Rat Model Of Vascular Dementia Research Articles

Effect of triptolide on cognitive dysfunction in vascular dementia rats through SIRT1/NF-κB signaling pathway

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.

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.

Sodium Dichloroacetate Stimulates Angiogenesis by Improving Endothelial Precursor Cell Function in an AKT/GSK-3β/Nrf2 Dependent Pathway in Vascular Dementia Rats.

Sodium dichloroacetate (DCA) is a mitochondrial pyruvate dehydrogenase kinase inhibitor, and has been shown to display vasoprotective effects in chronic ischemic stroke. The purpose of this study was to evaluate the therapeutic effect of DCA on vascular dementia (VD) and endothelial progenitor cell (EPC)-mediated angiogenesis. After cerebral ischemia-reperfusion in rats, DCA was administered continuously for 21 days; following which, histological analysis, and cognitive functional tests were conducted. Rat bone marrow-derived EPCs were isolated, their function and quantity were measured, and the effects of long-term administration of DCA on EPCs in a rat model of VD was studied. We found that long-term DCA administration improved cognitive function in VD rats, reduced brain infarct size and brain atrophy, increased VEGF and bFGF levels in vivo, promoted angiogenesis in damaged areas, and significantly improved EPC function in VD rats. Compared with the VD group, AKT, Nrf2, eNOS expression, and intracellular NO levels were elevated in EPCs of DCA-treated VD rats. In addition, GSK3β and intracellular ROS levels were decreased. Simultaneously, it was found that DCA directly acted on EPCs, and improved EPC functional behavior. Taken together, these findings suggested that long-term DCA administration improved cognitive function in a rat model of VD, and did so in part, by improving EPC function. Observations suggest that prolonged DCA administration might be beneficial in treating VD.

Ameliorative Effect of Phosphodiesterase-5 Inhibitor in Rat Model of Vascular Dementia.

Cerebral hypoperfusion has been considered as major risk factor for Vascular Dementia (VaD). The present study shows the potential of Tadalafil, a phosphodiesterase-5 inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced VaD in rats. BCCAo procedure was performed under anesthesia in wistar rats to induce VaD. Morris Water-Maze (MWM) parameter was employed on 7th day post-surgery to determine learning and memory. Escape latency time, time spent in target quadrant, Path length and average swim speed taken as important parameters in MWM. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxations and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. BCCAo produced significant impairment in endothelium dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myloperoxidase activity and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of Tadalafil (5 & 10 mg/kg, p. o.)/Donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that Tadalafil has shown efficacy in rat model of BCCAo induced VaD and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of VaD.

3-n-butylphthalide inhibits the apoptosis of nerve cells in rats with cerebral small vessel disease via the PI3K/Akt pathway.

The aim of this study was to investigate the effect of 3-n-butylphthalide (NBP) on the apoptosis of nerve cells in vascular dementia (VaD) model rats caused by cerebral small vessel disease (CSVD), and to explore its regulatory mechanism. The model of VaD was successfully established in rats by carotid artery ligation. All rats were randomly divided into three groups, including the sham operation group, model group and NBP group. The neurobehavioral score was used to verify whether the model was successfully established. The changes in learning and memory abilities of rats were detected via water maze experiment. The levels of Bcl-2-associated X protein (Bax) and cysteinyl aspartate specific proteinase-3 (Caspase-3) in the serum of rats was detected by enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was adopted to detect the apoptosis of nerve cells in brain tissues of rats. Moreover, the protein levels of phosphorylated phosphatidylinositol-3-kinase (PI3K) and phosphorylated protein kinase B (Akt) in brain tissues of rats were measured using Western blotting. Compared with the sham operation group, the neurobehavioral score of rats increased significantly, whereas learning and memory abilities decreased markedly in the model group. The levels of Bax and Caspase-3 in rat serum were remarkably up-regulated, and the apoptosis rate of nerve cells in brain tissues of rats increased significantly in the model group as well. Meanwhile, the levels of phosphorylated PI3K and phosphorylated Akt were notably declined. Compared with the model group, the neurobehavioral score decreased markedly, while learning and memory abilities were remarkably improved in the NBP group. The levels of Bax and Caspase-3 in rat serum were significantly down-regulated, and the apoptosis rate of nerve cells in brain tissues of rats were reduced in the NBP group. Furthermore, the protein levels of phosphorylated PI3K and phosphorylated Akt were remarkably elevated in the NBP group. NBP can improve the morphology of brain tissue cells and the learning and memory abilities, and inhibit the apoptosis of nerve cells in VaD model rats with CSVD. The possible underlying mechanism may be related to the activation of the PI3K/Akt signaling pathway.

Hwangryunhaedok-tang Exerts Neuropreventive Effect on Memory Impairment by reducing Cholinergic System Dysfunction and Inflammatory Response in Vascular Dementia Rat Model

Hwangryunhaedok-tang Exerts Neuropreventive Effect on Memory Impairment by reducing Cholinergic System Dysfunction and Inflammatory Response in Vascular Dementia Rat Model

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.

Effect of moxibustion on long-term memory in vascular dementia model rats

ObjectiveTo observe the effects on spatial long-term memory in the rats with vascular dementia (VD) treated with moxibustion for resolving stasis and promoting meridian circulation. MethodsThe modified 2-vascular occlusion (2-VO) method was used to prepare VD animal model. The rats were randomized into a sham-operation group, a model group, a moxibustion group and a western medication group, 15 rats in each one. In the moxibustion group, mild warm moxibustion was applied to “Băihuì (百会 GV 20)” “Dàzhuī (大椎 GV 14)” and “Shéntíng (神庭 GV 24)”, 20 min at each point, once a day, for 3 weeks consecutively. In the western medicaion group, mouse nerve growth factor (NGF) was injected intraperitoneally, 0.18 mL/kg, once a day, for 3 weeks consecutively. Morris water maze test was used, the time of the first passing platform, the frequency of passing-platform and swimming speed in 120 s were determined of the rats in each group. Western blot were used to test the protein expressions of hippocampal Nestin and DCX. ResultsAt the end of three courses of treatment, compared with sham-operation group, the difference was not significant statistically in swimming speed in the model group, the moxibustion group and the western medication group separately (all P > 0.05). Three days after modeling, the mean of escape latency was prolonged obviously in the modeled rats compared with the rats in the sham-operation group (88.84 ± 19.94 vs 18.15 ± 9.41, P < 0.01). At the end of three courses of treatment, compared with the sham-operation group(22.01 ± 10.07), the mean of escape latency was different statistically in the model group(89.18 ± 19.70), the moxibustion group(37.21 ± 13.31) and the western medication group separately(51.50 ± 16.15) , all P < 0.01. Compared with the model group, the mean of escape latency was shortened in the moxibustion group and western medication group respectively (37.21 ± 13.31 vs 89.18 ± 19.70, 51.50 ± 16.15 vs 89.18 ± 19.70, both P < 0.01). Compared with the western medication group, there was no statistical significant difference in the mean of escape latency in the moxibustion group (37.21 ± 13.31 vs 51.50 ± 16.15, P > 0.05). Compared with the sham-operation group, the frequency of passing-platform was decreased in the model group (0.73 ± 0.96 vs 2.60 ± 1.45, P < 0.01) ; compared with model group, the frequency of passing-platform was increased in the moxibustion group and the western medicine group and the statistically significant difference presented in the moxibustion group (2.06 ± 1.33 vs 0.73 ± 0.96, P < 0.01). Compared with the sham-operation group, the time of first passing-platform was prolonged in the model group (87.86 ± 33.25 vs 36.13 ± 29.76, P < 0.01). Compared with the model group, the time of first passing-platform was shortened in the moxibustion group and the western medicine group respectively (49.53 ± 29.48 vs 87.86 ± 33.25, P < 0.01; 58.98 ± 36.22 vs 87.86 ± 33.25, P < 0.05). After three courses of treatment, compared with the sham-operation group, Nestin expression was reduced in the model group, (0.33 ± 0.12 vs 0.51 ± 0.02, P < 0.05) and was increased in the moxibustion group and the western medication group respectively (1.33 ± 0.17 vs 0.51 ± 0.02, 1.39 ± 0.10 vs 0.51 ± 0.02, both P < 0.01). Compared with the model group, Nestin expression was increased in the moxibustion group and the western medication group, respectively (1.33 ± 0.17 vs 0.33 ± 0.12, 1.39 ± 0.10 vs 0.33 ± 0.12, both P < 0.01). Compared with the western medication group, the difference was not significant statistically in the moxibustion group (1.33 ± 0.17 vs 1.39 ± 0.10, P > 0.05). After three courses of treatment, compared with the sham-operation group, DCX expression was decreased in the model group, but without significant difference (0.44 ± 0.20 vs 0.51 ± 0.26, P > 0.05), the expression was increased in the moxibustion group and the western medication group respectively (0.98 ± 0.25 vs 0.51 ± 0.26, P < 0.05; 1.11 ± 0.43 vs 0.51 ± 0.26, P < 0.01). Compared with the model group, DCX expression was obviously increased in the moxibustion group and the western medication group (0.98 ± 0.25 vs 0.44 ± 0.20, 1.11 ± 0.43 vs 0.44 ± 0.20, both P < 0.01). The difference in DCX expression was not statistically significant between the western medication group and the moxibustion group (0.98 ± 0.25 vs 1.11 ± 0.43, P > 0.05). ConclusionMoxibustion apparently improves the long-term memory in VD rats.

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.

Effects of huayu tongluo moxibustion on learning and memory ability and the hippocampal BDNF/TrkB expressions in the rats of vascular dementia

To explore the effects of huayu tongluo (resolving stasis, promoting collateral circulation) moxibustion on learning and memory ability and the expressions of brain derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the rats of vascular dementia (VD) in the microenvironment of neurovascular niche. Using 2-vessel occlusion (2-VO), the VD rat models were duplicated. The neural stem cells (NSCs) labeled with lentiviral vector-mediated enhanced green fluorescent protein (EGFP) were co-cultured with endothelial progenitor cells (EPCs) to structure the NSCs + EPCs implant. The implant was transplanted into the lateral ventricle of VD rats and the VD rat models with neurovascular niche were established. In No.1 experiment, the successful-modeled rats were divided into 3 groups, i.e. a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 12 rats in each one. No any treatment was provided in the model group and the NSCs + EPCs blank group. The huayu tongluo moxibustion therapy was adopted in the NSCs + EPCs moxibustion group, in which, the suspending moxibustion technique was applied to "Baihui" (GV 20), "Dazhui" (GV 14) and "Shenting" (GV 24), 20 min at each acupoint. The treatment was given once every day and a 14-day treatment was as one course. Totally, 3 courses of treatment were required. At the end of treatment, Morris water maze experiment was adopted to determine the learning and memory ability of the rats in each group. In the No.2 experiment, the model rats were divided into 3 groups, a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 18 rats in each one. In each group, according to the durations of treatment, 3 subgroups were divided and 6 rats in each one. The intervention method was same as the No.1 experiment. Additionally, after corresponding treatment course, using perfusion, the brains were collected in each subgroup and the slices were frozen. BDNF/TrkB expressions were observed in the immunofluorescence test. After treatment, in the NSCs + EPCs moxibustion group, the escape incubation was reduced, the time of the first running-cross platform was shortened and the frequency of running-cross platform increased as compared with the model group and the NSCs + EPCs blank group (P<0.01, P<0.05). The protein expressions were increased in tendency among the 3 courses of treatment in the NSCs + EPCs moxibustion group, indicating the significant differences (all P<0.05), in which, the increase of the protein expressions in the NSCs + EPCs moxibustion group was better than the NSCs + EPCs blank group (P<0.05, P<0.01). The huayu tongluo moxibustion therapy is the effective approach to VD in clinical treatment. This therapy up-regulates the BDNF/TrkB protein expressions in the microenvironment of neurovascular niche, co-modulates NSCs-EPCs coupling mechanism, promotes nerve neogenesis and repairs the injured nerve.

Effect of Ghrelin on Memory Impairment in a Rat Model of Vascular Dementia

The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered 80 μg/kg ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.

A novel squaramide compound alleviates cognitive deficits through activation of Akt and Erk1/2 in a rat model of vascular dementia.

Vascular dementia is the second most common type of dementia, yet no effective treatment for it exists. Akt and Erk1/2 signaling pathways are involved in neuronal survival. It has been reported that bisperoxovanadium (pyridin-2-squaramide), a novel squaramide compound, protects against cerebral ischemia injury via activation of Akt and Erk1/2. Here, the potential neuroprotective effect of bisperoxovanadium is shown for the first time in a model of vascular dementia induced in 6-month-old male Sprague-Dawley rats by two-vessel occlusion injury applied to 6-month-old. Following this lesion, bisperoxovanadium (pyridin-2-squaramide) (1 mg/kg/day) was intragastrically administered for four successive weeks. The Morris water maze test estimated cognitive function. The morphological examination was performed by hematoxylin-eosin staining. Akt and Erk1/2 protein abundance were assessed by Western blot. Results showed that bisperoxovanadium (pyridin-2-squaramide) attenuated not only cognitive dysfunction but also alleviated histopathological changes in rats with vascular dementia. Moreover, bisperoxovanadium (pyridin-2-squaramide) ultimately reduced neuronal apoptosis represented by the Bax/Bcl-2 ratio in the CA1 (cornu ammonis 1) region of the hippocampus. Importantly, the levels of p-Akt(ser473) and p-Erk1/2(Thr202/Tyr204>) were increased after treatment with bisperoxovanadium (pyridin-2-squaramide). It is concluded that the novel squaramide compound bisperoxovanadium (pyridin-2-squaramide) might be effective in the treatment of vascular dementia by activation of Akt and Erk1/2.

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.

Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation in rat model of streptozotocin diabetes induced vascular dementia

Diabetes is one of the risk factors for the development of vascular dementia (VD), leading to endothelial dysfunction and cognitive impairment. Resveratrol has been shown to have antioxidant, antiinflammatory, and neuroprotective effects. The previous studies have also reported that resveratrol improves cognitive and vascular endothelial functions in several pathological conditions. In the present study we aimed to evaluate the effect of resveratrol on cognitive and vascular endothelial function and to explore the mechanisms of its effects in the streptozotocin-induced diabetic rat model of VD. Male Wistar rats were divided into 3 groups (n = 10 in each group): Control, diabetes (DM), DM + resveratrol (DM + RSV) groups. Rats from the DM + RSV group received resveratrol (20 mg/kg/day, ip) for 4 weeks after induction of diabetes and then cognitive functions of the rats were tested by the Morris water maze and a passive avoidance tests. After behavioral tests, endothelial function of thoracic aorta (the endothelium-dependent and -independent vasorelaxant responses) was investigated. To explore the mechanisms of resveratrol, endothelial eNOS, aortic superoxide dismutase (SOD), NADPH oxidase, heme oxygenase-1 (HO-1) levels, TNF-α and IL-1β expressions; serum SOD and NADPH oxidase levels and, hippocampal BDNF, TNF-α and IL-1β expressions were measured. It was shown that DM resulted in severe learning and memory deficits associated with endothelial dysfunction, increased expression of TNF-α and IL-1β, increased oxidative stress levels and decreased expression of eNOS and BDNF. In contrast, resveratrol treatment improved the cognitive decline. It was also found that chronic treatment with resveratrol ameliorated the impaired vascular reactivity. Reveratrol significantly reversed diabetes-induced changes of protein expression. Our data suggest that resveratrol prevents memory deficits, endothelial dysfunction, increased oxidative stress, inflammation and impairment of neurotrophin expression in a VD rat model. Thus, the vasculoprotective and neuroprotective effects of resveratrol may be beneficial in DM patients.

MicroRNA-210-5p Contributes to Cognitive Impairment in Early Vascular Dementia Rat Model Through Targeting Snap25

Vascular dementia (VD) is the most common form of dementia in elderly people. However, little is understood about the role of microRNAs (miRNAs) involved in cognitive impairment in early VD. Here, a VD model induced by chronic cerebral ischemia and fetal bovine serum (FBS)-free cell model that detects synapse formation was established to investigate the function of miRNAs in early VD. The microarray analysis and real-time reverse transcription polymerase chain reaction (RT-PCR) showed that miR-210-5p increased significantly in the hippocampus of rats with 4 weeks of ischemia. The VD model rats also displayed significant cognitive deficits and synaptic loss. The overexpression of miR-210-5p decreased the synaptic number in primary hippocampal neurons, whereas specific suppression of miR-210-5p resulted in the formation of more synapses. Additionally, intracerebroventricular (ICV) injection of miR-210-5p agomir to VD rats aggravated phenotypes of cognitive impairment and synaptic loss. These VD-induced phenotypes were effectively attenuated by miR-210-5p antagomir. Moreover, bioinformatic prediction revealed that synaptosomal-associated protein of 25 KDa (Snap25) mRNA is targeted by miR-210-5p. The miR-210-5p decreased the luciferase activities of 3’ untranslated region (3’UTR) of Snap25 mRNA. Mutation of predicted miR-210-5p binding sites in the 3’ UTR of Snap25 mRNA abolished the miR-210-5p-induced decrease in luciferase activity. Western blot and immunofluorescence staining confirmed that miR-210-5p targets Snap25. Finally, RT-quantitative PCR (qPCR) and immunofluorescence staining detected that miR-210-5p agomir downregulated Snap25 expression in the cornu ammonis1 (CA1) region of hippocampi in VD rats, whereas miR-210-5p antagomir upregulated Snap25 expression. Altogether, miR-210-5p contributes to cognitive impairment in chronic ischemia-induced VD model through the regulation of Snap25 expression, which potentially provides an opportunity to develop a new therapeutic strategy for VD.

DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats.

DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real-time quantitative polymerase chain reaction analysis revealed that plasticity-related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS-related markers decreased. The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other.

Acupuncture as a multifunctional neuroprotective therapy ameliorates cognitive impairment in a rat model of vascular dementia: A quantitative iTRAQ proteomics study.

Acupuncture has been reported to affect vascular dementia through a variety of molecular mechanisms. An isobaric tag for relative and absolute quantification (iTRAQ) with high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses makes it possible to attain a global profile of proteins. Hence, we used an iTRAQ-LC-MS/MS strategy to unravel the underlying mechanism of acupuncture. Wistar rats were subjected to vascular dementia with bilateral common carotid occlusion. Acupuncture was intervened for 2weeks at 3days after surgery. The Morris water maze was used to assess the cognitive function. Proteins were screened by quantitative proteomics and analyzed by bioinformatic analysis. Four differentially expressed proteins (DEPs) were validated by western blot. The reactive oxygen species (ROS) production, neuron cell loss, and long-term potentiation (LTP) were determined after western blot. Acupuncture at proper acupoints significantly improved cognitive function. A total of 31 proteins were considered DEPs. Gene ontology (GO) analysis showed that most of the DEPs were related to oxidative stress, apoptosis, and synaptic function, which were regarded as the major cellular processes related to acupuncture effect. Western blot results confirm the credibility of iTRAQ results. Acupuncture could decrease ROS production, increase neural cell survival, and improve LTP, which verified the three major cellular processes. Acupuncture may serve as a promising clinical candidate for the treatment of vascular dementia via regulating oxidative stress, apoptosis, or synaptic functions.

Synergistic Effects of Mesenchymal Stem Cell Transplantation and Repetitive Transcranial Magnetic Stimulation on Promoting Autophagy and Synaptic Plasticity in Vascular Dementia.

Repetitive transcranial magnetic stimulation (rTMS) and mesenchymal stem cells (MSCs) transplantation both showed therapeutic effects on cognition impairment in vascular dementia (VD) model rats. However, whether these two therapies have synergistic effects and the molecular mechanisms remain unclear. In our present study, rats were randomly divided into six groups: control group, sham operation group, VD group, MSC group, rTMS group, and MSC+rTMS group. The VD model rats were prepared using a modified 2VO method. rTMS treatment was implemented at a frequency of 5 Hz, the stimulation intensity for 0.5 Tesla, 20 strings every day with 10 pulses per string and six treatment courses. The results of the Morris water maze test showed that the learning and memory abilities of the MSC group, rTMS group, and MSC+rTMS group were better than that of the VD group, and the MSC+rTMS group showed the most significant effect. The protein expression levels of brain-derived neurotrophic factor, NR1, LC3-II, and Beclin-1 were the highest and p62 protein was the lowest in the MSC+rTMS group. Our findings demonstrated that rTMS could further enhance the effect of MSC transplantation on VD rats and provided an important basis for the combined application of MSC transplantation and rTMS to treat VD or other neurological diseases.

FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of vascular dementia

Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been demonstrated to be involved in VD progression. Molecular hydrogen is known for its powerful anti-oxidative, anti-apoptotic, and anti-inflammatory activities, and it is also involved in autophagy. However, the effects of hydrogen on VD remain unclear. The current study found that hydrogen-rich water (HRW) significantly alleviated spatial learning and memory impairments. Similar to donepezil treatment, HRW also inhibited neuron loss and shrinkage in the hippocampal CA1 region. In addition, we found that HRW significantly increased the Bcl-2/Bax expression ratio and decreased cleaved caspase-3 expression levels in the hippocampus of VD rats. Moreover, electron microscopy revealed that HRW decreased the number of autophagosomes. We also observed that HRW reduced the increased ratio of LC3-II/I and Beclin 1 expression and saliently upregulated p62 expression. Furthermore, FoxO1 (a major mediator of autophagy regulation) and Atg7 levels were apparently decreased in the hippocampus of HRW-treated bilateral common carotid artery occlusion (2VO) rats. Taken together, these data show that molecular hydrogen exerts beneficial effects on cognitive impairment induced by chronic cerebral hypoperfusion. FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of VD. Furthermore, the present findings highlight that HRW should be further investigated as a new therapeutic strategy for VD treatment in the future.

Genome‑wide DNA methylation profiling in a rat model with vascular dementia.

Vascular dementia (VaD), the second most prevalent type of dementia, is caused by reduced blood supply to the brain that results in cognitive impairment. Despite the efforts of numerous studies, the pathological mechanisms behind VaD remain unclear. The aim of the present study was to identify candidate genes that undergo changes in hippocampal DNA methylation owing to VaD. A genome-wide DNA methylation analysis was performed, using methylated DNA-binding domain sequencing. VaD model rats with cognitive impairment induced by bilateral common carotid artery occlusion were confirmed using the radial arm maze test. A total of 1,180 differentially methylated genes (DMGs) were identified, and functional annotation analysis revealed the DMGs to be enriched in 10 Gene Ontology biological processes. Network analysis using the STRING database indicated that seven genes were closely connected. Rats in the VaD model group demonstrated relative hypomethylation in the promoter region and increased mRNA expression of the hippocampal genes vascular endothelial growth factor (VEGFA) and kinase insert domain receptor, but only differences in VEGFA mRNA expression levels were determined to be statistically significant. In conclusion, these preliminary data from the functional annotation of hippocampal DMGs in the promoter region highlighted candidate genes for VaD that may contribute to the elucidation of its pathophysiology.