The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Tea intake or consumption and the risk of dementia: a meta-analysis of prospective cohort studies.

Purpose: Dementia affects as many as 130 million people, which presents a significant and growing medical burden globally. This meta-analysis aims to assess whether tea intake, tea consumption can reduce the risk of dementia, Alzheimer's disease (AD) and Vascular dementia (VD). Patients and methods: Cochrane Library, PubMed and Embase were searched for cohort studies from inception to November 1, 2022. The Newcastle Ottawa Quality Assessment Scale (NOS) was applied to evaluate the risk of bias of the included studies. We extracted the data as the relative risks (RRs) for the outcome of the interest, and conducted the meta-analysis utilizing the random effect model due to the certain heterogeneity. Sensitivity analysis were performed by moving one study at a time, Subgroup-analysis was carried out according to different ages and dementia types. And the funnel plots based on Egger's and Begger's regression tests were used to evaluate publication bias. All statistical analyses were performed using Stata statistical software version 14.0 and R studio version 4.2.0. Results: Seven prospective cohort studies covering 410,951 individuals, which were published from 2009 and 2022 were included in this meta-analysis. The methodological quality of these studies was relatively with five out of seven being of high quality and the remaining being of moderate. The pooling analysis shows that the relationship between tea intake or consumption is associated with a reduced risk of all-cause dementia (RR = 0.71, 95% CI [0.57-0.88], I2 = 79.0%, p < 0.01). Further, the subgroup-analysis revealed that tea intake or consumption is associated with a reduced risk of AD (RR = 0.88, 95% CI [0.79-0.99], I2 = 52.6%, p = 0.024) and VD (RR = 0.75, 95% CI [0.66-0.85], I = 0.00%, p < 0.001). Lastly, tea intake or consumption could reduce the risk of all-cause dementia to a greater degree among populations with less physical activity, older age, APOE carriers, and smokers. Conclusion: Our meta-analysis demonstrated that tea (green tea or black tea) intake or consumption is associated with a significant reduction in the risk of dementia, AD or VD. These findings provide evidence that tea intake or consumption should be recognized as an independent protective factor against the onset of dementia, AD or VD.

Cerebralcare Granule® combined with nimodipine improves cognitive impairment in bilateral carotid artery occlusion rats by reducing lipocalin-2.

AIMS: Clinically, Cerebralcare Granule® (CG) has been widely utilized to treat various types of headache, chronic cerebral insufficiency and other diseases, and the effect is significant. Clinical studies have shown that CG can significantly relieve vascular dementia (VaD), however, the molecular mechanisms haven't been established. To clear the therapeutic mechanisms of CG against VaD, a hypothesis was proposed that CG could treat neurovascular injury by inhibiting the production of lipocalin-2 (LCN 2). MAIN METHODS: 90 dementia rats were selected by water maze test and randomly divided into 6 groups, including nimodipine (NM), CG L (low dose) (0.314 g kg-1), CG H (high dose) (0.628 g kg-1), and combined group (CG + NM). And in vitro neuronal cell OGD modeling to evaluate the effect of CG on JAK2/STAT3. KEY FINDINGS: CG could significantly shorten the escape latency of two-vessel occlusion (2-VO) rats, increase their exploratory behavior, alleviate the symptoms of VaD and improve the ultrastructural pathological damage of neurovascular unit and accelerate the recovery of cerebral blood perfusion. CG combined with NM is better than NM alone. It was further showed that CG could inhibit the pathogenicity of LCN 2 through JAK2/STAT3 pathway and suppress the production of inflammatory cytokines. It plays a role in the protection of cerebral microvasculature and BBB in 2-VO rats. SIGNIFICANCE: Taken together, there data has supported notion that CG can protect the integrity of cerebral blood vessels and BBB and improve cognitive impairment through mainly inhibiting LCN 2, which provides scientific evidence for clinical application.

GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides J. Ellis (Fructus Gardenia) is a traditional Chinese medicine with diverse pharmacological functions, such as anti-inflammation, anti-depression, as well as improvement of cognition and ischemia brain injury. GJ-4 is a natural extract from Gardenia jasminoides J. Ellis (Fructus Gardenia) and has been proved to improve memory impairment in Alzheimer's disease (AD) mouse model in our previous studies. AIM OF THE STUDY: This study aimed to evaluate the therapeutic effects of GJ-4 on vascular dementia (VD) and explore the potential mechanisms. MATERIAL AND METHODS: In our experiment, a focal cerebral ischemia and reperfusion rat model was successfully developed by the middle cerebral artery occlusion and reperfusion (MCAO/R). GJ-4 (10 mg/kg, 25 mg/kg, 50 mg/kg) and nimodipine (10 mg/kg) were orally administered to rats once a day for consecutive 12 days. Learning and memory behavioral performance was assayed by step-down test and Morris water maze test. The neurological scoring test was performed to evaluate the neurological function of rats. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and Nissl staining were respectively employed to determine the infarct condition and neuronal injury of the brain. Iba1 immunohistochemistry was used to show the activation of microglia. Moreover, the synaptic damage and inflammatory level were detected by Western blot. RESULTS: GJ-4 could significantly improve memory impairment, cerebral infraction, as well as neurological deficits of VD rats induced by MCAO/R. Further research indicated VD-induced neuronal injury was alleviated by GJ-4. In addition, GJ-4 could protect synapse of VD rats by upregulating synaptophysin (SYP) expression, post synaptic density 95 protein (PSD95) expression, and downregulating N-Methyl-D-Aspartate receptor 1 (NMDAR1) expression. Subsequent investigation of the underlying mechanisms identified that GJ-4 could suppress neuroinflammatory responses, supported by inhibited activation of microglia and reduced expression of inflammatory proteins, which ultimately exerted neuroprotective effects on VD. Further mechanistic study indicated that janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway was inhibited by GJ-4 treatment. CONCLUSION: These results suggested that GJ-4 might serve as a potential drug to improve VD. In addition, our study indicated that inhibition of neuroinflammation might be a promising target to treat VD.

Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review.

BACKGROUND: A growing number of epidemiological studies indicate that metabolic syndrome (MetS) and its associated features play a key role in the development of certain degenerative brain disorders, including Alzheimer's disease and vascular dementia. Produced by several different medicinal plants, berberine is a bioactive alkaloid with a wide range of pharmacological effects, including antidiabetic effects. However, it is not clear whether berberine could prevent the development of dementia in association with diabetes. OBJECTIVE: To give an overview of the therapeutic potential of berberine as a treatment for dementia associated with diabetes. SEARCH STRATEGY: Database searches A and B were conducted using PubMed and ScienceDirect. In search A, studies on berberine's antidementia activities were identified using "berberine" and "dementia" as search terms. In search B, recent studies on berberine's effects on diabetes were surveyed using "berberine" and "diabetes" as search terms. INCLUSION CRITERIA: Clinical and preclinical studies that investigated berberine's effects associated with MetS and cognitive dysfunction were included. DATA EXTRACTION AND ANALYSIS: Data from studies were extracted by one author, and checked by a second; quality assessments were performed independently by two authors. RESULTS: In search A, 61 articles were identified, and 22 original research articles were selected. In search B, 458 articles were identified, of which 101 were deemed relevant and selected. Three duplicates were removed, and a total of 120 articles were reviewed for this study. The results demonstrate that berberine exerts beneficial effects directly in the brain: enhancing cholinergic neurotransmission, improving cerebral blood flow, protecting neurons from inflammation, limiting hyperphosphorylation of tau and facilitating ß-amyloid peptide clearance. In addition, evidence is growing that berberine is effective against diabetes and associated disorders, such as atherosclerosis, cardiomyopathy, hypertension, hepatic steatosis, diabetic nephropathy, gut dysbiosis, retinopathy and neuropathy, suggesting indirect benefits for the prevention of dementia. CONCLUSION: Berberine could impede the development of dementia via multiple mechanisms: preventing brain damages and enhancing cognition directly in the brain, and indirectly through alleviating risk factors such as metabolic dysfunction, and cardiovascular, kidney and liver diseases. This study provided evidence to support the value of berberine in the prevention of dementia associated with MetS.

Preventative effects of alpha-naphtho flavone in vascular dementia.

Vascular dementia (VaD) refers to the loss of reasoning, planning, judgment, and memory as a result of reduced blood flow, inflammation, activation of immune cells, and neurodegenerative processes. Here, we tested the preventive effects of alpha-naphthoflavone (ANF) on a model of vascular dementia induced by four-vessel occlusion (4VO) in rats. Animals were treated orally for 5 consecutive days with 10 mg/kg of donepezil (a traditional therapeutic drug) and 40 and 80 mg/kg ANF. The treatment with ANF exerted effects that were similar to those induced by donepezil. This included prevention of cognitive impairment, alterations in the plasma levels of homocysteine and nitrate and the activity of acetylcholinesterase and myeloperoxidase and the tissue level of glutathione, and thiobarbituric acid reactive substances in the brain tissues. These findings suggest that herbal-derived ANF is as effective as traditional drugs in vascular dementia.

A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia.

Atherosclerosis is an inflammatory chronic disease affecting arterial vessels and leading to vascular diseases, such as stroke and myocardial infarction. The relationship between atherosclerosis and risk of neurodegeneration has been established, in particular with vascular cognitive impairment and dementia (VCID). Systemic atherosclerosis increases the risk of VCID by inducing cerebral infarction, or through systemic or local inflammatory factors that underlie both atherosclerosis and cognition. Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are involved in inflammatory processes, but with opposite roles. Specifically, omega-3 PUFAs exert anti-inflammatory properties by competing with omega-6 PUFAs and displacing arachidonic acid in membrane phospholipids, decreasing the production of pro-inflammatory eicosanoids. Experimental studies and some clinical trials have demonstrated that omega-3 PUFA supplementation may reduce the risk of different phenotypes of atherosclerosis and cardiovascular disease. This review describes the link between atherosclerosis, VCID and inflammation, as well as how omega-3 PUFA supplementation may be useful to prevent and treat inflammatory-related diseases.

Intake of psyllium seed husk reduces white matter damage in a rat model of chronic cerebral hypoperfusion.

Vascular dementia (VaD) develops through a pre-VaD step during which blood vessels narrow due to atherosclerosis attributed to risk factors, including hyperlipidemia. This is followed by a VaD progression step during which inadequate blood supply results in white matter damage and consequent cognitive impairment. Furthermore, administration of arabinoxylan attenuated white matter damage in a rat model of VaD. Thus, we hypothesized that consumption of psyllium seed husk (PSH), containing a high level of arabinoxylan (~60%), could inhibit the VaD progression step. To test this hypothesis, rats were supplemented with PSH at various dosages for 33 days in a model of bilateral common carotid artery occlusion. PSH supplementation decreased astrocytic and microglial activation in the optic tract (opt) and, consequently, attenuated white matter damage in the opt. Attenuation of white matter damage resulted in improvement of pupillary light reflex, an indicator reflecting intactness of the opt. In addition, PSH treatment improved survival of glial cells cultured under hypoxic and glucose-deprived conditions by inhibiting both apoptosis and autophagy. These findings indicate that PSH consumption can inhibit the VaD progression step through a decrease of white matter damage. Therefore, these results support our hypothesis that PSH consumption prevents VaD due to the high arabinoxylan content in the rat model. PSH consumption has already been shown to reduce risk factors, thereby inhibiting the pre-VaD step. Consequently, PSH consumption can contribute to the prevention of VaD by inhibiting both the pre-VaD and VaD progression steps. In conclusion, our rat study suggests that PSH might be a candidate to explore its use in clinical studies to reduce VaD.

Zinc, Carnosine, and Neurodegenerative Diseases.

Zinc (Zn) is abundantly present in the brain, and accumulates in the synaptic vesicles. Synaptic Zn is released with neuronal excitation, and plays essential roles in learning and memory. Increasing evidence suggests that the disruption of Zn homeostasis is involved in various neurodegenerative diseases including Alzheimer's disease, a vascular type of dementia, and prion diseases. Our and other numerous studies suggest that carnosine (ß-alanyl histidine) is protective against these neurodegenerative diseases. Carnosine is an endogenous dipeptide abundantly present in the skeletal muscles and in the brain, and has numerous beneficial effects such as antioxidant, metal chelating, anti-crosslinking, and anti-glycation activities. The complex of carnosine and Zn, termed polaprezinc, is widely used for Zn supplementation therapy and for the treatment of ulcers. Here, we review the link between Zn and these neurodegenerative diseases, and focus on the neuroprotective effects of carnosine. We also discuss the carnosine level in various foodstuffs and beneficial effects of dietary supplementation of carnosine.

Hypercholesterolaemia and vascular dementia.

Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors-diabetes, hypercholesterolaemia, hypertension and smoking-are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet not fully understood. Similarly, the effects of lipids and lipid-lowering therapy on preventing or treating dementia remain unclear; the few trials that have assessed lipid-lowering therapy for preventing (two trials) or treating (four trials) dementia found no evidence to support the use of lipid-lowering therapy for these indications. It is appropriate to treat those patients with vascular risk factors that meet criteria for lipid-lowering therapy for the primary and secondary prevention of cardiovascular and cerebrovascular events, and in line with current guidelines. Managing the individual patient in a holistic manner according to his or her own vascular risk profile is recommended. Although the paucity of randomized controlled evidence makes for challenging clinical decision making, it provides multiple opportunities for on-going and future research, as discussed here.

Chronic treatment with resveratrol, a natural polyphenol found in grapes, alleviates oxidative stress and apoptotic cell death in ovariectomized female rats subjected to chronic cerebral hypoperfusion.

OBJECTIVES: Resveratrol appears to have neuroprotective potential in various animal models of brain disorders including cerebral ischemia and neurodegenerative diseases. Chronic cerebral hypoperfusion is a well-known pathological condition contributing to the neurodegenerative diseases such as vascular dementia. Purpose of the present study is to evaluate the possible therapeutic potential of resveratrol in a model of vascular dementia of ovariectomized female rats. Assessment of the potential was based on the determination of brain oxidative status, caspase-3 level, glial fibrillary acidic protein (GFAP), and neuronal damage on hippocampus and cerebral cortex. METHODS: For creating the model of chronic cerebral hypoperfusion, ovariectomized female Wistar rats were subjected to the modified two vessel occlusion method, with the right common carotid artery being occluded first and the left one a week later. RESULTS: At the 15th day following the ligation, neuronal damage was accompanied by the increased immunoreactivities of both GFAP and caspase-3, and significant neurodegeneration was evident in the hippocampus and cortex, all of which were significantly alleviated with resveratrol treatment (10 mg/kg). Biochemical analysis revealed that the resveratrol treatment decreased lipid peroxidation and restored reduced glutathione level as well. DISCUSSION: The collected data of the present study suggest that the administration of resveratrol may provide a remarkable therapeutic benefit for vascular dementia, which is most likely related to the prevention of both apoptotic cell death and oxidative stress. We believe that therapeutic efficacy of resveratrol deserves to be tested for potential clinical application in postmenopausal elderly women suffering from vascular dementia.

Study on active ingredient and mechanism in preventing vascular dementia of Tianzhusan coming from Tujia medicine.

To make clear of the absorbed components of Tianzhusan (TZS) and its possible mechanism in preventing vascular dementia (VD), the rats' models of VD were prepared by a permanent ligation of the bilateral common carotid arteries. After 60 days, rats were administrated with TZS for 0.1 g x kg(-1), and the volume is 0.02 mL x g(-1). After 3 days, the medicated serum was prepared and detected by UPLC, and then we predicted the possible chemical structure of the absorbed components of TZS. According to the absorbed components, the potential targets of TZS were found by ligand profiling of Discovery Studio 3.5. All of these target genes were submitted to DAVID onine for gene set enrichment analysis (GSEA). The 5 absorbed components of TZS have been predicted, and four of them have been identified as parishin B, parishin C, parishin, pennogenin-3-O-alpha-L-rhamnopyranosy-(1-->2)-beta-D-glucoside. Through reverse finding targets, we got 861 pharmacophore models and 9 pathways from KEGG, BIOCARTA after document verification. These results showed that the efficacy mechanism of TZS on VD perhaps were be related with these absorbed components and pathways. If the traditional herbs could be proved effective by efficacy tests, the serum pharmacochemistry, computer-aided drug design, system biology and other technologies can be used in the next experiments, which will be beneficial to fast discovery of material basis and mechanisms of traditional medicine coming form ethnic minorities.

Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response.

Emerging evidence suggests acupuncture could exert neuroprotection in the vascular dementia via anti-oxidative effects. However, the involvement of Nrf2, a master regulator of antioxidant defense, in acupuncture-induced neuroprotection in vascular dementia remains undetermined. The goal of our study was to investigate the contribution of Nrf2 in acupuncture and its effects on vascular dementia. Morris water maze and Nissl staining were used to assess the effect of acupuncture on cognitive function and hippocampal neurodegeneration in experimental vascular dementia. The distribution of Nrf2 in neurons in hippocampus, the protein expression of Nrf2 in both cytosol and nucleus, and the protein and mRNA levels of its downstream target genes NQO1 and HO-1 were detected by double immunofluorescent staining, Western blotting and realtime PCR analysis respectively. Cognitive function and microglia activation were measured in both wild-type and Nrf2 gene knockout mice after acupuncture treatment. We found that acupuncture could remarkably reverse the cognitive deficits, neuron cell loss, reactive oxygen species production, and decreased cerebral blood flow. It was notable that acupuncture enhanced nuclear translocation of Nrf2 in neurons and up-regulate the protein and mRNA levels of Nrf2 and its target genes HO-1 and NQO1. Moreover, acupuncture could significantly down-regulated the over-activation of microglia after common carotid artery occlusion surgery. However, the reversed cognitive deficits, neuron cell loss and microglia activation by acupuncture were abolished in Nrf2 gene knockout mice. In conclusion, these findings provide evidence that the neuroprotection of acupuncture in models of vascular dementia was via the Nrf2 activation and Nrf2-dependent microglia activation.

Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling.

BACKGROUND: Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. METHODS: Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. RESULTS: Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. CONCLUSION: Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.

Salidroside prevents cognitive impairment induced by chronic cerebral hypoperfusion in rats.

OBJECTIVE: To investigate the effects of salidroside on cognitive dysfunction induced by chronic cerebral hypoperfusion in rats. METHODS: Male Sprague-Dawley rats (n = 36) were divided into three groups (n = 12 per group): sham operation; bilateral permanent occlusion of the common carotid arteries (2-VO); 2-VO + salidroside. Rats received 20 mg/kg per day salidroside or vehicle intraperitoneal injection beginning the day before surgery and continuing until 34 days postoperatively. Cognitive function was evaluated by Morris water maze test and hippocampal long-term potentiation (LTP) measurement. Hippocampal neuronal apoptosis was evaluated via immunofluorescence. RESULTS: Chronic cerebral hypoperfusion caused marked cognitive deficit and LTP inhibition. These effects were largely ameliorated by salidroside administration. Salidroside prevented caspase-3 activation, increased the ratio of Bax/Bcl-2, and reversed hippocampal neuronal loss induced by chronic cerebral hypoperfusion. CONCLUSIONS: Salidroside prevents cognitive deficits caused by chronic cerebral hypoperfusion in rats, and alleviates apoptosis in the hippocampal CA1 area.

Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia.

Angiotensin II type 2 (AT(2)) receptor activation has been reported to play a role in cognitive function, although its detailed mechanisms and pathologic significance are not fully understood. We examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) could prevent cognitive decline associated with hypoperfusion in the brain.We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. Azilsartan (0.1 mg/kg/day) or C21 (10 µg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) and inflammatory cytokine levels were also determined. Wild-type (WT) mice showed significant prolongation of escape latency after BCAS, and this cognitive impairment was attenuated by pretreatment with azilsartan. Cognitive impairment was more marked in AT(2) receptor knockout (AT(2)KO) mice, and the preventive effect of azilsartan on cognitive decline was weaker in AT(2)KO mice than in WT mice, suggesting that the improvement of cognitive decline by azilsartan may involve stimulation of the AT(2) receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. The decrease in CBF in the BCAS-treated group was blunted by C21 treatment, and the increase in TNF-α and MCP-1 mRNA expression after BCAS was attenuated by C21 treatment. These findings indicate that direct AT(2) receptor stimulation attenuates ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and a reduction of inflammation.

Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia.

ETHNOPHARMACOLOGICAL RELEVANCE: The Renshen Shouwu capsule (RSSW) is a patented Traditional Chinese Medicine (TCM), that has been proven to improve memory and is widely used in China to apoplexy syndrome and memory deficits. To investigate the neuroprotective and therapeutic effect of the Renshen Shouwu standardized extract (RSSW) on ischemic brain neuronal injury and impairment of learning and memory related to Vascular Dementia (VD) induced by a focal and global cerebral ischemia-reperfusion injury in rats. MATERIAL AND METHODS: Using in vivo rat models of both focal ischemia/reperfusion (I/R) injuries induced by a middle cerebral artery occlusion (MCAO), and VD with transient global brain I/R neuronal injuries induced by a four-vessel occlusion (4-VO) in Sprague-Dawley (SD) rats, RSSW (50,100, and 200 mg kg(-1) body weights) and Egb761® (80 mg kg(-1)) were administered orally for 20 days (preventively 6 days+therapeutically 14 days) in 4-VO rats, and for 7 days (3 days preventively+4 days therapeutically) in MCAO rats. Learning and memory behavioral performance was assayed using a Morris water maze test including a place navigation trial and a spatial probe trial. Brain histochemical morphology and hippocampal neuron survival was quantified using microscope assay of a puffin brain/hippocampus slice with cresyl violet staining. RESULTS: MCAO ischemia/reperfusion caused infarct damage in rat brain tissue. 4-VO ischemia/reperfusion caused a hippocampal neuronal lesion and learning and memory deficits in rats. Administration of RSSW (50, 100, and 200mg/kg) or EGb761 significantly reduced the size of the insulted brain hemisphere lesion and improved the neurological behavior of MCAO rats. In addition, RSSW markedly reduced an increase in the brain infarct volume from an I/R-induced MCAO and reduced the cerebral water content in a dose-dependent way. Administration of RSSW also increased the pyramidal neuronal density in the hippocampus of surviving rats after transient global brain ischemia and improved the learning and memory ability of rats with 4-VO induced vascular dementia in a dose-dependent manner. CONCLUSIONS: The in vivo results suggested that RSSW has significant neuroprotective effects against MCAO and 4-VO I/R injury and a therapeutic effect on cognitive disorders in VD rats. RSSW also improved the learning and memory ability of VD rats. These results convincingly demonstrated that RSSW may be useful to prevent and treat ischemia/reperfusion injury and vascular dementia disease.

Curcumin induces ABCA1 expression and apolipoprotein A-I-mediated cholesterol transmembrane in the chronic cerebral hypoperfusion aging rats.

Cerebral hypoperfusion or aging often results in the disturbances of cholesterol and lipoprotein, which have been well depicted as a common pathological status contributing to neurodegenerative diseases such as vascular dementia (VaD) and Alzheimer's dementia (AD). The pathway of the liver X receptor-ß (LXR-ß)/retinoic X receptor-α (RXR-α)/ABCA1 plays a vital role in lipoprotein metabolism. Curcumin, a kind of phenolic compound, has been widely used. It has been reported that curcumin can reduce the levels of cholesterol in serum, but the underlying mechanisms are poorly understood. In this study, we evaluated the effects of curcumin on the cholesterol level in brain, vascular cognitive impairment and explored whether the mechanisms for those effects are through activating LXR-ß/RXR-α and ABCA1 expression and apoA-I. With a Morris water test, we found that curcumin treatment could attenuate cognitive impairment. With HE and Nissl staining, we found that curcumin could significantly ameliorate the abnormal changes of pyramidal neurons. Meanwhile, the expression of LXR-ß, RXR-α, ABCA1 and apoA-I mRNA and protein were increased in a dose-dependent manner after curcumin treatment. Interestingly, both serum HDL cholesterol and total cholesterol levels were statistically higher in the curcumin treatment group than those other groups. We conclude that curcumin has the ability to activate permissive LXR-ß/RXR-α signaling and thereby modulate ABCA1 and apoA-I-mediated cholesterol transmembrane transportation, which is a new preventive and therapeutic strategy for cerevascular diseases.

Omega-3 fatty acids: benefits for cardio-cerebro-vascular diseases.

BACKGROUND AND PURPOSE: Intracranial artery stenosis (ICAS) is a narrowing of an intracranial artery, which is a common etiology for ischemic stroke. In this commentary, we review key aspects of the discrimination between non-stroke controls and ischemic stroke patients on the background of phospholipid ω3-fatty acid (DHA, EPA) composition. The discussion is embedded in the presentation of general effects of long-chain ω3 polyunsaturated fatty acids (PUFAs) in cardio-cerebro-vascular diseases (CCVDs) and Alzheimer dementia (AD). SUMMARY OF COMMENTARY: ICAS is a common stroke subtype and has emerged as a major factor in recurrent stroke and vascular mortality. DHA and EPA are important fatty acids to distinguish between NCAS (no cerebral arteriosclerotic stenosis) and ICAS in stroke. The risk of ICAS is inversely correlated with the DHA content in phospholipids. Furthermore, a mechanistic explanation has been proposed for the beneficial effects of PUFAs in CCVDs and AD. CONCLUSIONS: Whereas the beneficial effects of EPA/DHA for cardiovascular diseases and stroke seem to be beyond question, preventive effects in patients with very mild cognitive dysfunction and beginning Alzheimer's disease undoubtedly need confirmation by larger clinical trials. A collaborative international basic science approach is warranted considering cautiously designed studies in order to avoid ethical problems.

[Neuroprotective effect of ferulic acid in vitro].

OBJECTIVE: To investigate the neuroprotective effect of ferulic acid on PC12 cells injuries. METHODS: With three models of PC12 cells injured by hypoxia, excitatory amino acids (EAA) and radical, the effect of ferulic acid on injured PC12 cells was observed by MTT assay. RESULTS: Compared with three models, ferulic acid (1-100 micromol/L) could promote cell viability notably (P<0.05 or P<0.01). CONCLUSION: Ferulic acid has notable protective effect on PC12 cells injured by hypoxia, EAA and radical.