Rat Model Of Vascular Dementia Research Articles

Tong-Qiao-Huo-Xue Decoction promotes synaptic remodeling via cAMP/PKA/CREB pathway in vascular dementia rats

BackgroundTong-Qiao-Huo-Xue Decoction (TQHXD) is a traditional Chinese medicinal formula widely used in the treatment of vascular dementia (VD). Although it has demonstrated good clinical efficacy, the specific molecular mechanisms underlying its therapeutic effects on VD remain unclear. ObjectiveThis study aimed to elucidate the neuroprotective mechanisms of TQHXD to provide a scientific basis for the clinical treatment of VD. MethodsThe chemical components of TQHXD were qualitatively analyzed using ultra-performance liquid chromatography (UPLC) and gas chromatography (GC). Network pharmacology predicted the potential protective mechanisms of TQHXD against VD. A rat model of VD was established through bilateral vessel occlusion (2-VO), and an oxygen-glucose deprivation/reperfusion (OGD/R) model was used to induce damage to neuronal cells of the hippocampus. In vivo experiments assessed changes in cerebral blood flow, learning and memory capabilities, hippocampal neuronal morphology, dendritic length, dendritic spine density, and synapse number in rats. We examined the expression of synaptic remodeling-related proteins and pathway proteins in the hippocampal region. In vitro assays evaluated cell viability, apoptosis, reactive oxygen species (ROS) levels, and expression of synaptic remodeling-related proteins and signaling pathway. ResultsMultiple active components were identified in TQHXD. KEGG enrichment analysis suggested that the therapeutic effects of TQHXD on VD may be related to the cAMP signaling pathway. Treatment with TQHXD significantly improved learning and memory performance in VD rats, improved hippocampus morphology, and increased dendritic length, dendritic spine density, and number of synapses. Furthermore, TQHXD improved cell viability, reduced apoptosis, and decreased intracellular ROS levels in vitro. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay results collectively demonstrated that TQHXD upregulated the expression of synaptic remodeling-related proteins and pathway-related proteins both in vivo and in vitro. ConclusionsTQHXD treated VD by promoting synaptic remodeling in hippocampal neurons, likely through activation of the cAMP/PKA/CREB pathway.

Profiling hippocampal expression of long non-coding RNA GM12371 in a rat model of vascular dementia

BackgroundDementia, characterized by synaptic dysfunction and memory loss, presents a significant challenge in medical research. Long non-coding RNAs (lncRNAs), known for their crucial roles in regulating gene expression, represent a gap in knowledge regarding their specific involvement in synaptic structure, transmission, and plasticity. This study aims to investigate the dynamic changes in hippocampal lncRNA GM12371 expression in response to acute and chronic hypoperfusion in the rat brain using the 2VO model.MethodsThe 2VO model was induced by permanently occluding the common carotid arteries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate hippocampal lncRNA GM12371 expression at both acute (day 4) and chronic (day 28) stages post-2VO surgery. Comparative analysis was conducted with a sham-operated group.ResultsA notable reduction in GM12371 expression was observed in the rat hippocampus on day 4 following 2VO surgery compared to the sham group (P < 0.05). However, there was no significant difference in GM12371 expression between the sham and 2VO-28 groups.ConclusionThese findings suggest that the downregulation of GM12371 is a response to acute hippocampal blood flow reduction but tends to normalize during the chronic phase of cerebral hypoperfusion. This dynamic regulation of GM12371 expression may be significant in the adaptive response to vascular dementia. Further clinical studies are warranted to investigate potential peripheral alterations in GM12371 expression in individuals with dementia.

Molecular profiling of a rat model of vascular dementia: Evidences from proteomics, metabolomics and experimental validations

Decrease of cerebral blood flow is the primary cause of vascular dementia (VD), but its pathophysiological mechanisms are still not known. This study aims to profile the molecular changes of a rat model of VD induced by bilateral common carotid artery ligation. The Morris water maze and new object recognition tasks were used to test the cognitive function of rats. Hematoxylin and Eosin (HE) staining was used to detect pathological changes in the hippocampus. After confirming the model, proteomics was used to detect differentially expressed proteins in the hippocampus, and metabolomics was used to detect differential metabolites in rat serum. Thereafter, bioinformatics were used to integrate and analyze the potential molecular profile. The results showed that compared with the sham control group, the spatial and recognition memory of the rats were significantly reduced, and pathological changes were observed in the hippocampal CA1 region of the model group. Proteomic analysis suggested 206 differentially expressed proteins in the hippocampus of VD rats, with 117 proteins upregulated and 89 downregulated. Protein-protein interaction network analysis suggested that those differentially expressed proteins might play crucial roles in lipid metabolism, cell adhesion, intracellular transport, and signal transduction. Metabolomics analysis identified 103 differential metabolites, and comparison with the human metabolome database revealed 22 common metabolites, which predicted 265 potential targets. Afterwards, by intersecting the predicted results from metabolomics with the differentially expressed proteins from proteomics, we identified five potential targets, namely ACE, GABBR1, Rock1, Abcc1 and Mapk10. Furthermore, western blotting confirmed that compared with control group, hippocampal GABBR1 and Rock1 were enhanced in the model group. Together, this study showed the molecular profile of VD rats through a combination of proteomics, metabolomics, and experimental confirmation methods, offering crucial molecular targets for the diagnosis and treatment of VD.

Platelet-rich plasma protects hippocampal neurons and memory functions in a rat model of vascular dementia.

Platelet-rich plasma (PRP) is a promising biomaterial rich in bioactive growth factors, offering potential as a therapeutic agent for various diseases. However, its effectiveness in central nervous system disorders like vascular dementia (VaD) remains underexplored. This study investigated the potential of PRP to mitigate VaD progression in vivo. A rat model of VaD was established via bilateral common carotid artery occlusion and hypovolemia operation. Rats were randomly assigned to receive either PRP or platelet-poor plasma (PPP)-the latter being a byproduct of PRP preparation and used as a reference standard-resulting in the groups designated as 'operated group (OP)+PRP' and 'OP+PPP', respectively. PRP or PPP (500 μl) was administered intraperitoneally on the day of the operation and postoperative days 2, 4, 6, and 8. Cognitive function was assessed using the Y-maze, Barnes maze, and passive avoidance tests. On postoperative day 8, hippocampal samples were subjected to histological and semi-quantitative analyses. OP exhibited significant memory decline compared to controls, while the 'OP+PRP' group showed notable improvement. Histological analysis revealed increased neuronal loss and neuroinflammation in OP hippocampi, mitigated in 'OP+PRP'. Semi-quantitative analysis showed decreased expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) in OP, restored in 'OP+PPP' and further in 'OP+PRP'. These results highlight PRP's protective effects against VaD-induced hippocampal damage and cognitive impairment, partially attributed to BDNF/TrkB pathway upregulation.

Inhibition of histone methyltransferase promotes cognition and mitochondrial function in vascular dementia model

Vascular dementia (VD) is one of the most common forms of dementia worldwide, characterized by problems with reasoning, planning, judgment, and memory. This study investigated the effect of a histone methyltransferase inhibitor on cognition and mitochondrial function in a rat model of VD, as well as its impact on H2O2-induced neurotoxicity in hippocampal neuronal cultures. In the in vivo experiments, VD was induced by bilateral occlusion of the common carotid artery (CCA) for one month. The histone methyltransferase inhibitor, BIX01294, was administered intracerebroventricularly for one month (22.5 µg.kg−1 three times/week). On day 30, behavioral tests, including the novel object recognition test and elevated plus maze test, were conducted. Mitochondrial enzyme activities, including aconitase, α-ketoglutarate dehydrogenase (α-KG), complex I, and complex IV, were evaluated in the hippocampus of rats following CCA ligation. In the in vitro experiments, the effect of BIX01294 (50–600 μM) on H2O2 (400 µM)-induced cytotoxicity in hippocampal neuronal cells was assessed using the MTT assay. Flow cytometry was performed to evaluate apoptosis. Our findings revealed that BIX01294 effectively improved memory function, Krebs cycle enzyme activity, and mitochondrial function in the rat model of VD. Moreover, in vitro results showed that BIX01294 at a concentration of 100 µM significantly reversed the cytotoxicity and apoptosis induced by H2O2 in neuronal cells. These findings suggest that BIX01294 may have the potential to improve VD complications by reducing oxidative stress and inhibiting histone methylation.

Tongqiao Yizhi granule repress the nuclear factor kappa-b/nucleotide oligomerization domain-like receptors 3/caspase-1 pyroptosis pathway in the hippocampus to counter vascular dementia in rats.

To explore the mechanism by which Tongqiao Yizhi granule (, TQYZKL) intervenes pyroptosis to treat vascular dementia (VaD) in a rat model. The rat model of VaD was established by two-vessel occlusion (2VO). The rats were randomly divided into Sham group, Model group, Nimodipine group, TQYZKL (6.2 g?kg-1?d-1), TQYZKL (12.4 g?kg-1?d-1), TQYZKL (24.8 g?kg-1?d-1). The Morris water maze (MWM) test was carried out to test the learning and memory function; Hematoxylin-eosin staining and transmission electron microscopy (TEM) to observe the pathological damage in the hippocampus; Tunel fluorescence staining to detect neuronal pyroptosis in the hippocampus. The expression levels of pyroptosis-related proteins, namely Golgi peripheral membrane protein p65 (P65), nucleotide oligomerization domain-like receptors 3 (NLRP3), caspase-1 and Gasdermin D (GSDMD), were detected using Western blotting and reverse transcription polymerase chain reaction. Moreover, the serum levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were determined through the enzyme-linked immunosorbent assay. The study revealed that TQYZKL effectively improved the ability of VaD ratsto learn and memorize, relieved the pathological damage in the hippocampus, restored neuronal morphology, and reduced the expression of pyroptosis-related proteins P65, NLRP3, caspase-1, GSDMD-N, IL-18 and IL-1β (P < 0.05). TQYZKL inhibits neuronal pyroptosis in the hippocampus of VaD rats by regulating nuclear factor kappa-B/NLRP3/caspase-1 signaling pathway, thus exerting a therapeutic effect on VaD in the rats.

Astaxanthin Rescues Memory Impairments in Rats with Vascular Dementia by Protecting Against Neuronal Death in the Hippocampus.

Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST)has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25mg/kg per day for 4weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD.

Treadmill exercise prevents recognition memory impairment in VD rat model and enhancement of hippocampal structural synaptic plasticity.

In vascular dementia (VD), memory impairment caused by the damage of synaptic plasticity is the most prominent feature that afflicts patients and their families. Treadmill exercise has proven beneficial for memory by enhancing synaptic plasticity in animal models including stroke, dementia, and mental disorders. The aim of this study was to examine the effects of treadmill exercise on recognition memory and structural synaptic plasticity in VD rat model. Male Sprague-Dawley rats were randomly assigned into four groups: control group (C group, n=6), vascular dementia group (VD group, n=6), treadmill exercise and vascular dementia group (Exe-VD group, n=6), and treadmill exercise group (Exe group, n=6). Four-week treadmill exercise was performed in the Exe-VD and Exe groups. Then, the common carotid arteries of rats in the VD and Exe-VD groups were identified to establish the VD model. Behavior tests (open-field test and novel recognition memory test) were adopted to evaluate anxiety-like behavior and recognition memory. Transmission electron microscopy and Golgi staining were performed to observe synaptic ultrastructure and spine density in the hippocampus. Our study demonstrated that VD rat exhibited significantly anxiety-like behavior and recognition impairment (p <.01), while treadmill exercise significantly alleviated anxiety-like behavior and improved recognition memory in VD rat (p <.01). Transmission electron microscopy revealed that hippocampal synapse numbers were significantly decreased in the VD group compared to the control group (p <.05). These alterations were reversed by treadmill exercise, and the rats exhibited healthier synaptic ultrastructure, including significantly increased synapse (p <.05). Meanwhile, golgi staining revealed that the spine numbers of the hippocampus were significantly decreased in the VD group compared to the control group (p <.05). When compared with the VD group, hippocampal spine numbers were significantly increased in the Exe-VD group (p <.05). The improvement of VD-associated recognition memory by treadmill exercises is associated with enhanced structural synaptic plasticity in VD rat model.

Hydrogen Attenuates Cognitive Impairment in Rat Models of Vascular Dementia by Inhibiting Oxidative Stress and NLRP3 Inflammasome Activation.

Vascular dementia (VaD) is the second most common form of dementia worldwide. Oxidative stress and neuroinflammation are important factors contributing to cognitive dysfunction in patients with VaD. The antioxidant and anti-inflammatory properties of hydrogen are increasingly being utilized in neurological disorders, but conventional hydrogen delivery has the disadvantage of inefficiency. Therefore, magnesium silicide nanosheets (MSNs) are used to release hydrogen in vivo in larger quantities and for longer periods of time to explore the appropriate dosage and regimen. In this study, it is observed that hydrogen improved learning and working memory in VaD rats in the Morris water maze and Y-maze, which elicits improved cognitive function. Nissl staining of neurons shows that hydrogen treatment significantly improves edema in neuronal cells. The expression and activation of reactive oxygen species (ROS), Thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), caspase-1, and IL-1β in the hippocampus are measured via ELISA, Western blotting, real-time qPCR, and immunofluorescence. The results show that oxidative stress indicators and inflammasome-related factors are significantly decreased after 7dMSN treatment. Therefore, it is concluded that hydrogen can ameliorate neurological damage and cognitive dysfunction in VaD rats by inhibiting ROS/NLRP3/IL-1β-related oxidative stress and inflammation.

The low and high doses administration of lutein improves memory and synaptic plasticity impairment through different mechanisms in a rat model of vascular dementia.

Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

Edaravone dexborneol attenuates cognitive impairment in a rat model of vascular dementia by inhibiting hippocampal oxidative stress and inflammatory responses and modulating the NMDA receptor signaling pathway

Exploring the intricate pathogenesis of Vascular Dementia (VD), there is a noted absence of potent treatments available in the current medical landscape. A new brain-protective medication developed in China, Edaravone dexboeol (EDB), has shown promise due to its antioxidant and anti-inflammatory properties, albeit with a need for additional research to elucidate its role and mechanisms in VD contexts. In a research setup, a VD model was established utilizing Sprague-Dawley (SD) rats, subjected to permanent bilateral typical carotid artery occlusion (2VO). Behavioral assessment of the rats was conducted using the Bederson test and pole climbing test, while cognitive abilities, particularly learning and memory, were evaluated via the novel object recognition test and the Morris water maze test. Ensuing, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), IL-1β, IL-6, IL-4, and tumor necrosis factor-α (TNF-α) were determined through Enzyme-Linked Immunosorbent Assay (ELISA). Synaptic plasticity-related proteins, synaptophysin (SYP), post-synaptic density protein 95 (PSD-95), and N-methyl-D-aspartate (NMDA) receptor proteins (NR1, NR2A, NR2B) were investigated via Western blotting technique. The findings imply that EDB has the potential to ameliorate cognitive deficiencies, attributed to VD, by mitigating oxidative stress, dampening inflammatory responses, and modulating the NMDA receptor signaling pathway, furnishing new perspectives into EDB’s mechanism and proposing potential avenues for therapeutic strategies in managing VD.

Inhibition of Glial Activation and Subsequent Reduction in White Matter Damage through Supplementation with a Combined Extract of Wheat Bran, Citrus Peel, and Jujube in a Rat Model of Vascular Dementia.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. In our previous studies, we showed that wheat bran extract (WBE) reduced white matter damage in a rat VaD model and improved memory in a human clinical trial. However, starch gelatinization made the large-scale preparation of WBE difficult. To simplify the manufacturing process and increase efficacy, we attempted to find a decoction containing an optimum ratio of wheat bran, sliced citrus peel, and sliced jujube (WCJ). To find an optimal ratio, the cell survival of C6 (rat glioma) cultured under hypoxic conditions (1% O2) was measured, and apoptosis was assessed. To confirm the efficacies of the optimized WCJ for VaD, pupillary light reflex, white matter damage, and the activation of astrocytes and microglia were assessed in a rat model of bilateral common carotid artery occlusion (BCCAO) causing chronic hypoperfusion. Using a combination of both searching the literature and cell survival experiments, we chose 6:2:1 as the optimal ratio of wheat bran to sliced citrus peel to sliced jujube to prepare WCJ. We showed that phytic acid contained only in wheat bran can be used as an indicator component for the quality control of WCJ. We observed in vitro that the WCJ treatment improved cell survival by reducing apoptosis through an increase in the Bcl-2/Bax ratio. In the BCCAO experiments, the WCJ-supplemented diet prevented astrocytic and microglial activation, mitigated myelin damage in the corpus callosum and optic tract, and, consequently, improved pupillary light reflex at dosages over 100 mg/kg/day. The results suggest that the consumption of WCJ can prevent VaD by reducing white matter damage, and WCJ can be developed as a safe, herbal medicine to prevent VaD.

7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD.VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20mg/kg) and Donepezil (10mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1β, and NF-kβ), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats.Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus.These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

Baicalein ameliorates cognitive impairment of vascular dementia rats via suppressing neuroinflammation and regulating intestinal microbiota

Neuroinflammation induced by chronic cerebral hypoperfusion (CCH) plays a crucial role in the pathophysiologic mechanisms of vascular dementia (VD). A growing body of research has found that intestinal microbiota is associated with a variety of central nervous system disorders and that there is a relationship between intestinal microbiota dysbiosis and cognitive dysfunction and inflammatory responses. Baicalein belongs to the class of flavonoids and has a variety of biological functions, including anti-inflammatory, antioxidant and anti-apoptotic. Baicalein has a significant improvement in memory and learning, and can be used as a potential drug for the protection and treatment of central nervous system disorders. Whether baicalein has an ameliorative effect on cognitive impairment in VD, and whether its mechanism is related to the inhibition of inflammatory response and regulation of intestinal microbiota has not been reported. We used bilateral common carotid artery occlusion (BCCAO) to establish a VD rat model. Morris water maze (MWM) test showed that baicalein improved cognitive dysfunction in VD rats. We applied HE staining, immunofluorescence and ELISA to observe that baicalein treatment significantly improved CCH-induced neuronal damage in the CA1 region of the hippocampus, and reduced glial cell activation and release of pro-inflammatory factors. Western blot showed that baicalein inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway in VD rats. We applied 16 S rDNA sequencing to analyze the composition of the intestinal microbiota. The results showed that baicalein modulated the diversity and composition of the intestinal microbiota, and suppressed the relative abundance of inflammation-associated microbiota in VD rats. In conclusion, this study found that baicalein ameliorated cognitive impairment, attenuated hippocampal inflammatory responses, inhibited the TLR4/MyD88/NF-κB signaling pathway, and modulated intestinal microbiota in VD rats.

Integration of metabolomics and network pharmacology technology to explain the effect mechanisms of Danggui Buxue decoction in vascular dementia.

Danggui Buxue decoction (DBD) is a traditional Chinese medicine herbal decoction that has a good therapeutic effect on vascular dementia (VaD). However, its pharmacodynamic substances and underlying mechanisms are ambiguous. The work aimed to decipher the pharmacodynamic substances and molecular mechanisms of DBD against VaD rats based on gas chromatography-mass spectrometry metabonomics, network pharmacology, molecular docking, and experimental verification. The results indicated that DBD significantly improved the learning abilities and cognitive impairment in the VaD rat model. Integration analysis of the metabolomics and network pharmacology approach revealed that DBD might primarily affect arachidonic acid (AA) and inositol phosphate metabolic pathways by regulating the platelet activation signaling pathways. Six core targets (TNF [tumor necrosis factor], IL-6 [interleukin 6], PTGS2 [prostaglandin-endoperoxide synthase 2], MAPK1, MAPK3, and TP53) in the platelet activation signaling pathways also had a good affinity to seven main active components (saponins, organic acids, flavonoids, and phthalides) of DBD through the verification of molecular docking. Enzyme-linked immunosorbent assay results (ELISA) showed that the levels of TNF, IL-6, PTGS2, thromboxane B2, and caspase-3 in the platelet activation signaling pathway can be regulated by DBD. Our results indicated that DBD treated VaD mainly by modulating the platelet activation signaling pathway, and AA and inositol phosphate metabolism.

Fucoidan protects CA1 pyramidal neurons of the hippocampus and preserves the cognitive profile of rats subjected to transient forebrain ischemia

Fucoidan, a polysaccharide derived from brown seaweeds, especially Fucus Vesiculosus has been documented as an effective neuroprotectant. This study investigates the efficacy of fucoidan in mitigating the cognitive deficits in the rat model of vascular dementia induced through the 4-vessel occlusions (4VO) method. Male Wistar rats weighing about 250–300 g were randomly assigned into four groups, sham, lesion (4VO), 4VO + F5mg/kg, and 4VO + F50mg/kg. The rats were assessed for cognitive behaviour performance through novel object task, T-maze and Morris water maze, and finally, the hippocampus from the brain was harvested to quantify the profile of CA1 pyramidal neurons through CFV staining and the expression of inflammatory markers and angiogenic markers were quantified through western blot assessment on day7 and 30 of the study period. The rats were treated with fucoidan at a dose of 50 mg/kg. body weight showed improved spatial learning and memory compared to the lesion group and the cytoarchitecture of CA1 pyramidal cells was observed to be well preserved. The expression of IL1β, IL6, TNFα, NFk-B, CD68 and HIFα were found to be down-regulated, while on the contrary the VEGFR2 and angiopoietin-1 were up regulated in the 4VO + F50mg/kg group when compared with the lesion group. In conclusion, this study ascertains the role of fucoidan in support of the cognitive profile of rats subjected to vascular dementia and in preserving the CA1 pyramidal neurons of the hippocampus by regulating the inflammatory and angiogenic factors.

Gens PSD-95 and GSK-3β expression improved by hair follicular stem cells-conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia.

Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. The rats were divided into four groups of control (n=9), sham-operation (n=10), VaD with vehicle (n=9), and VaD with CM (n=12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open-field (OP), passive-avoidance, and Morris-water maze. The field-potential recording was used to investigate basal synaptic transmission (BST) and long-term potentiation (LTP). Subsequently, the hippocampus was dissected, and real-time PCR was used to quantify the expression levels of β1-catenin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-β), glycogen synthase kinase-3β (GSK-3β), postsynaptic density protein 95 (PSD-95), and NR2B genes. The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of β1-catenin, IGF-1, PSD-95, and TGF-β genes decreased, whereas NR2B and GSK-3β expression increased. Treatment with CM restores the expression of PSD-95 and GSK-3β as well as fear-memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.

Botanical Mixture Containing Nitric Oxide Metabolite Enhances Neural Plasticity to Improve Cognitive Impairment in a Vascular Dementia Rat Model.

Vascular dementia (VD), caused by impaired cerebral blood flow, is the most common form of dementia after Alzheimer's disease (AD) in the elderly and is characterized by severe neuronal damage and cognitive decline. Nitric oxide (NO) is an important determinant of vascular homeostasis, and its deficiency is associated with the progression of VD. In this study, we investigated the role of nitrite ion, a NO metabolite in a botanical mixture (BM) of fermented garlic, fermented Scutellaria baicalensis, and Rhodiola rosea on neuron loss and cognitive impairment using a VD rat model. The BM containing the NO metabolite alleviated cognitive deficits and enhanced neural plasticity, as reflected by an increase in long-term potentiation. The BM also alleviated neuron apoptosis, decreased GFAP expression, and oxidative stress, and increased parvalbumin and brain-derived neurotrophic factor (BDNF) levels. These results indicate that BM exerts neuroprotective effects and alleviates cognitive dysfunction while enhancing neuroplasticity, and thus has therapeutic potential against VD.

MiR-181a regulates mitophagy and improves cognitive function in vascular dementia via targeting PINK1/Parkin pathway

This study investigates the mechanism of miR-181a in cognitive function and mitophagy in vascular dementia. A rat model of vascular dementia was established by common carotid artery ligation and then divided into model group (n= 10), mimics group (n= 10), inhibitors group (n= 10), NC group (n= 10), and the remaining 10 rats were in sham operation group. The rats in mimics group were intravenously injected with miR-181a mimics and rats in inhibitors group were injected with miR-181a inhibitors. Model group and mimics group rats had a longer time on the 3rd to 4th day than sham operation group, and inhibitors group had a shorter time than model group and mimics group (allP&lt;0.05). Time in quadrant of the cylindrical platform in model group and mimics group was shortened while it was prolonged in inhibitors group (P&lt; 0.05). miR-181a mRNA level in model group, inhibitors group and NC group was lower. On the contrary, PINK1 and Parkin level was higher. miR-181a mRNA level was higher in mimics group with lower levels of PINK1 and Parkin (P&lt;0.05). miR-181a level in mimics group was significantly increased and PINK1 and Parkin mRNA was decreased. miR-181a mRNA level in inhibitors group decreased significantly, while PINK1 and Parkin mRNA was increased (P&lt;0.05). Parkin expression in mimics group and NC group was reduced. Up-regulation of miR-181 (mimics group) can target and inhibit PINK1/Parkin mRNA, thereby inhibiting mitophagy. miR-181a downregulation in mitochondria can promote PINK1/Parkin expression, thereby activating mitophagy in rats with vascular dementia, alleviating mitochondrial dysfunction, and improving the cognitive ability of rats.

Dendrobium Nobile Polysaccharides Attenuates Ferroptosis and Improves Cognitive Function in Vascular Dementia Rats.

To investigate the neuroprotective effect and mechanism of Dendrobium nobile polysaccharide (DNP) on vascular dementia (VD) rats. VD model rats were prepared by permanent ligation of bilateral common carotid arteries. Cognitive function was tested by morris water maze test, mitochondrial morphology and ultrastructure of hippocampal synapses were tested by transmission electron microscopy, GSH, xCT, GPx4, and PSD-95 expressions were tested by western blot and PCR. The number of platform crossing was significantly increased, and the escape latency was significantly shorter in DNP group. The expressions of GSH, xCT and GPx4 in the hippocampus were up-regulated in DNP group. Moreover, the synapses of DNP group were relatively intact and synaptic vesicles increased, the length of synaptic active zone and PSD thickness were significantly increased, and PSD-95 protein expression was significantly up-regulated compared VD group. DNP may take a neuroprotective effect by inhibiting ferroptosis in VD.