Pathogenesis Of Vascular Dementia Research Articles

Dl-3-n-butylphthalide regulates cholinergic dysfunction in chronic cerebral hypoperfusion rats.

ObjectivesTo investigate whether dl-3-n-butylphthalide (NBP) affects cholinergic system function and ameliorates cognitive decline in a rat model of vascular dementia (VaD).MethodsThe VaD rat model was established by bilateral common carotid artery ligation (two-vessel occlusion, 2VO). Rats were divided into five groups: control, sham, 2VO, 2VO+NBP (80 mg/kg; intragastric), and 2VO+donepezil (1 mg/kg; intragastric). Treatments were administered once daily for 2 weeks from day 21 post-surgery. Spatial learning and memory were evaluated by Morris water maze performance. Hippocampal choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) expressions were detected using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction methods.ResultsThe daily escape latency was significantly longer in 2VO rats than in the sham or control groups, while the time spent in the target quadrant was significantly shorter. The daily escape latency of the 2VO+NBP group was significantly shorter compared with the 2VO group. Following NBP treatment, ChAT, AChE, VAChT, and BDNF expressions were significantly upregulated in the hippocampus.ConclusionsCentral cholinergic dysfunction may be involved in VaD pathogenesis. NBP treatment significantly improved spatial learning and memory in VaD rats, and may enhance cholinergic system function via BDNF-mediated neuroprotection.

TREM2 Overexpression Attenuates Cognitive Deficits in Experimental Models of Vascular Dementia.

Neuroinflammation plays a prominent role in the pathogenesis of vascular dementia (VD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor mainly expressed on microglia and has been known for its anti-inflammatory properties during immune response. However, data evaluating the effects of TREM2 in VD are lacking. Therefore, the present study is aimed at investigating the role of TREM2 in VD. In this study, the mouse model of VD was induced by transient bilateral common carotid artery occlusion (BCCAO). We compared the hippocampal gene and protein expressions of TREM2 between the VD mice and sham-operated mice at different time points. The TREM2 mRNA and protein expression levels in the VD mice were higher than those in the sham-operated mice. The cognitive deficits of VD mice were observed in the Morris water maze test. Interestingly, overexpression of TREM2 by intracerebroventricular injection of a lentiviral vector that encoded TREM2 (LV-TREM2) significantly improved the spatial learning and memory and attenuated the hippocampal neural loss in VD mice. Further mechanistic study revealed that overexpression of TREM2 significantly inhibited microglia M1 polarization by decreasing inducible nitric oxide synthase (iNOS) and proinflammatory cytokines expression levels and conversely enhanced microglia M2 polarization by increasing Arginase-1 (Arg-1) and anti-inflammatory cytokine expression levels. These results strongly suggest that TREM2 provides a protective effect in VD via modulating the phenotype of activated microglia and may serve as a novel potential therapeutic target for VD.

Expression of circular RNAs in the vascular dementia rats

PurposeCircular RNAs (circRNAs) are a class of endogenous noncoding RNA molecules that lack free 5' and a 3' end poly(A) tail. CircRNAs are enriched in neural tissues, and have been found to be associated with various diseases of the central nervous system. This study aimed to examine key circRNAs involved in vascular dementia(VD) model rats. MethodsTotal RNA-seq profiles of hippocampus samples from normal and vascular dementia rats were extracted and high throughput sequencing was performed. Quantitative real-time polymerase chain reaction (qPCR) was used to confirm the circRNA expression profiles. Differential expression of circRNA has been used for analysis via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The circRNA-miRNA-mRNA network was then constructed. ResultsThe data of high-throughput sequencing showed that there were 425 circRNAs differentially expressed between VD and normal rats (fold change (FC)≥2.0 and p-value< 0.05). In the VD group, a total of 237 were significantly upwardly revised, while the other 188 were downwardly revised. Eleven of these expressed more than 10 times in the VD model rats. The Expression levels of 10 circRNAs (circ_Map2k5, circ_Ulk2, circ_Plekha5, circ_Plcl1, circ_Sntg1, circ_Morc3, circ_Rims1, circ_ Stxbp5l, circ_ Agtpbp1, circ_Lrrc28) were verified by qPCR, which were persistent with RNA-seq data(P < 0.05). GO analysis indicated that majority of predicted target genes were involved in biological processes, such as cellular processes, nervous system development, etc. Cellular component, such as cellular parts, intracellular parts, cytoplasm and molecular function, such as binding, catalytic activity, etc. Moreover, KEGG analysis showed that many genes were enriched in cholinergic synapses, the MAPK signaling pathways, GABAergic synapses, metabolic pathways, the mTOR signaling pathways, and so on. ConclusionsOur results suggest the involvement of different ncRNA expression patterns in the pathogenesis (are associated with the pathogenesis of VD. Our findings provide a novel perspective for further research into potential mechanisms of VD and might facilitate the development of novel therapeutics targeting ncRNAs.

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (β-alanyl histidine) as a possible therapeutic agent for vascular dementia.

Association between Metformin and Cognitive impairment-A Review

Cognitive impairment is a devastating neurodegenerative disorder. Neurodegenerative changes are associated with interrupted glucose metabolism, lipid metabolism, amyloid peptides and neurofibrillary tangles deposition. Metabolic alteration aggravates aging of brain and pathogenesis of cognitive impairment. Insulin resistance and dysfunction occurring in diabetes mellitus is also a predominant etiological factor in aggravating the pathogenesis of vascular dementia and cognitive impairment. Use of metformin for 6 years or more is significantly related with the minimal risk of cognitive decline. Metformin will improve the depressive performance and modify the metabolism of glucose in depressed patients along with diabetes mellitus. It is proved to prevent cognitive decline by several ways at the same time few research outcomes point out the contradictory effect of metformin on cognitive function, which will be an important target for research on cognitive function, dementia and alzheimer's disease.

Metabolic profiling deciphering the potential targets of Yi-Gan San against vascular dementia in rat

Vascular dementia (VaD) is widely recognized as the second most common type of dementia, yet effective treatments are still lacking. Traditional Chinese medicine Yi-Gan San (YGS) has potent efficacy on treating VaD in clinical practice. However, the underlying mechanism is still unclear. In the present study, a UPLC-QTOFMS-based metabolomic method was established to explore the therapeutic mechanisms of YGS on VaD. Experimental VaD model was induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2-VO]) in rats. Cognitive function, pathological changes and oxidative stress condition in the brains of VaD rats were assessed using Morris water maze tests, hematoxylin-eosin staining and antioxidant assays (MDA, SOD, GSH and GSH-Px), respectively. UPLC-QTOFMS combined with computational systems analysis were conducted to study the changes of metabolic networks in serum of rats. The results indicated that VaD model was established successfully and 2-VO caused a decline in spatial learning and memory and hippocampal histopathological abnormalities of rats. YGS significantly improved the cognitive impairment induced by 2VO and attenuated hippocampal histopathological abnormalities. The inducement of 2-VO significantly elevated the level of MDA, and reduced SOD and GSH-Px activities, and YGS can significantly regulate the levels. We have identified 34 significantly changed metabolites related to 2-VO-induced VaD, and YGS can significantly regulate the abnormalities of 24 metabolites. Metabolic pathway enrichment analysis revealed that the mechanisms of YGS against 2-VO-induced VaD may be attributed to modulating the metabolic disorders of arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study provides new experimental information on the pathogenesis of VaD, unravels the potential targeted metabolic pathways of YGS against VaD on the whole metabolic network and highlights the importance of metabolomics as a potential tool for deciphering drug-targeted metabolic pathways.

Possible mechanisms of lycopene amelioration of learning and memory impairment in rats with vascular dementia.

Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress; therefore, we hypothesized that lycopene can reduce the level of oxidative stress in vascular dementia. A vascular dementia model was established by permanent bilateral ligation of common carotid arteries. The dosage groups were treated with lycopene (50, 100 and 200 mg/kg) every other day for 2 months. Rats without bilateral carotid artery ligation were prepared as a sham group. To test the ability of learning and memory, the Morris water maze was used to detect the average escape latency and the change of search strategy. Hematoxylin-eosin staining was used to observe changes of hippocampal neurons. The levels of oxidative stress factors, superoxide dismutase and malondialdehyde, were measured in the hippocampus by biochemical detection. The levels of reactive oxygen species in the hippocampus were observed by dihydroethidium staining. The distribution and expression of oxidative stress related protein, neuron-restrictive silencer factor, in hippocampal neurons were detected by immunofluorescence histochemistry and western blot assays. After 2 months of drug administration, (1) in the model group, the average escape latency was longer than that of the sham group, and the proportion of straight and tend tactics was lower than that of the sham group, and the hippocampal neurons were irregularly arranged and the cytoplasm was hyperchromatic. (2) The levels of reactive oxygen species and malondialdehyde in the hippocampus of the model group rats were increased, and the activity of superoxide dismutase was decreased. (3) Lycopene (50, 100 and 200 mg/kg) intervention improved the above changes, and the lycopene 100 mg/kg group showed the most significant improvement effect. (4) Neuron-restrictive silencer factor expression in the hippocampus was lower in the sham group and the lycopene 100 mg/kg group than in the model group. (5) The above data indicate that lycopene 100 mg/kg could protect against the learning-memory ability impairment of vascular dementia rats. The protective mechanism was achieved by inhibiting oxidative stress in the hippocampus. The experiment was approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2014-025) in June 2014.

Iron dysregulation in vascular dementia: Focused on the AMPK/autophagy pathway

Recent researches suggested that iron dysregulation play an important role in the pathogenesis of vascular dementia (VD). Iron deposition had been found in hippocampus in vascular dementia model in recent research. Nevertheless, the underlying mechanisms of iron deposition and its neurotoxicity in vascular dementia was still unclear. Thus, our research was aimed at whether the neurotoxicity of iron was associated with autophagy regulation. We established a chronic cerebral hypoperfusion model in the rat brain in order to mimic the vascular dementia using permanent bilateral common carotid artery occlusion (2VO). The preparation of iron overloaded rats model by intraperitoneal injection of iron dextran. Following, we tested the learning and memory function of each group using Morris Water Maze. Consequently, we analyzed the iron content and iron transport related molecules (TFR1, DMT1) in hippocampus. Furthermore, we examined the effect of iron deposition on autophagy-related molecules including AMPK, Beclin1 and LC3 and the number of autophagosomes in hippocampus. Last, we tested the apoptosis of neurons in hippocampus. We found that iron deposition in hippocampus in model groups which accompanied the decline of learning and memory function. And the expression of TFR1 and DMT1 were up-regulated in model groups. Moreover, iron deposition up-regulated the expression of AMPK, Beclin1 and LC3 and increase the number of autophagosomes in hippocampus. And the expression of Bax was up-regulated and Bcl-2 was down-regulated in iron deposition groups. To sum up, our data suggested that iron deposition increased AMPK/autophagy pathway associated molecules in the hippocampus and promoted neuronal apoptosis, which might be a new pathogenesis in vascular dementia.

Honokiol Attenuates the Memory Impairments, Oxidative Stress, Neuroinflammation, and GSK-3β Activation in Vascular Dementia Rats.

Vascular dementia (VaD) is caused by chronic decreases in brain blood flow and accounts for 15-20% of dementia cases worldwide. In contrast to Alzheimer's disease (AD), no effective drug treatments are currently available for VaD. Previous studies have suggested that oxidative stress and neuroinflammation in the brain play important roles in the pathogenesis of VaD. Honokiol (HKL) is a well-known bioactive and nutraceutical compound that can act as an antioxidant and anti-inflammatory molecule. HKL can protect against memory impairments in AD mouse models. In this study, we explored whether the application of HKL was also protective against the insult of chronic cerebral hypoperfusion (CCH) in rats. We found that HKL supplementation prevented the memory impairments in the inhibitory avoidance step-down and Morris water maze tasks in CCH rats. HKL also suppressed the levels of oxidative stress and inflammation in CCH rats. Moreover, HKL prevented dendritic spines abnormalities in CCH rats. We also found that HKL inhibited the activity of GSK-3β, which may be critical for the neuroprotective activity of HKL. Thus, our study demonstrated the protective role of HKL in VaD.

Effects of autophagy on synaptic-plasticity-related protein expression in the hippocampus CA1 of a rat model of vascular dementia

This study aimed to explore the relationship between autophagy and synaptic plasticity in the pathogenesis of vascular dementia (VD). The autophagy inhibitor 3-methyladenine (3-MA) and the autophagy agonist rapamycin (Rap) were injected into the lateral ventricles of rats, and a rat VD model was established using a modified four-vessel occlusion method. The expression of LC3-II, synaptophysin (Syn), and postsynaptic density protein 95 (PSD-95) in the CA1 area of the rat hippocampus were detected using western blotting. Decreased Syn and PSD-95 expression in the VD group was accompanied by an increased LC3-II/LC3-I ratio. The expression of Syn and PSD-95 increased after 3-MA application, but decreased following Rap application. The LC3-II/LC3-I ratio was negatively correlated with Syn and PSD-95 expression. These findings suggest that autophagy may regulate synaptic plasticity in the hippocampus in a VD model of rats. Inhibition of autophagy is beneficial to the remodeling of synapses in the hippocampal CA1 area of the VD rat model, and this may provide a theoretical basis for the treatment and prevention of VD.

Emodin inhibits zinc-induced neurotoxicity in neuroblastoma SH-SY5Y cells.

Emodin is a natural anthraquinone derivative with numerous beneficial effects, including antioxidant properties, anti-tumor activities, and protecting the nerves. Zinc-induced neurotoxicity plays a crucial role in the pathogenesis of vascular dementia (VD) and Parkinson’s disease (PD). Here, the protective activity of emodin inhibiting zinc-induced neurotoxicity and its molecular mechanisms such as cellular Zn2+ influx and zinc-induced gene expression were examined using human neuroblastoma cells (SH-SY5Y cells). Our findings showed that emodin obviously enhanced cell viability and reduced cell apoptosis and lactate dehydrogenase release. Bedsides, we detected a decrease of intracellular Zn2+ concentration after SH-SY5Y cells were pretreated with emodin. Simultaneously, the expression of zinc transporter-1, metallothionein-1, and metallothionein-2 were weakened in emodin-pretreated SH-SY5Y cells. In addition, emodin prevented the depletion of NAD+ and ATP induced by zinc. Emodin also reduced intracellular reactive oxygen species and endoplasmic reticulum-stress levels. Strikingly, emodin elevated SH-SY5Y cell viability and inhibited cell apoptosis caused by AMP-activated protein kinase signaling pathway activation. Thus, emodin could protect against neurotoxicity induced by Zn2+ in neuroblastoma SH-SY5Y cells. It is expected to have future therapeutic potential for VD or PD and other neurodegenerative diseases.

Fastigial nucleus stimulation ameliorates cognitive impairment via modulating autophagy and inflammasomes activation in a rat model of vascular dementia.

It has been reported that the fastigial nucleus (FSN) plays an important role in the development of vascular dementia (VD). Both autophagy and inflammation are functionally involved in the pathogenesis of VD. In this study, we aimed to evaluate the therapeutic effect of electrical cerebellar fastigial nucleus stimulation (FNS) in VD treatment, as well as the effect of FNS on autophagy and inflammation. A Morris water maze was used to evaluate the effect of FNS on the learning and memory ability of VD rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to study the apoptosis status of neuron cells in different groups of rats. In addition, immunohistochemistry (IHC) assay, real-time polymerase chain reaction, and Western blot analysis were carried out to measure the expression of various factors involved in autophagy and inflammation. Rats with artery occlusion or FSN damages showed longer escape latency and spent less time in the target quadrant. In addition, FNS treatment could help to partly recover the lost learning and memory ability in VD rats. Meanwhile, FNS treatment could alleviate neuron cell apoptosis by downregulating light chain 3-II expression and NLRP3 expression. In addition, the expression of caspase-1, interleukin 1β (IL-1β), and IL-18 was markedly reduced in VD rats treated by FNS. FNS treatment exerted a therapeutic effect during VD treatment by suppressing the autophagy process and by inhibiting inflammatory responses, thus alleviating neuron cell apoptosis and reducing the severity of VD.

IL-10 targets Th1/Th2 balance in vascular dementia.

The pathogenesis of vascular dementia (VD) is not fully elucidated. Th1/Th2 balance may change in VD, leading to numerous inflammatory cytokines secretion. Interleukin-10 (IL-10) is an immune suppressor, while its function in VD and correlation with Th1/Th2 balance are still unclear. The healthy male rats were randomly divided into three groups, including sham group, model group, and IL-10 group. Th1 and Th2 cytokines IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α) expressions in the serum were tested by enzyme-linked immunosorbent assay (ELISA). IL-10 expression in brain tissue and peripheral blood was detected by Real-Time PCR and ELISA. The correlation relationship between IL-10 and T helper cells 1/2 (Th1/Th2) cytokines was analyzed. Hippocampus cell apoptosis was determined by caspase 3 activity kit. Nuclear transcription factor 2 κB (NF-κB) expression was evaluated by Western blot. IL-10 levels were decreased, caspase 3 activity was enhanced, NF-κB expression was declined, IL-2 and TNF-α secretion were up-regulated, while IL-4 and IL-6 secretion were reduced in hippocampus tissue and peripheral blood from VD model rat compared to sham group (p<0.05). IL-10 significantly attenuated caspase 3 activity, up-regulated NF-κB expression, reduced IL-2 and TNF-α secretion, and enhanced IL-4 and IL-6 secretion (p<0.05). IL-10 was negatively correlated with Th1 cytokines and positively correlated with Th2 cytokines (p<0.05). IL-10 expression declined in VD and participated in regulating Th1/Th2 balance. IL-10 participated in VD incidence and development through regulating cell apoptosis and NF-κB expression.

A Mini-Review of the NADPH oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD.

Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer’s disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD.

Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats.

Oxidative stress and inflammation have been implicated in the pathogenesis of vascular dementia (VD). Thioredoxin-interacting protein (TXNIP) plays a vital role in oxidative stress and NOD-like receptor protein 3 (NLRP3) inflammasome activation. There is evidence that acupuncture has an antioxidative and neuroprotective effect in VD. In this study, we investigated whether acupuncture can attenuate cognitive impairment via inhibiting TXNIP-associated oxidative stress and inflammation in VD rats. Both common carotid arteries were occluded (2-vessel occlusion [2VO]) in rats to model VD. The neuroprotective effect of acupuncture was assessed by the Morris water maze and Nissl staining. Oxidative stress was assessed by detecting levels of reactive oxygen species, DNA oxidation, and antioxidase. Western blot, real-time PCR, and immunofluorescence were used to detect the expression of TXNIP, NLRP3, caspase-1, and IL-1β. A TXNIP siRNA intraventricular injection was applied to investigate whether acupuncture mimicked the effect of TXNIP inhibitor. Our findings demonstrated that VD rats treated with acupuncture had reduced hippocampal neuronal loss and oxidative stress. The upregulation of TXNIP, NLRP3, caspase-1, and IL-1β induced by 2VO was also reversed by acupuncture. Furthermore, TXNIP siRNA had a similar effect as acupuncture on cognition, hippocampal neurons, and ROS production in VD rats. In conclusion, our study suggests that the neuroprotective effects of acupuncture in VD are mediated through reducing expression of TXNIP-associated oxidative stress and inflammation.

Effect of hippocampal L‑NBP on BDNF and TrkB expression and neurological function of vascular dementia rats.

The pathogenesis of vascular dementia (VD) is associated with neuronal degeneration, apoptosis or necrosis following ischemic brain injury. L‑butylphthalide (L‑NBP), has been demonstrated to exhibit potent anti‑ischemic and anti‑VD effects, however the associated specific mechanism remains to be elucidated. The present study generated a VD rat model, in which the effect of L‑NBP on neurological function and expression levels of brain‑derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) were observed. A total of 90male Sprague Dawley rats were randomly divided into sham, model and L‑NBP groups (n=30). The VD model was generated by ligation of bilateral common carotid artery. A Morris water maze was used to test learning and memory functions. Animals were then sacrificed and cortical and hippocampal tissues were extracted. Hematoxylin and Eosin staining was used to observe brain tissue injury, and reverse transcription‑quantitative polymerase chain reaction was employed to measure BDNF and TrkB mRNA levels. Western blotting was employed to measure BDNF, TrkB and serine‑threonine protein kinase (Akt) protein levels. Immunohistochemistry staining was used to detect the N‑methyl‑D‑aspartate receptor (NMDAR) levels. VD rats exhibited elongated escape latency and lower crossing times, with significant neuronal damage. L‑NBP treatment shortened escape latency, increased crossing times and improved cortical and hippocampal injury. BDNF, TrkB, Akt and NMDAR expressions in the treatment group were significantly increased compared with the model group (P<0.05). L‑NBP may therefore enhance hippocampal expression of BDNF, TrkB, Akt and NMDAR, decrease ischemic injury of VD rats, and improve learning and memory.

Elucidation of mechanism of blood-brain barrier damage for prevention and treatment of vascular dementia.

It is well-known that the blood-brain barrier (BBB) plays significant roles in transporting intravascular substances into the brain. The BBB in cerebral capillaries essentially impedes the influx of intravascular compounds from the blood to the brain, while nutritive substances, such as glucose, can be selectively transported through several types of influx transporters in endothelial cells. In the choroid plexus, intravascular substances can invade the parenchyma as fenestrations exist in endothelial cells of capillaries. However, the substances cannot invade the ventricles easily as there are tight junctions between epithelial cells in the choroid plexus. This restricted movement of the substances across the cytoplasm of the epithelial cells constitutes a blood-cerebrospinal fluid barrier (BCSFB). In the brain, there are circumventricular organs, in which the barrier function is imperfect in capillaries. Accordingly, it is reasonable to consider that intravascular substances can move in and around the parenchyma of the organs. Actually, it was reported in mice that intravascular substances moved in the corpus callosum, medial portions of the hippocampus, and periventricular areas via the subfornical organs or the choroid plexus. Regarding pathways of intracerebral interstitial and cerebrospinal fluids to the outside of the brain, two representative drainage pathways, or perivascular drainage and glymphatic pathways, are being established. The first is the pathway in a retrograde direction to the blood flow through the basement membrane in walls of cerebral capillaries, the tunica media of arteries, and the vessels walls of the internal carotid artery. The second is in an anterograde direction to blood flow through the para-arterial routes, aquaporin 4-dependent transport through the astroglial cytoplasm, and para-venous routes, and then the fluids drain into the subarachnoid CSF. These fluids are finally considered to drain into the cervical lymph nodes or veins. These clearance pathways may play a role in maintenance of the barrier in the entire brain. Obstruction of the passage of fluids through the perivascular drainage and glymphatic pathways as well as damage of the BBB and BCSFB may induce several kinds of brain disorders, such as vascular dementia. In this review, we focus on the relationship between damage of the barriers and the pathogenesis of vascular dementia and introduce recent findings including our experimental data using animal models.

Uric acid is associated with vascular dementia in Chinese population.

ObjectiveMounting evidence suggests that oxidative stress is involved in the pathogenesis of vascular dementia (VD). Uric acid (UA) has long been implicated as a critical cause of cardiovascular disease. Nevertheless, UA was also expected to play an important role in antioxidant and neuroprotection recently. We hypothesized that UA may have a protective role against VD. The aim of this study was to investigate the link between serum UA and cognitive dysfunction in VD.Materials and MethodsThere were altogether 127 VD subjects and 81 nondemented controls enrolled in our study. Serum UA, demographic, and clinical characteristics were recorded at baseline, and all participants underwent Mini‐Mental State Examination (MMSE) at the beginning of the trial.ResultsThe VD group showed lower MMSE scores and serum UA levels than nondemented controls and there was significant statistical difference between the two groups (p < .05). Demographic and clinical characteristics such as age, gender, education, body mass index (BMI), total cholesterol (TC), triglycerides (TG), high‐density lipoprotein cholesterol (HDL), low‐density lipoprotein cholesterol (LDL), blood urea nitrogen (BUN), and serum creatinine (Scr) did not differ dramatically between groups (p > .05). In VD subjects, there was a positive correlation between serum UA and MMSE scores (r = .32, p < .05), and this correlation was independent of demographic and clinical characteristics (β = .272, p < .05).Conclusions VD subjects have dramatically lower serum UA levels in comparison to nondemented controls. Lower serum UA levels are linked to cognitive dysfunction and could serve as a potential predictor for VD.

Effects of a Cardiotonic Medicine, Danshen Pills, on Cognitive Ability and Expression of PSD-95 in a Vascular Dementia Rat Model

A widely used Chinese cardiotonic proprietary medicine, compound Danshen dripping pills (CDDP, Fufang Danshen Diwan) has also begun to be used for treatment of vascular dementia (VaD). We tried to explore the mechanism of CDDP action in this case. A VaD experimental model was built in rats by bilateral ligation of the common carotid arteries. The cognitive ability of experimental animals was evaluated in the Morris water maze test. Synaptic ultrastructural changes in the hippocampus were detected by transmission electron microscopy; expression of PSD-95 mRNA in the hippocampus was examined using hybridization in situ. The latter index (mRNA expression) in the VaD group was significantly lower than those in the CDDP and sham-operated groups (P < 0.05). CDDP treatment considerably improved disturbed ultrastructural synaptic characteristics in the hippocampus of VaD rats. The mean escape latency in the Morris water maze test was significantly shorter in CDDP-treated VaD rats, compared with that those of the VaD group (P < 0.05). In the CDDP group compared to the VaD one, escape strategies improved from edge and random searches to more linear swim pathway (P < 0.05). Thus, decreasing expression of PSD-95 plays an important role in the pathogenesis of VaD. CDDP treatment improves the learning and memory ability of VaD rats by improving neural synaptic ultrastructural characteristics and increasing expression of PSD-95 mRNA in the hippocampus.

Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion?

Vascular dementia (VD) is defined as a progressive neurodegenerative disease of cognitive decline, attributable to cerebrovascular factors. Numerous studies have demonstrated that chronic cerebral hypoperfusion (CCH) is associated with the initiation and progression of VD and Alzheimer's disease (AD). Suitable animal models were established to replicate such pathological condition in experimental research, which contributes largely to comprehending causal relationships between CCH and cognitive impairment. The most widely used experimental model of VD and CCH is permanent bilateral common carotid artery occlusion in rats. In CCH models, changes of learning and memory, cerebral blood flow (CBF), energy metabolism, and neuropathology initiated by ischemia were revealed. However, in order to achieve potential therapeutic targets, particular mechanisms in cognitive and neuropathological changes from CCH to dementia should be investigated. Recent studies have shown that hypoperfusion resulted in a chain of disruption of homeostatic interactions, including oxidative stress, neuroinflammation, neurotransmitter system dysfunction, mitochondrial dysfunction, disturbance of lipid metabolism, and alterations of growth factors. Evidence from experimental studies that elucidate the damaging effects of such imbalances suggests their critical roles in the pathogenesis of VD. The present review provides a summary of the achievements in mechanisms made with the CCH models, permits an understanding of the causative role played by CCH in VD, and highlights preventative and therapeutic prospects.