Exploring the Oxidative Stress Mechanism of Buyang Huanwu Decoction in Intervention of Vascular Dementia Based on Systems Biology Strategy.

OBJECTIVE: To explore the oxidative stress mechanism of modified Buyang Huanwu decoction (MBHD) in intervention of vascular dementia (VD) based on systems biology strategy. METHODS: In this study, through the reverse virtual target prediction technology and transcriptomics integration strategy, the active ingredients and potential targets of MBHD treatment of VD were analyzed, and the drug-disease protein-protein interaction (PPI) network was constructed. Then, bioinformatics analysis methods are used for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis, and finally find the core biological process. After that, in animal models, low-throughput technology is used to detect gene expression and protein expression of key molecular targets in oxidative stress-mediated inflammation and apoptosis signaling pathways to verify the mechanism of MBHD treatment of VD rats. Finally, the potential interaction relationship between MBHD and VD-related molecules is further explored through molecular docking technology. RESULTS: There are a total of 54 MBHD components, 252 potential targets, and 360 VD genes. The results of GO enrichment analysis and pathway enrichment analysis showed that MBHD may regulate neuronal apoptosis, nitric oxide synthesis and metabolism, platelet activation, NF-κB signaling pathway-mediated inflammation, oxidative stress, angiogenesis, etc. Among them, SIRT1, NF-κB, BAX, BCL-2, CASP3, and APP may be important targets for MBHD to treat VD. Low-throughput technology (qRT-PCR/WB/immunohistochemical technology) detects oxidative stress-mediated inflammation and apoptosis-related signaling pathway molecules. The molecular docking results showed that 64474-51-7, cycloartenol, ferulic acid, formononetin, kaempferol, liquiritigenin, senkyunone, wallichilide, xanthinin, and other molecules can directly interact with NF-κB p65, BAX, BCL-2, and CASP3. CONCLUSION: The active compounds of MBHD interact with multiple targets and multiple pathways in a synergistic manner, and have important therapeutic effects on VD mainly by balancing oxidative stress/anti-inflammatory and antiapoptotic, enhancing metabolism, and enhancing the immune system.

Efficacy of tanshinone IIA and mesenchymal stem cell treatment of learning and memory impairment in a rat model of vascular dementia.

OBJECTIVE: To investigate the efficacy of administration of tanshinone Ⅱ A (TSA) combined with mesenchymal stem cells (MSCs) for the treatment of learning and memory impairment caused by vascular dementia (VaD) and to determine the underlying mechanism. METHODS: Modified four-vessel occlusion was used to establish a VaD model in rats, and their spatial learning and memory capacity was assessed by the Morris water maze. The rats were randomized into MSCs, TSA, MSCs combined with TSA, vehicle and sham groups. Histological changes were determined by hematoxylin and eosin staining, and the hippocampal neuron apoptosis ratio was assessed by flow cytometry. Western blotting was performed to detect Bcl-2 and Bax expression. The reactive oxidative species (ROS) levels and the activity of total superoxide dismutase (T-SOD), an antioxidant enzyme in the rat hippocampus, were determined. RESULTS: TSA combined with MSCs treatment administered by intravenous injection in the tail significantly attenuated cognitive deficits in the VaD model compared with the vehicle group (P < 0.01), and its protective effect on cognitive function was greater than that obtained by treatment with MSCs or TSA alone. Furthermore, TSA combined with MSCs treatment achieved synergistic effects in suppressing neuronal apoptosis in the rat hippocampus caused by global brain ischemia via up-regulating the expression of Bcl-2, an anti-apoptosis protein, and decreasing the expression of Bax, a pro-apoptotic protein. In addition, TSA combined with MSCs treatment attenuated ROS production and enhanced T-SOD activity in the rat hippocampus, and the antioxidant effect was greater than that of treatment with MSCs or TSA alone. CONCLUSION: TSA combined with MSCs treatment improved the spatial learning and memory capacity in a VaD model via suppressing neuronal apoptosis and antioxidant activity in the hippocampus, and this improvement was greater with combined treatment than with treatment with MSCs or TSA alone.

Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

Does a Live Performance Impact Synchronization to Musical Rhythm in Cognitively Impaired Elderly?

BACKGROUND: Music-based interventions appear to be efficient approaches to improve emotional, social, and cognitive functioning of patients with neurodegenerative diseases. OBJECTIVE: Because benefits seem to increase with patient's motor involvement, we studied sensorimotor synchronization (SMS) abilities of patients with cognitive impairments (Alzheimer's disease, vascular and mixed dementia) and of patients with no evidence of cognitive impairments. More specifically, we compared the impact of a live performance by a musician to a video recording on SMS. METHODS: SMS to a metronomic or a musical stimulus was assessed while patients watched a live musician or his pre-recorded video. RESULTS: SMS to a metronome was better than to music but this effect was modulated by the social context. While SMS to a metronome was better when facing a video than a live performance, there was no impact of social context on SMS to music. No group differences of SMS were found. CONCLUSION: The decrease in SMS to a metronome in a live performance may be due to social pressure. Such a pressure might be removed in pleasant social activities, like moving with music in a group, explaining the lack of effect on SMS to music. We found no performance differences in groups, suggesting relatively spared SMS in cognitively impaired patients. By showing that it is possible to encourage patients to synchronize with others, even when facing a video, our results indicate that SMS can be used as a relevant predictor in clinical trials and open up promising therapeutic options for isolated patients.

Biomarkers Related to Endothelial Dysfunction and Vascular Cognitive Impairment: A Systematic Review.

INTRODUCTION: The damage in the endothelium and the neurovascular unit appears to play a key role in the pathogenesis of vascular cognitive impairment (VCI). Although there have been many advances in understanding the physiopathology of this disease, several questions remain unanswered. The association with other degenerative diseases and the heterogeneity of its clinical spectrum establish a diagnostic problem, compromising a better comprehension of the pathology and halting the development of effective treatments. The investigation of biomarkers is an important movement to the development of novel explicative models and treatment targets involved in VCI. METHODS: We searched MEDLINE considering the original research based on VCI biomarkers in the past 20 years, following prespecified selection criteria, data extraction, and qualitative synthesis. RESULTS: We reviewed 42 articles: 16 investigated plasma markers, 17 analyzed neuropathological markers, 4 studied CSF markers, 4 evaluated neuroimaging markers (ultrasound and MRI), and 1 used peripheral Doppler perfusion imaging. CONCLUSIONS: The biomarkers in these studies suggest an intrinsic relationship between endothelial dysfunction and VCI. Nonetheless, there is still a need for identification of a distinctive set of markers that can integrate the clinical approach of VCI, improve diagnostic accuracy, and support the discovery of alternative therapies.

Acupuncture Attenuates Inflammation in Microglia of Vascular Dementia Rats by Inhibiting miR-93-Mediated TLR4/MyD88/NF-κB Signaling Pathway.

BACKGROUND: It is widely accepted that inflammation may contribute to cognitive impairment in patients with vascular dementia (VD). Our prior clinical researches have reported that acupuncture can alleviate cognitive function in VD, but the underlying mechanisms are still unclear. The purpose of this research was to explore whether acupuncture alleviates cognitive impairment by suppressing the microRNA-93- (miR-93-) mediated Toll-like receptor (TLR) signaling pathway, which triggers inflammatory responses in the central nervous system. METHODS: VD was established by permanent bilateral common carotid artery occlusion in male Wistar rats. Three days after operation, the rats began daily treatment with acupuncture for two weeks. The levels of miR-93, Toll-like receptors (TLR2 and TLR4), intracellular signaling molecules (myeloid differentiation factor 88 (MyD88) and nuclear factor-kappa B (NF-κB)), and inflammatory cytokines were subsequently detected. TLR4 colocalized with neurons, microglia, and astrocytes in the hippocampus was evaluated. Neuroinflammation and cognitive function were determined after intracerebroventricular injection of TLR4 antagonist TAK-242 or agonist lipopolysaccharide (LPS) with or without acupuncture. RESULTS: We found that acupuncture notably repressed the expression of inflammatory cytokines in the hippocampus and plasma of VD rats. The expression of TLR4, but not TLR2, was markedly downregulated by acupuncture, accompanied by a decrease in miR-93 and MyD88/NF-κB signaling pathway activation. The overexpression of TLR4 in microglia, but not in astrocytes and neurons, was reversed by acupuncture. Furthermore, intracerebroventricular injection of TAK-242 had similar effects to acupuncture on inflammation and cognitive function, while LPS injection abolished the beneficial effects of acupuncture. CONCLUSIONS: Taken together, these findings provide evidence that acupuncture attenuates cognitive impairment associated with inflammation through inhibition of the miR-93-mediated TLR4/MyD88/NF-κB signaling pathway in experimental VD. Acupuncture serves as a promising alternative therapy and may be an underlying TLR4 inhibitor for the treatment of VD.

Non-pharmacological treatment changes brain activity in patients with dementia.

Non-pharmacological treatment (NPT) improves cognitive functions and behavioural disturbances in patients with dementia, but the underlying neural mechanisms are unclear. In this observational study, 21 patients with dementia received NPTs for several months. Patients were scanned using magnetoencephalography twice during the NPT period to evaluate NPT effects on resting-state brain activity. Additionally, cognitive functions and behavioural disturbances were measured using the Mini-Mental State Examination (MMSE-J) and a short version of the Dementia Behaviour Disturbance Scale (DBD-13) at the beginning and the end of the NPT period. In contrast to the average DBD-13 score, the average MMSE-J score improved after the NPT period. Magnetoencephalography data revealed a reduced alpha activity in the right temporal lobe and fusiform gyrus, as well as an increased low-gamma activity in the right angular gyrus. DBD-13 score changes were correlated with beta activity in the sensorimotor area. These findings corroborate previous studies confirming NPT effects on brain activity in healthy participants and people at risk of dementia. Our results provide additional evidence that brains of patients with dementia have the capacity for plasticity, which may be responsible for the observed NPT effects. In dementia, NPT might lead to improvements in the quality of life.

Germinated Brown Rice Attenuates Cell Death in Vascular Cognitive Impaired Mice and Glutamate-Induced Toxicity In HT22 Cells.

Germinated brown rice (GBR) with unpolishing, soaking, and germinating processes can improve the texture, flavor, and nutritional value, including GABA and phenolic contents. The effect of GBR was first investigated in vascular cognitive impaired mice and glutamate-induced toxicity in HT22 cells with respect to standard pure GABA. Feeding mice with GBR for 5 weeks showed neuroprotection. In this study, the modified bilateral common carotid artery occlusion mice model was mild but a significant difference in cognitive impairment was still shown. Like pure GABA, GBR decreased cognitive deficits in memory behavioral tests and significantly attenuated hippocampal neuronal cell death at P < 0.001. Similarly to 0.125 µM of GABA, 100 µg/mL of GBR increased HT22 cell viability after glutamate toxicity. GBR affected less apoptotic cell death and less blocking by the GABAA antangonist bicuculline in comparison to GABA. When the results are taken together, the underlying mechanism of GBR protection may mediate though the GABAA receptor and its phenolic contents.

Network topology and machine learning analyses reveal microstructural white matter changes underlying Chinese medicine Dengzhan Shengmai treatment on patients with vascular cognitive impairment.

With the increasing incidence of cerebrovascular diseases and dementia, considerable efforts have been made to develop effective treatments on vascular cognitive impairment (VCI), among which accumulating practice-based evidence has shown great potential of the traditional Chinese medicine (TCM). Current randomized double-blind controlled trial has been designed to evaluate the 6-month treatment effects of Dengzhan Shengmai (DZSM) capsules, one TCM herbal preparations on VCI, and to explore the underlying neural mechanisms with graph theory-based analysis and machine learning method based on diffusion tensor imaging (DTI) data. A total of 82 VCI patients were recruited and randomly assigned to drug (45 with DZSM) and placebo (37 with placebo) groups, and neuropsychological and neuroimaging data were acquired at baseline and after 6-month treatment. After treatment, compared to the placebo group, the drug groups showed significantly improved performance in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) score (p < 0.001) and the other cognitive domains. And with the reconstruction of white matter structural network, there were more streamlines connecting the left thalamus and right hippocampus in the drug groups (p < 0.001 uncorrected), with decreasing nodal efficiency of the right olfactory associated with slower decline in the general cognition (r = -0.364, p = 0.048). Moreover, support vector machine classification analyses revealed significant white matter network alterations after treatment in the drug groups (accuracy of baseline vs. 6-month later, 68.18 %). Taking together, the present study showed significant efficacy of DZSM treatment on VCI, which might result from white matter microstructure alterations and the topological changes in brain structural network.

Bushenhuoxue improves cognitive function and activates brain-derived neurotrophic factor-mediated signaling in a rat model of vascular dementia.

OBJECTIVE: To explore the protective mechanisms of the Traditional Chinese Medicine Bushenhuoxue (BSHX) in a rat model of vascular dementia (VD). METHODS: A rat model of VD was developed using bilateral common carotid artery occlusion (BCCAO). Rats were administered BSHX (10.14 or 5.07 g/kg), nimodipine (11.06 mg/kg; positive control), or saline (control) by gavage daily for 30 d post-surgery. Learning and memory abilities were assessed using the Morris water maze. Morphological changes in the hippocampus were observed using light microscopy (hematoxylin and eosin staining) and transmission electron microscopy (TEM). The mRNA and protein expression levels of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), phosphatidyl inositol 3-kinase (PI3K), serine/threonine kinase (AKT), and cAMP response element binding protein (CREB) were measured by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. RESULTS: Compared with the sham group, rats with BCCAO exhibited impaired learning and memory abilities (Morris water maze) and showed abnormalities in neuronal morphology (light microscopy) and ultrastructure (TEM) in the hippocampus. They also had decreased mRNA and protein expressions of BDNF, TrkB, PI3K, AKT, and CREB in hippocampal tissue (all P < 0.05). In rats with BCCAO, administration of BSHX attenuated deficits in learning and memory, improved the morphology and ultrastructure of hippocampal neurons, and enhanced mRNA and protein expression levels of BDNF, TrkB, PI3K, AKT, and CREB (all P < 0.05). CONCLUSION: BSHX may protect hippocampal neurons and improve learning and memory abilities, at least in part via the activation of BDNF/TrkB/PI3K/AKT/CREB signaling.

Therapeutic effect of piracetam with nimodipine on vascular dementia after cerebral infarction.

This article investigated the clinical effects of piracetam with nimodipine in the treatment of vascular dementia (VD) after cerebral infarction. 98 patients with vascular dementia after cerebral infarction were selected and divided into the control group and the study group according to the treatment method. The control group was treated with nimodipine alone. The study group was treated with piracetam on the basis of this observation, and we test the ADL (life ability score), MoCA(montreal cognitive assessment scale), ADAS-Cog(alzheimer's scale-cognition), MMSE(mental status examination) scores and quality of life scores before and after treatment in the two groups. Before treatment, there were no significant differences in ADL, MoCA, and ADAS-Cog scores between the two groups (P>0.05). After treatment, the ADL, MoCA, and ADAS-Cog scores of the study group were superior to the control group. The difference was statistically significant (P<0.05). There was no significant difference in MMSE scores between the two groups before treatment and 1 month after treatment (P>0.05). The MMSE scores of the study group were better than the control group after 3 months of treatment and half a year after treatment. The difference was statistically significant (P <0.05). Before treatment, there was no significant difference in the quality of life scores between the two groups (P>0.05). After treatment, the quality of life scores was significantly higher than the control group, and the difference was statistically significant (P<0.05). For patients with vascular dementia after cerebral infarction, piracetam combined with nimodipine can improve the cognitive function, improve the quality of life, and have a significant clinical effect.

Herbal Medicine for Vascular Dementia: An Overview of Systematic Reviews.

INTRODUCTION: Vascular dementia (VaD), a severe neurologic condition related to aging of the cerebrovascular structure, has been treated with herbal medications and products. In this overview of systematic reviews (SRs) on the effects of herbal medications, we aimed to summarize the current clinical evidence on the benefits of herbal drugs and to propose an evidence map outlining their effects on VaD. METHODS: SRs assessing their effects on cognitive function or performance and the associated safety, published until December 2018, were located from PubMed, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, China National Knowledge Infrastructure, and Oriental Medicine Advanced Searching Integrated System. A Measurement Tool to Assess systematic Reviews 2 was used to assess their overall confidence. A bubble plot was proposed to present the depth and width of the current status of the evidence supporting the use of individual herbal drugs. RESULTS: Ten SRs (4 on individual herbal medications and 6 on various herbal drugs) were included. The overall evidence on herbal medicines suggests that they are effective in improving cognitive function and performance. Individual herbal medications including FuFangHaiShe, NaoXinTong, YinDanXing- NaoTong, NaoMaiTai, ShenFuTang, and TongXinLuo showed favourable effects when assessed via a minimal mental state examination score but have limited evidence supporting their effectiveness due to the scarcity of randomized controlled trials. Concerning safety, most SRs did not outline the estimated risk ratio of adverse events. CONCLUSION: Herbal medications might have benefits for VaD patients but they need to be evaluated further.

In search of multimodal brain alterations in Alzheimer's and Binswanger's disease.

Structural and functional brain abnormalities have been widely identified in dementia, but with variable replicability and significant overlap. Alzheimer's disease (AD) and Binswanger's disease (BD) share similar symptoms and common brain changes that can confound diagnosis. In this study, we aimed to investigate correlated structural and functional brain changes in AD and BD by combining resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI. A group independent component analysis was first performed on the fMRI data to extract 49 intrinsic connectivity networks (ICNs). Then we conducted a multi-set canonical correlation analysis on three features, functional network connectivity (FNC) between ICNs, fractional anisotropy (FA) and mean diffusivity (MD). Two inter-correlated components show significant group differences. The first component demonstrates distinct brain changes between AD and BD. AD shows increased cerebellar FNC but decreased thalamic and hippocampal FNC. Such FNC alterations are linked to the decreased corpus callosum FA. AD also has increased MD in the frontal and temporal cortex, but BD shows opposite alterations. The second component demonstrates specific brain changes in BD. Increased FNC is mainly between default mode and sensory regions, while decreased FNC is mainly within the default mode domain and related to auditory regions. The FNC changes are associated with FA changes in posterior/middle cingulum cortex and visual cortex and increased MD in thalamus and hippocampus. Our findings provide evidence of linked functional and structural deficits in dementia and suggest that AD and BD have both common and distinct changes in white matter integrity and functional connectivity.

Protective Effect of Hyperbaric Oxygen Therapy on Cognitive Function in Patients with Vascular Dementia.

Recent studies have shown that hyperbaric oxygen (HBO) has a therapeutic effect on vascular dementia (VD); however, the exact mechanism remains unclear. This article aims to reveal the protective effects and underlying mechanisms of HBO on VD. A total of 158 patients with VD were prospectively included in the study and were randomly divided into control group and HBO group. The control group was given conventional treatment and the HBO group was treated with HBO in addition to conventional treatment. The following HBO protocol was practiced: 5 days per week, 60 min each, 100% oxygen at 2 standard atmospheric pressures for 12 weeks. The Mini-Mental State Examination (MMSE) scores and serum Humanin levels were detected before and after treatments in both groups. The baseline characteristics were not different dramatically between groups (p > 0.05). There was no significant difference in MMSE scores and serum Humanin levels between the two groups before treatment (p > 0.05). After treatment, compared with the control group, the MMSE scores and serum Humanin levels in the HBO group were significantly increased (p < 0.05). Spearman correlation analysis showed that the serum Humanin levels were positively correlated with MMSE scores (r = 0.409, p < 0.05) and this correlation was independent of baseline characteristics (ß = 0.312, p < 0.05). HBO therapy can improve cognitive function in patients with VD, and its mechanism may be related to elevated serum Humanin levels.

Hwangryunhaedok-Tang Exerts Neuropreventive Effect on Memory Impairment by Reducing Cholinergic System Dysfunction and Inflammatory Response in a Vascular Dementia Rat Model.

Hwangryunhaedok-tang (HRT) is a traditional oriental herbal formula used in Asian countries for treating inflammatory diseases and controlling fever. Our present study aimed to determine whether HRT has therapeutic effects for patients with vascular dementia (VaD) using a bilateral common carotid artery occlusion (BCCAO) rat model and assessing spatial memory impairment and activation of neuroinflammation. BCCAO was performed in male Sprague Dawley rats to induce VaD, and oral HRT was administered daily for 30 d. Our data showed that HRT ameliorated BCCAO-induced memory and cognitive impairment in behavioral tests. In addition, HRT reversed cholinergic dysfunction and neuronal damage in the hippocampus of BCCAO rats. Furthermore, HRT attenuated microglial activation and reduced the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) induced by BCCAO. Simultaneous high-performance liquid chromatography analysis of HRT using index compounds from the herbal composition revealed that both HRT ethanol extract and commercial HRT granules primarily comprise geniposide, baicalin, and berberine. Our study showed that HRT administration resulted in the prevention of neuronal injury induced by BCCAO through improvement of cholinergic dysfunction and inhibition of neuroinflammatory responses, suggesting that HRT may have potential as a treatment for VaD.

Effect of acupuncture at 3-points for intelligence on vascular dementia: Protocol for a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Vascular dementia (VD) is a commonly-seen disease in the elderly. What is more, "Acupuncture at 3-points for intelligence" is one of the most important components of "Jin's three-needle therapy" created by Rui Jin, a professor of Guangzhou University of Chinese Medicine, which can be used in the VD patients. In this article, researchers will assess the clinical efficacy and safety of acupuncture at 3-points for intelligence in the treatment of VD. METHODS: A systematic literature search for articles up to September 2018 will be conducted using 9 databases: PubMed, Cochrane Library, Embase, CNKI, CBM, VIP, Wanfang database, OASIS, and CiNii. Inclusion criteria are randomized controlled trials (RCTs) of acupuncture at 3-points for intelligence on treating VD. The primary outcome measures will be scores reflecting the neurological function of participants based on common medical scales. Hemorheology indexes, homocysteine (Hcy), acetylcholine (Ach), nitric oxide (NO), and adverse events will also be assessed. Stata V.13.0 software will be used for data synthesis, sensitivity analysis, meta-regression, subgroup analysis, and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias. Egger and Begg tests will be further performed to conduct quantitative evaluation of publication bias and to evaluate the symmetry of funnel plot. We will use the Grading of Recommendations Assessment, Development, and Evaluation system to assess the quality of evidence. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: Our study will provide the evidence for the clinical efficacy and safety of acupuncture at 3-points for intelligence in the treatment of VD.

Harpagoside Rescues the Memory Impairments in Chronic Cerebral Hypoperfusion Rats by Inhibiting PTEN Activity.

Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer's disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens, a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in Aß- and MPTP-induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3ß, downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD.

Evaluating Peripersonal Space through the Functional Transcranial Doppler: Are We Paving the Way for Early Detecting Mild Cognitive Impairment to Dementia Conversion?

BACKGROUND: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose. OBJECTIVE: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC. METHODS: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer's disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and backward the face. RESULTS: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up). CONCLUSIONS: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training.

Acupuncture Prevents the Impairment of Hippocampal LTP Through ß1-AR in Vascular Dementia Rats.

It is widely accepted that the synaptic dysfunction and synapse loss contribute to the cognitive deficits of vascular dementia (VD) patients. We have previously reported that acupuncture improved cognitive function in rats with VD. However, the mechanisms involved in acupuncture improving cognitive ability remain to be elucidated. The present study aims to investigate the pathways and molecules involved in the neuroprotective effect of acupuncture. We assessed the effects of acupuncture on hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation. Acupuncture enhanced LTP and norepinephrine (NE) levels in the hippocampus. Inhibition of the ß-adrenergic receptor (AR), but not the α-AR, was able to block the effects of acupuncture on hippocampal LTP. Furthermore, inhibition of ß1-AR, not ß2-AR, abolished the enhanced LTP induced by acupuncture. The expression analysis revealed a significant upregulation of ß1-AR and unchanged ß2-AR with acupuncture, which supported the above findings. Specifically, increased ß1-ARs in the dentate gyrus were expressed on neurons exclusively. Taken together, the present data supports a beneficial role of acupuncture in synaptic plasticity challenged with VD. A likely mechanism is the increase of NE and activation of ß1-AR in the hippocampus.

Puerarin Up-regulates Methyl-CpG Binding Protein 2 Phosphorylation in Hippocampus of Vascular Dementia Rats.

OBJECTIVE: To observe the effect of puerarin on methyl-CpG binding protein 2 (MeCP2) phosphorylation (pMeCP2) in the hippocampus of a rat model of vascular dementia (VD). METHODS: Thirty-six healthy Sprague-Dawley rats were randomly assigned to the sham-operated group, dementia group and puerarintreated group using a random number table (n=12 per group). The modifified permanent bilateral common carotid artery occlusion method was used to establish the VD model. The sham-operated and dementia groups were given 2 mL/d of saline, while the puerarin-treated group was given 100 mg/(kg•d) of puerarin for 17 days. The learning and memory abilities were evaluated by the Morris water maze test. Hematoxylin-eosin staining, immunohistochemical (IHC) staining and Western blot analysis were carried out to observe changes in neuron morphology and in level of pMeCP2 in the hippocampus, respectively. RESULTS: The morphologies of rat hippocampal neurons in the puerarintreated group were markedly improved compared with the dementia group. The escape latency of the dementia group was significantly longer than the sham-operated group (P<0.05), while the puerarin-treated group was obviously shorter than the dementia group (P<0.05). Cross-platform times of the dementia group were signifificantly decreased compared with the sham-operated group (P<0.05), while the puerarin-treated group was obviously increased compared with the dementia group (P<0.05). IHC staining showed no significant difference in the number of MeCP2 positive cells among 3 groups (P>0.05). The number of pMeCP2 positive cells in the CA1 region of hippocampus in the dementia group was signifificantly increased compared with the sham-operated group, and the puerarin-treated group was signifificantly increased compared with the dementia group (both P<0.05). Western blot analysis showed no signifificant difference of MeCP2 expression among 3 groups (P>0.05). The expression of pMeCP2 in the dementia group was signifificantly increased compared with the sham-operated group, while it in the puerarin-treated group was signifificantly increased compared with the dementia group (P<0.05). CONCLUSION: Puerarin could play a role in the protection of nerve cells through up-regulating pMeCP2 in the hippocampus, improving neuron morphologies, and enhancing learning and memory ablities in a rat model of VD.