, the levels of IL-4 and IL-10 were decreased in serum and hippocampus (P<0.05, P<0.01). Compared with the model group, in the acupuncture group, the escape latency of hidden platform test and reversal platform test was shortened (P<0.01), the residence time of the original platform quadrant of the probe test was prolonged (P<0.05), the proportion of Th1 cells was decreased, the proportion of Th2 cells was increased and the ratio of Th1 / Th2 cells was decreased in peripheral blood (P<0.05), the levels of TNF-α and IFN-γ were decreased, the levels of IL-4 and IL-10 were increased in serum and hippocampus (P<0.05, P<0.01).@*CONCLUSION@#Acupuncture can improve the cognitive dysfunction and reduce the intracerebral neuroinflammation in VD rats, its mechanism may relate to the regulation of Th1/Th2 cells balance and reduce the inflammatory reaction in peripheral blood.

Vascular mild cognitive impairment and its relationship to hemoglobin A1c levels and apolipoprotein E genotypes in the Dominican Republic / Comprometimento cognitivo leve vascular e sua relação com os níveis de hemoglobina a1c e genótipos apolipoproteína e na república dominicana

ABSTRACT. Dementia and vascular mild cognitive impairment (VaMCI) currently impose a tremendous human and economic burden on patients from aging populations and their families worldwide. Understanding the interplay of cardiometabolic risk factors and apolipoprotein E (APOE) may direct us to a more personalized medicine and preventative care in MCI and dementia. Objective: To evaluate the relationship of cardiometabolic risk factors with MCI and assess the APOE genotype's role in an elderly cohort in the Dominican Republic. Methods: We studied a cohort of 180 participants 65 years of age and older using a combined assessment of cardiometabolic risk factors, neuropsychological battery tests, and APOE genotyping. We used the number of failed tests as a proxy to predict MCI. Results: We found that patients with the ε3-ε4 APOE genotype had 2.91 higher number of failed cognitive tests (p=0.027) compared to patients with the ε3-ε3 genotyped. The rate of test failures increased 10% (p=0.025) per unit increase in HbA1c percentage. Conclusions: Increased Hemoglobin A1c levels and ε3-ε4 APOE genotypes seem to have an association with the development of VaMCI.

RESUMO. A demência e o comprometimento cognitivo leve vascular (VaMCI) atualmente impõem uma enorme carga humana e econômica aos pacientes de populações envelhecidas e suas famílias em todo o mundo. Compreender a interação dos fatores de risco cardiometabólicos e apolipoproteína E (APOE) pode nos direcionar para uma medicina mais personalizada e de cuidados preventivos em MCI e demência. Objetivo: Avaliar a relação dos fatores de risco cardiometabólicos com o MCI e o papel do genótipo APOE em uma coorte de idosos na República Dominicana. Métodos: Estudamos uma coorte de 180 participantes com 65 anos de idade ou mais, utilizando uma avaliação combinada de fatores de risco cardiometabólicos, uma bateria de testes neuropsicológicos e genotipagem APOE. Adotou-se o número de testes com mau desempenho para o diagnóstico de MCI. Resultados: Verificou-se que os pacientes com o genótipo ε3-ε4 do APOE apresentaram 2,91 vezes mais testes cognitivos com mau desempenho (p=0,027) em comparação com os pacientes com o genótipo ε3-ε3. A taxa de falhas de teste aumentou 10% (p=0,025) por aumento de unidade na porcentagem de HbA1c. Conclusões: Níveis mais altos de HbA1c e os genótipos ε3-ε4 do APOE parecem estar associados ao desenvolvimento de VaMCI.