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-1ß, 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.

Butylphthalide combined with donepezil for the treatment of vascular dementia: a meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. METHODS: Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software. RESULTS: Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment. CONCLUSION: Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.

Effects of schisandrin B on hypoxia-related cognitive function and protein expression in vascular dementia rats.

Vascular dementia (VD) a heterogenous group of brain disorders in which cognitive impairment is attributable to vascular risk factors and cerebrovascular disease. A common phenomenon in VD is a dysfunctional cerebral regulatory mechanism associated with insufficient cerebral blood flow, ischemia and hypoxia. Under hypoxic conditions oxygen supply to the brain results in neuronal death leading to neurodegenerative diseases including Alzheimer's (AD) and VD. In conditions of hypoxia and low oxygen perfusion, expression of hypoxia-inducible factor 1 alpha (HIF-1α) increases under conditions of low oxygen and low perfusion associated with upregulation of expression of hypoxia-upregulated mitochondrial movement regulator (HUMMR), which promotes anterograde mitochondrial transport by binding with trafficking protein kinesin 2 (TRAK2). Schisandrin B (Sch B) an active component derived from Chinese herb Wuweizi prevented ß-amyloid protein induced morphological alterations and cell death using a SH-SY5Y neuronal cells considered an AD model. It was thus of interest to determine whether Sch B might also alleviate VD using a rat bilateral common carotid artery occlusion (BCAO) dementia model. The aim of this study was to examine the effects of Sch B in BCAO on cognitive functions such as Morris water maze test and underlying mechanisms involving expression of HIF-1α, TRAK2, and HUMMR levels. The results showed that Sch B improved learning and memory function of rats with VD and exerted a protective effect on the hippocampus by inhibition of protein expression of HIF-1α, TRAK2, and HUMMR factors. Evidence indicates that Sch B may be considered as an alternative in VD treatment.

A novel phthalein component ameliorates neuroinflammation and cognitive dysfunction by suppressing the CXCL12/CXCR4 axis in rats with vascular dementia.

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanxiong, a plant of the Umbelliferae family, is a genuine medicinal herb from Sichuan Province. Phthalides are one of its main active components and exhibit good protective effect against cerebrovascular diseases. However, the mechanism by which phthalides exert neuroprotective effects is still largely unclear. AIM OF THE STUDY: In this study, we extracted a phthalein component (named as QBT) from Ligusticum Chuanxiong, and investigated its neuroprotective effects against vascular dementia (VaD) rats and the underlying mechanism, focusing on the chemokine 12 (CXCL12)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis. METHODS: A rat model of VaD was established, and treated with QBT. Cognitive dysfunction in VaD rats was assessed using the Y-maze, new object recognition, and Morris water maze tests. Neuronal damage and inflammatory response in VaD rats were examined through Nissl staining, immunofluorescence, enzyme-linked immunospecific assay, and western blotting analysis. Furthermore, the effects of QBT on CXCL12/CXCR4 axis and its downstream signaling pathways, Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor-κB (NF-κB), were investigated in VaD rats and BV2 microglial cells exposed to oxygen glucose deprivation. RESULTS: QBT significantly alleviated cognitive dysfunction and neuronal damage in VaD rats, along with inhibition of VaD-induced over-activation of microglia and astrocytes and inflammatory response. Moreover, QBT exhibited anti-inflammatory effects by inhibiting the CXCL12/CXCR4 axis and its downstream JAK2/STAT3 and PI3K/AKT/NF-κB pathways, thereby attenuating the neuroinflammatory response both in vivo and in vitro. CONCLUSION: QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, exerting neuroprotective effects by suppressing neuroinflammatory response through inhibition of the CXCL12/CXCR4 axis.

Effect of butylphthalide combined with idebenone on vascular dementia: A retrospective observational analysis.

To explore the efficacy and safety of butylphthalide combined with idebenone in the treatment of vascular dementia. The clinical data of 126 patients with vascular dementia who were admitted to our hospital between March 2021 and February 2023 were retrospectively reviewed. Among them, 62 patients received butylphthalide alone (single group) and 64 patients received butylphthalide combined with idebenone (combined group). Cognitive function scores, serum inflammatory factor levels, oxidative stress index levels, and incidence of adverse reactions were compared between the 2 groups before and after treatment. After treatment, the Hasegawa Dementia Scale, Mini Mental State Examination Scale, and activities of daily living scores in both groups were higher than before treatment, and the scores in the combined group were higher than before treatment (P < .05). After treatment, the levels of serum C-reactive protein, tumor necrosis factor-α, and interleukin 6 in both groups were lower than those before treatment, and those in the combined group were lower than those in the simple group (P < .05). After treatment, the levels of serum glutathione peroxidase and superoxide dismutase in the 2 groups were higher than those before treatment, and the level of malondialdehyde was lower than that before treatment. The levels of serum glutathione peroxidase and superoxide dismutase in the combined group were higher than those in the simple group, and the level of malondialdehyde was lower than that in the simple group (P < .05). There was no significant difference in the incidence of adverse reactions between the combined group (6.25%) and the simple group (3.23%) (P > .05). Compared with butylphthalide alone, intervention of butylphthalide combined with idebenone on vascular dementia can effectively reduce the degree of inflammatory and oxidative stress reactions, improve cognitive function, and promote the ability to perform activities of daily living in a safe manner.

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 20 mg/kg) and Donepezil (10 mg/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-1ß, and NF-kß), 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.

Nasal Administration of bFGF-Loaded Nanoliposomes Attenuates Neuronal Injury and Cognitive Deficits in Mice with Vascular Dementia Induced by Repeated Cerebral Ischemia‒Reperfusion.

Introduction: Basic fibroblast growth factor (bFGF) shows great potential for preventing vascular dementia (VD). However, the blood‒brain barrier (BBB) and low bioavailability of bFGF in vivo limit its application. The present study investigated how nasal administration of bFGF-loaded nanoliposomes (bFGF-lips) affects the impaired learning and cognitive function of VD mice and the underlying mechanism involved. Methods: A mouse model of VD was established through repeated cerebral ischemia‒reperfusion. A Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and cognitive function of the mice. Hematoxylin and eosin (HE) staining, Nissl staining and TUNEL staining were used to evaluate histopathological changes in mice in each group. ELISA and Western blot analysis were used to investigate the molecular mechanism by which bFGF-lips improve VD incidence. Results: Behavioral and histopathological analyses showed that cognitive function was significantly improved in the bFGF-lips group compared to the VD and bFGF groups; in addition, abnormalities and the apoptosis indices of hippocampal neurons were significantly decreased. ELISA and Western blot analysis revealed that bFGF-lips nasal administration significantly increased the concentrations of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), bFGF, B-cell lymphoma 2 (Bcl-2), phosphorylated protein kinase B (PAKT), nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1) in the hippocampus of bFGF-lips mice compared with the VD and bFGF groups. Furthermore, the concentrations of malondialdehyde (MDA), caspase-3 and B-cell lymphoma 2-associated X (Bax) were clearly lower in the bFGF-lips group than in the VD and bFGF groups. Conclusion: This study confirmed that the nasal administration of bFGF-lips significantly increased bFGF concentrations in the hippocampi of VD mice. bFGF-lips treatment reduced repeated I/R-induced neuronal apoptosis by regulating apoptosis-related protein concentrations and activating the phosphatidylinositol-3-kinase (PI3K)/(AKT)/Nrf2 signaling pathway to inhibit oxidative stress.

Impact of prescribed opioid use on development of dementia among patients with chronic non-cancer pain.

We aimed to examine the association between opioid use and the development of dementia in patients with chronic non-cancer pain in South Korea. Data were extracted from the National Health Insurance Service database in South Korea. Adult patients diagnosed with musculoskeletal diseases with chronic non-cancer pain between 2010 and 2015 were included in the analysis. Patients who were prescribed opioids regularly and continuously for ≥ 90 days were classified as opioid users. In total, 1,261,682 patients with chronic non-cancer pain were included in the final analysis, of whom 21,800 (1.7%) were opioid users. From January 1, 2016 to December 31, 2020, 35,239 (2.8%) patients with chronic non-cancer pain were newly diagnosed with dementia. In the multivariable model, opioid users showed a 15% higher risk of developing dementia than the control group. Additionally, opioid users showed a 15% and 16% higher risk of developing Alzheimer's disease and unspecified dementia, respectively, than the control group, but did not show any significant differences for vascular dementia. Among adult patients with chronic non-cancer pain, opioid users were at a higher risk of developing dementia than the control group; the risk was significantly higher for Alzheimer's disease but not for vascular dementia in this study. Our results suggest that in patients with CNCP, public health strategies should target opioid users for early dementia detection and intervention.

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.

Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia.

AIM: In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND: VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE: The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS: The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS: AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION: This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.

ß-asarone improves cognitive impairment and alleviates autophagy in mice with vascular dementia via the cAMP/PKA/CREB pathway.

BACKGROUND: Vascular dementia (VD) is the second most common type of dementia after Alzheimer's disease. ß-asarone, a major component of Acorus tatarinowii Schott, is important in neurodegenerative and neurovascular diseases. Studies have confirmed that ß-asarone can mitigate autophagy and reduce damage in hypoxic cells. We also reported that ß-asarone improves learning and memory. This study further clarifies whether ß-asarone attenuates cerebral ischaemic injury by acting through the cAMP/PKA/CREB pathway in VD model mice. METHODS: Here, genes and potential pathways that may be targeted by ß-asarone for the treatment of transient cerebral ischaemia (TCI) and cognitive impairment (CI) were obtained using network pharmacology. The two-vessel occlusion method was used to establish the VD model. The Morris water maze test was used to evaluate the effects on memory. Then, the protein levels of mitofusin-2 (Mfn2), brain-derived neurotrophic factor (BDNF), optic atrophy 1 (OPA1), cyclic adenosine monophosphate (cAMP), myelin basic protein (MBP), matrix metalloproteinase-9 (MMP9) and neuron specific enolase (NSE) were determined by ELISA. The levels of superoxide dismutase (SOD) and malonaldehyde (MDA) were measured using commercial kits. Then, qRT-PCR was employed to investigate the expression of the candidate genes screened from the protein-protein interaction (PPI) network. Furthermore, the expression of the autophagy-related proteins Beclin-1, (microtubule-associated protein light chain 3) LC3, p62, postsynaptic density protein 95 (PSD95), protein kinase A (PKA), pPKA, cyclic-AMP response binding protein (CREB), and pCREB was determined by western blotting. The expression of autophagy-related proteins, PSD95 and translocase of outer mitochondrial membrane 20 (TOM20) was determined by immunofluorescence analyses. RESULTS: The network pharmacological analysis showed 234 targets related to ß-asarone, 1,118 genes related to TCI and 2,039 genes associated with CI. Our results confirm that ß-asarone treatment not only alleviated brain damage in the VD model by improving mitochondrial and synaptic function, reducing neuronal injury and upregulating the expression of antioxidants but also effectively improved the cognitive behaviour of VD model mice. Moreover, ß-asarone downregulated VD-induced RELA and CCND1 mRNA expression. In addition, we validated that ß-asarone increased the phosphorylation of PKA and CREB and upregulated cAMP protein expression. The results showed that the cAMP/PKA/CREB signalling pathway was upregulated. Moreover, ß-asarone administration decreased the protein expression levels of Beclin-1 and LC3 and increased the expression levels of p62 in VD model mice. CONCLUSIONS: ß-asarone inhibits Beclin-1-dependent autophagy and upregulates the cAMP/PKA/CREB signalling pathway to attenuate mitochondrial and synaptic damage from cerebral ischaemia and improve learning and cognitive abilities in VD model mice.

[Research progress in mechanism of puerarin in treating vascular dementia].

Vascular dementia(VD) is a condition of cognitive impairment due to acute and chronic cerebral hypoperfusion. The available therapies for VD mainly focus on mitigating cerebral ischemia, improving cognitive function, and controlling mental behavior. Achievements have been made in the basic and clinical research on the treatment of VD with traditional Chinese medicine(TCM) active components, including Ginkgo leaf extract, puerarin, epimedium, tanshinone, and ginsenoside. Most of these components have anti-inflammatory, anti-apoptotic, anti-oxidant, and neuroprotective effects, and puerarin demonstrates excellent performance in mitigating cholinergic nervous system disorders and improving synaptic plasticity. Puerarin, ginkgetin, and epimedium are all flavonoids, while tanshinone is a diterpenoid. Puerariae Lobatae Radix, pungent in nature, can induce clear Yang to reach the cerebral orifices and has the wind medicine functions of ascending, dispersing, moving, and scurrying. Puerariae Lobatae Radix entering collaterals will dredge blood vessels to promote blood flow, and that entering the sweat pore will open the mind, which is in line with the TCM pathogenesis characteristics of VD. This study reviews the progress in the mechanism of puerarin, the main active component of Puerariae Lobatae Radix, in treating VD. Puerarin can ameliorate cholinergic nervous system disorders, reduce excitotoxicity, anti-inflammation, inhibit apoptosis, alleviate oxidative stress injury, enhance synaptic plasticity, up-regulate neuroprotective factor expression, promote cerebral circulation metabolism, and mitigate Aß injury. The pathways of action include activating nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE), vascular endothelial growth factor(VEGF), extracellular regulated protein kinases(ERK), phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt), Janus-activating kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3), AMP-activated protein kinase(AMPK), as well as inhibiting the tumor necrosis factor α(TNF-α), transient receptor potential melastatin 2(TRPM2)/N-methyl-D-aspartate receptor(NMDAR), p38 mitogen-activated protein kinase(p38 MAPK), Toll-like receptor 4(TLR4)/nuclear factor-kappaB(NF-κB), early growth response 1(Egr-1), and matrix metalloproteinase 9(MMP-9). By reviewing the papers about the treatment of VD by puerarin published by CNKI, Wanfang, VIP, PubMed, and Web of Science in the last 10 years, this study aims to support the treatment and drug development for VD.

Insilico Screening of Pentacyclic Triterpenoids against Vascular Dementia Target's.

Vascular dementia (VaD) accounts to 30% of cases and is predicted as second most common form of dementia after Alzheimer's disease by WHO. Earlier studies reported that plant-derived pentacyclic triterpenoids possess a wide range of pharmacological activities but these compounds are not extensively studied for their neuroprotective potential against VaD. This in silico approach was designed to screen 20 pentacyclic triterpenoid plant compounds against known targets of VaD using Flare software. S-Adenyl homocysteine hydrolase, Acetylcholinesterase, and Butyrylcholinesterase were selected as important VaD targets, and various parameters like intermolecular interaction energies, binding energy, and dock scores were analyzed and compared between selected ligands. Our results showed that Ursolic acid has lowest binding energy when docked with most of the target proteins, and among all 20 pentacyclic triterpenoids studied, only three ligands Betulinic acid, Ambolic acid, and Madecassic acid, showed better binding energy scores, and they can be shortlisted as lead compounds to further study their therapeutic potential against VaD using in vitro and in vivo animal models.

Gastrodin relieves cognitive impairment by regulating autophagy via PI3K/AKT signaling pathway in vascular dementia.

Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression, which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002, a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.

Edaravone Dexborneol Alleviates Neuroinflammation by Reducing Neuroglial Cell Proliferation and Suppresses Neuronal Apoptosis/Autophagy in Vascular Dementia Rats.

More and more evidence shows that the pathological mechanism of vascular dementia (VD) is closely related to oxidative stress injury, cell apoptosis, autophagy, inflammatory response, excitatory amino acid toxicity, synaptic plasticity change, calcium overload, and other processes. Edaravone dexborneol (EDB) is a new type of neuroprotective agent that can improve the neurological damage caused by an ischemic stroke. Previous studies showed that EDB has effects on synergistic antioxidants and induces anti-apoptotic responses. However, it remains unclear whether EDB can affect apoptosis and autophagy by activating the PI3K/Akt/mTOR signaling pathway and its impact on the neuroglial cells. In this study, we established the VD model of rats by bilateral carotid artery occlusion to explore the neuroprotective effect of EDB and its mechanism. Morris Water Maze test was applied to assess the cognitive function of rats. H&E and TUNEL staining were applied to observe the cellular structure of the hippocampus. Immunofluorescence labeling was used to observe the proliferation of astrocytes and microglia. ELISA was applied to examine the levels of TNF-α, IL-1ß and IL-6, and RT-PCR was applied to examine their mRNA expression levels. Western blotting was applied to examine apoptosis-related proteins (Bax, Bcl-2, Caspase-3), autophagy-related proteins (Beclin-1, P62, LC3B), PI3K/Akt/mTOR signaling pathway proteins and their phosphorylation levels. The results indicated that EDB ameliorates learning and memory in rats subjected to the VD model, alleviates neuroinflammatory response by reducing the proliferation of the neuroglial cell and inhibits apoptosis and autophagy, which may be mediated by the PI3K/Akt/mTOR signaling pathway.

Melatonin suppresses inflammation and blood‒brain barrier disruption in rats with vascular dementia possibly by activating the SIRT1/PGC-1α/PPARγ signaling pathway.

Chronic cerebral hypoxia (CCH) is caused by a reduction in cerebral blood flow, and cognitive impairment has been the predominant feature that occurs after CCH. Recent reports have revealed that melatonin is proficient in neurodegenerative diseases. However, the molecular mechanism by which melatonin affects CCH remains uncertain. In this study, we aimed to explore the role and underlying mechanism of melatonin in inflammation and blood‒brain barrier conditions in rats with CCH. Male Wistar rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to establish the VAD model. Rats were randomly divided into four groups: Sham, BCCAO, BCCAO treated with melatonin (10 mg/kg), and BCCAO treated with resveratrol (20 mg/kg). All drugs were administered once daily for 4 weeks. Our results showed that melatonin attenuated cognitive impairment, as demonstrated by the Morris water maze tests. Furthermore, melatonin reduced the activation of inflammation by attenuating the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (pIκBα), causing the suppression of proteins related to inflammation and inflammasome formation. Moreover, immunohistochemistry revealed that melatonin reduced glial cell activation and proliferation, which were accompanied by Western blotting results. Additionally, melatonin also promoted the expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor-gamma (PPARγ), causing attenuated blood‒brain barrier (BBB) disruption by increasing tight junction proteins. Taken together, our results prove that melatonin treatment modulated inflammation and BBB disruption and improved cognitive function in VaD rats, partly by activating the SIRT1/PGC-1α/PPARγ signaling pathway.

Persicaria minor ameliorates the cognitive function of chronic cerebral hypoperfusion rats: Metabolomic analysis and potential mechanisms.

Persicaria minor (P. minor) is a herbal plant with many uses in food, perfume, and the medical industry. P. minor extract contains flavonoids with antioxidant and anticholinesterase capacity, which could enhance cognitive functions. P. minor extract has been proven to enhance memory. However, its role in an animal model of chronic cerebral hypoperfusion (CCH), which resembles human vascular dementia, has yet to be explored. Therefore, the present study investigates the effects of chronic (14 days) administration of aqueous P. minor extract on different stages of learning and memory processes and the metabolic pathways involved in the chronic cerebral hypoperfused rats induced by the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery. Chronic treatment of P. minor extract at doses of 200 and 300 mg/kg, enhanced recognition memory of the PBOCCA rats. P. minor extract (200 mg/kg) was also found to restore the spatial memory impairment induced by CCH. A high dose (300 mg/kg) of the P. minor extract significantly increased the expression of both ACh and GABA neurotransmitters in the hippocampus. Further, distinctive metabolite profiles were observed in rats with different treatments. Three major pathways involved in the cognitive enhancement mechanism of P. minor were identified. The present findings demonstrated an improving effect of P. minor extract on memory in the CCH rat model, suggesting that P. minor extract could be a potential treatment for vascular dementia and Alzheimer's patients. P. minor is believed to improve cognitive deficits by regulating pathways involved in retinol, histidine, pentose, glucuronate, and CoA metabolism.

Effect of Huangdisan grain on improving cognitive impairment in VD rats and its mechanism in immune inflammatory response.

BACKGROUND: Vascular dementia (VD) is the second most common type of dementia after Alzheimer's disease (AD). Although the incidence rate is very high, there is no definitive treatment for VD. And it has serious impact on the quality of life of VD patients. In recent years, more and more studies about the clinical efficacy and pharmacological effects of traditional Chinese medicine (TCM) in the treatment of VD have been conducted. And Huangdisan grain has been used to treat VD patients with a good curative effect in clinic. OBJECTIVE: This study was designed to investigate the effect of Huangdisan grain on the inflammatory response and cognitive function of VD rats modeled by bilateral common carotid artery occlusion (BCCAO), that aimed to improve the treatment methods for VD. METHODS: 8-week-old healthy SPF male Wistar rats (280 ± 20 g) were randomly divided into the normal group (Gn, n = 10), sham operated group (Gs, n = 10), and operated group (Go, n = 35). The VD rat models in Go group were established by BCCAO. 8 weeks after surgery, the operated rats were screened by the hidden platform trail of Morris Water Maze (MWM), and the rats with cognitive dysfunction were further randomly divided into the impaired group (Gi, n = 10) and TCM group (Gm, n = 10). The VD rats in Gm group were given the intragastric administration of Huangdisan grain decoction once a day for 8 weeks, and the other groups were given intragastric administration of normal saline. Then the cognitive ability of rats in each group was detected by the MWM Test. The lymphocyte subsets in peripheral blood and hippocampus of rats were measured by flow cytometry. The levels of cytokines (IL-1ß, IL-2, IL-4, IL-10, TNF-α, INF-γ, MIP-2, COX-2, iNOS) in peripheral blood and hippocampus were measured by ELISA (enzyme linked immunosorbent assay). The number of Iba-1+ CD68+ co-positive cells in the CA1 region of hippocampus was measured by immunofluorescence. RESULTS: Compared with the Gn group, the escape latencies of the Gi group were prolonged (P < 0.01), the time spent in the former platform quadrant was shortened (P < 0.01), and the number of times of crossing over the former platform location was reduced (P < 0.05). But compared with the Gi group, the escape latencies of Gm group were shortened (P < 0.01), the time spent in the former platform quadrant was prolonged (P < 0.05), and the number of times of crossing over the former platform location was increased (P < 0.05). The number of Iba-1+ CD68+ co-positive cells in the CA1 region of hippocampus of VD rats in Gi group was increased (P < 0.01) compared with the Gn group. And the proportions of T Cells, CD4+ T Cells, CD8+ T Cells in the hippocampus were increased (P < 0.01). The level of pro-inflammatory cytokines in the hippocampus was increased significantly, such as IL-1ß (P < 0.01), IL-2 (P < 0.01), TNF-α (P < 0.05), IFN-γ (P < 0.01), COX-2 (P < 0.01), MIP-2 (P < 0.01) and iNOS (P < 0.05). And the level of IL-10 (P < 0.01), a kind of anti-inflammatory cytokine, was decreased. The proportions of T Cells (P < 0.05), CD4+ T Cells (P < 0.01) and NK Cells (P < 0.05) in the peripheral blood of the VD rats in Gi group were decreased, and the level of IL-1ß, IL-2, TNF-α, IFN-γ, COX-2, MIP-2 and iNOS was increased significantly (P < 0.01) compared with the Gn group. Meanwhile, the level of IL-4 and IL-10 was decreased (P < 0.01). Huangdisan grain could reduce the number of Iba-1+ CD68+ co-positive cells in the CA1 region of hippocampus (P < 0.01), decrease the proportions of T Cells, CD4+ T Cells, CD8+ T Cells and the level of IL-1ß, MIP-2 in hippocampus (P < 0.01) of VD rats. Moreover, it could rise the proportion of NK Cells (P < 0.01) and the level of IL-4 (P < 0.05), IL-10 (P < 0.05), and decrease the level of IL-1ß (P < 0.01), IL-2 (P < 0.05), TNF-α (P < 0.01), IFN-γ (P < 0.01), COX-2 (P < 0.01) and MIP-2 (P < 0.01) in peripheral blood of VD rats. CONCLUSION: This study indicated that Huangdisan grain could decrease the activation of microglia/macrophages, regulate the proportions of lymphocyte subsets and the level of cytokines, which could adjust the immunologic abnormalities of VD rats, and ultimately improve cognitive function.

Dl-3-n-butylphthalide promotes synaptic plasticity by activating the Akt/ERK signaling pathway and reduces the blood-brain barrier leakage by inhibiting the HIF-1α/MMP signaling pathway in vascular dementia model mice.

AIMS: DL-3-n-butylphthalide (NBP) exerts beneficial effects on global cognitive functions, but the underlying molecular mechanisms are still poorly understood. The present study aimed to investigate whether NBP mediates synaptic plasticity and blood-brain barrier (BBB) function, which play a pivotal role in the pathogenesis of vascular dementia (VaD), in a mouse model of bilateral common carotid artery stenosis (BCAS). METHODS: NBP was administered to model mice at a dose of 80 mg/kg by gavage for 28 days after surgery. Cognitive function was evaluated by behavioral tests, and hippocampal synaptic plasticity was evaluated by in vivo electrophysiological recording. Cerebral blood flow (CBF), hippocampal volume, and white matter integrity were measured with laser speckle imaging (LSI) and MRI. In addition, BBB leakage and the expression of proteins related to the Akt/ERK and HIF-1α/MMP signaling pathways were assessed by biochemical assays. RESULTS: NBP treatment alleviated cognitive impairment, hippocampal atrophy, and synaptic plasticity impairment induced by BCAS. In addition, NBP treatment increased CBF, promoted white matter integrity, and decreased BBB leakage. Regarding the molecular mechanisms, in mice  with BCAS, NBP may activate the Akt/ERK signaling pathway, which upregulates the expression of synapse-associated proteins, and it may also inhibit the HIF-1α/MMP signaling pathway, thereby increasing the expression of tight junction (TJ) proteins. CONCLUSION: In conclusion, our results demonstrated the therapeutic effects of NBP in improving cognitive function via a wide range of targets in mice subjected to BCAS.

Efficacy of Artemisia annua Linné in improving cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia animal model.

BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. Currently, no FDA-approved drugs are available for the treatment of VaD. Artemisia annua Linné (AA) is known to have antioxidant properties, but its effects and mechanisms of action on cognitive impairment are still unknown. PURPOSE: In this study, the improvement in cognitive impairment by AA in terms of protection against oxidative stress, neuroinflammation, and preservation of the integrity of the neurovascular unit (NVU) was assessed in an animal model of VaD with bilateral common carotid artery occlusion (BCCAO). METHODS: Eight-week-old male Wistar rats were allowed to adapt for four weeks, and BCCAO was induced at 12 weeks of age. The rats were randomly assigned into four groups, with seven rats in each group: sham group without BCCAO, VaD group that received oral administration of distilled water after BCCAO surgery, and two AA groups that received oral administration of 150 mg/kg or 750 mg/kg AA after BCCAO surgery for 8 weeks. Nine weeks after BCCAO surgery, the cognitive function of the rats was evaluated and accumulated oxidative stress was assessed by immunohistochemistry, immunofluorescence, and western blotting. Damage to the components of the NVU was evaluated, and sirtuin (Sirt) 1 and 2 expression and nuclear factor-erythrocyte 2-associated factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) activation were investigated to assess the reduction in cell signaling and antioxidant pathways. RESULTS: BCCAO-induced cerebral perfusion decreased memory function and induced neuroinflammation and oxidative stress. But AA treatment mitigated cognitive impairment and reduced neuroinflammation and oxidative stress caused by chronic cerebral hypoperfusion. AA extracts activated the Nrf2/Keap1/activating antioxidant response elements pathway and maintained Sirt 1 and 2, subsequently leading to the maintenance of neurons, improved construct of microvessels, increased platelet-derived growth factor receptor beta, and platelet-endothelial cell adhesion molecule-1 associated with the blood-brain barrier integrity. CONCLUSION: AA is effective in alleviating BCCAO-induced cognitive decline and its administration may be a useful therapeutic approach for VaD.