Treatment Of Vascular Cognitive Impairment Research Articles

Diagnosis and treatment of vascular cognitive impairment, the use of citicoline: A review

Diagnosis and treatment of vascular cognitive impairment, the use of citicoline: A review

REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP trial): a study protocol for a randomized, double-blind, placebo-controlled trial.

Carotid artery stenosis or occlusion (CASO) is a major cause of vascular cognitive impairment (VCI). There is currently no effective treatment for VCI induced by CASO. Resveratrol, a type of polyphenol, improves cognitive performance in rat CASO models via pleiotropic effects. Furthermore, we previously reported the longevity gene, SIRT1, which can be activated by resveratrol, improves cognitive and cerebral blood flow impairment in mouse CASO models by activating endothelial nitric oxide synthase. However, clinical evidence remains limited. The REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP) trial is a randomized, double-blind, placebo-controlled trial involving patients with asymptomatic CASO. Each participant will receive either 150 mg/day of resveratrol or a placebo for 35 weeks. The primary objective is to determine whether resveratrol improves cognitive impairment, as assessed using the Alzheimer's disease Assessment Scale-cognitive subscale 13. One of our secondary objectives is to determine whether resveratrol improves cerebral hemodynamic impairment as assessed via 15O-gas positron emission tomography. We will recruit 100 patients (50 per group). The REVAMP trial may provide valuable insights into new therapeutic options, as multitarget neuroprotection could potentially improve cognitive function along with enhancements in cerebral hemodynamic status in patients with asymptomatic CASO.Clinical trial registration: The REVAMP trial was prospectively registered in the Japan Registry of Clinical Trials (jRCTs051230013) on April 13, 2023.

Volatile oil of Angelica sinensis Radix improves cognitive function by inhibiting miR-301a-3p targeting Ppp2ca in cerebral ischemia mice

Ethnopharmacological relevanceAngelica Sinensis Radix (ASR) is a commonly used Chinese medicine known for its effects on tonifying blood, promoting blood circulation, and alleviating pain associated with menstrual regulation. Additionally, it has been used in the treatment of vascular cognitive impairment (VCI). The primary pharmacodynamic agent within ASR is volatile oil of Angelica Sinensis Radix (VOASR), which has demonstrated efficacy in combating cognitive impairment, although its mechanism remains unclear. ObjectiveThis study aimed to elucidate the potential molecular mechanisms underlying VOASR's improvement of cognitive function in cerebral ischemic mice. MethodsA model of cerebral ischemic mice was established through unilateral common carotid artery occlusion (UCCAO) surgery, followed by intervention with VOASR. Cognitive function was assessed using the Morris water maze (MWM) test, while RT-qPCR was utilized to measure the differential expression of miR-301a-3p in the hippocampus. To evaluate cognitive function and hippocampal protein differences, wild-type mice and miR-301a-3p knockout mice were subjected to the MWM test and iTRAQ protein profiling. The relationship between miR-301a-3p and potential target genes was validated through a Dual-Luciferase Reporter experiment. RT-qPCR and Western blot were employed to determine the differential expression of Ppp2ca and synaptic plasticity-related proteins in the mouse hippocampus. ResultsIntervention with VOASR significantly improved cognitive impairment in cerebral ischemic mice and reduced the expression of miR-301a-3p in the hippocampus. Our findings suggest that miR-301a-3p may regulate cognitive function by targeting Ppp2ca. Furthermore, VOASR intervention led to an increase in the expression of Ppp2ca and synaptic plasticity-related proteins. ConclusionOur study indicates that VOASR may be involved in regulating cognitive function by inhibiting miR-301a-3p, consequently increasing the expression of Ppp2ca and synaptic plasticity proteins. These results provide a new target and direction for the treatment of cognitive dysfunction.

Identification of Candidate Genes Associated With Development of Vascular Cognitive Impairment by Integrated Bioinformatics Analysis Combined With Biological Experiments.

The morbidity and mortality associated with vascular cognitive impairment (VCI) generally increase steeply, and health systems will face increasing demand for services. The present study aims to screen key genes to give new insight into the mechanisms and treatment of VCI based on bioinformatic approaches combined with biological experiments in rats. The gene expression data of VCI patients contained in the GSE122063 data set were downloaded from the Gene Expression Omnibus. We performed a weighted gene co-expression network analysis to identify a hub module and 44 hub genes. Two hundred and seventy-seven differentially expressed genes (DEGs) were analyzed using R software by the "limma" package. STRING database was used to construct protein-protein interaction (PPI) network, after which 36 hub genes were identified through Cytoscape. Functional enrichment analysis revealed that these genes from the yellow module and 277 DEGs were mainly associated with these pathways, such as Staphylococcus aureus infection, complement, and coagulation cascades. These biological functions are related to inflammatory cell activation and inflammatory response. The key genes of VCI were the overlapping hub genes from the yellow module and the PPI network. The expressions of hub genes in rats were determined by quantitative reverse transcription-polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. In conclusion, C1QA, C1QB, C1QC, CD163, and FCGR2A were highly expressed in the hippocampus of VCI rats, and they can serve as candidate biomarkers for the diagnosis and prognosis of VCI. Finally, molecular docking results suggested that 5 genes interact with Bisphenol A. These findings open a new avenue to investigate molecular mechanisms for preventing or treating VCI.

A serum metabolomics study of vascular cognitive impairment patients based on Traditional Chinese medicine syndrome differentiation.

Objective: Vascular cognitive impairment (VCI) accounts for approximately 50%-70% of all dementia cases and poses a significant burden on existing medical systems. Identifying an optimal strategy for preventing VCI and developing efficient symptomatic treatments remains a significant challenge. Syndrome differentiation represents a fundamental approach for personalized diagnosis and treatment in Traditional Chinese Medicine (TCM) and aligns with the principles of precision medicine. The objective of this study was to elucidate the metabolic characteristics of VCI based on TCM syndrome differentiation, thus providing novel insights into the diagnosis and treatment of VCI. Methods: A 2-year cross-sectional cognitive survey was conducted in four communities in Beijing between September 2020 and November 2022. The syndrome differentiation of participants was based on the Kidney-Yang Deficiency Syndrome Scale (KYDSS), which was originally developed by Delphi expert consultation. The identification of serum metabolites was performed by Ultra performance liquid chromatography (UPLC) analysis coupled with an electrospray ionization quadruple time-of-flight mass spectrometer (ESI-QTOF MS). Multivariate, univariate, and pathway analyses were used to investigate metabolic changes. Logistic regression models were also used to construct metabolite panels that were capable of discerning distinct groups. Phospholipase A2 (PLA2) levels were measured by a commercial ELISA kit. Results: A total of 2,337 residents completed the survey, and the prevalence of VCI was 9.84%. Of the patients with VCI, those with Kidney-Yang deficiency syndrome (VCIS) accounted for 70.87% of cases and exhibited more severe cognitive impairments. A total of 80 participants were included in metabolomics study, including 30 with VCIS, 20 without Kidney-Yang deficiency syndrome (VCINS), and 30 healthy control participants (C). Ultimately, 45 differential metabolites were identified when comparing the VCIS group with group C, 65 differential metabolites between the VCINS group and group C, and 27 differential metabolites between the VCIS group and the VCINS group. The downregulation of phosphatidylethanolamine (PE), and phosphatidylcholine (PC) along with the upregulation of lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), phosphatidic acid (PA) and phospholipase A2 (PLA2) can be considered as the general metabolic characteristics associated with VCI. Dysfunction of glycerophospholipids, particularly LPEs and PCs, was identified as a key metabolic characteristic of VCIS. In particular Glycerophospho-N-Arachidonoyl Ethanolamine (GP-NArE) was discovered for the first time in VCI patients and is considered to represent a potential biomarker for VCIS. The upregulation of PLA2 expression was implicated in the induction of alterations in glycerophospholipid metabolism in both VCIS and VCINS. Moreover, robust diagnostic models were established based on these metabolites, achieving high AUC values of 0.9322, 0.9550, and 0.9450, respectively. Conclusion: These findings contribute valuable information relating to the intricate relationship between metabolic disorders in VCI, neurodegeneration and vascular/neuroinflammation. Our findings also provide a TCM perspective for the precise diagnosis and treatment of VCI in the context of precision medicine.

A mini-review on functional magnetic resonance imaging on brain structure of vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the initial stage of vascular dementia (VaD). Early diagnosis and treatment of VCI are crucial to prevent the progression of VaD. In order to gain a better understanding of VCI, this study aimed to investigate the use of advanced imaging techniques such as structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI). These techniques allow researchers to observe the structural and functional changes in the brain that are associated with VCI. Functional magnetic resonance imaging (fMRI) and sMRI techniques have been widely used in studies focusing on gray matter, brain networks, and functional abnormalities during rest. By searching and summarizing recent literature, this study has provided valuable evidence on the use of advanced imaging techniques in understanding and treating VCI. The findings from this study can aid in the development of early intervention strategies for patients with VCI, potentially slowing down or even halting the progression of VCI to full-blown VaD.

Cerebral venous congestion alters brain metabolite profiles, impairing cognitive function

Vascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease, and pathological changes in cerebral vascular structure and function are pivotal causes of VCI. Cognitive impairment caused by arterial ischemia has been extensively studied the whole time; the influence of cerebral venous congestion on cognitive impairment draws doctors’ attention in recent clinical practice, but the underlying neuropathophysiological alterations are not completely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in cognitive-behavioral deterioration and possible electrophysiological mechanisms. Using cerebral venous congestion rat models, we found these rats exhibited decreased long-term potentiation (LTP) in the hippocampal dentate gyrus and impaired spatial learning and memory. Based on untargeted metabolomics, N-acetyl-L-cysteine (NAC) deficiency was detected in cerebral venous congestion rats; supplementation with NAC appeared to ameliorate synaptic deficits, rescue impaired LTP, and mitigate cognitive impairment. In a cohort of cerebral venous congestion patients, NAC levels were decreased; NAC concentration was negatively correlated with subjective cognitive decline (SCD) score but positively correlated with mini-mental state examination (MMSE) score. These findings provide a new perspective on cognitive impairment and support further exploration of NAC as a therapeutic target for the prevention and treatment of VCI.

Treatment of Vascular Cognitive Impairment: A Bibliometric Analysis over a 12-Year Period

Treatment of Vascular Cognitive Impairment: A Bibliometric Analysis over a 12-Year Period

Effects of Dl-3-n-butylphthalide on cognitive functions and blood–brain barrier in chronic cerebral hypoperfusion rats

Vascular cognitive impairment (VCI) has been one of the major types of cognitive impairment. Blood–brain barrier damage plays an essential part in the pathogenesis of VCI. At present, the treatment of VCI is mainly focused on prevention, with no drug clinically approved for the treatment of VCI. This study aimed to investigate the effects of DL-3-n-butylphthalide (NBP) on VCI rats. A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to mimic VCI. The feasibility of the mBCCAO model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET), and Morris Water Maze. Subsequently, the Morris water maze experiment, Evans blue staining, and western blot of tight junction protein were performed to evaluate the effect of different doses of NBP (40 mg/kg, 80 mg/kg) on the improvement of cognitive impairment and BBB disruption induced by mBCCAO. Immunofluorescence was employed to examine the changes in pericyte coverage in the mBCCAO model and the effect of NBP on pericyte coverage was preliminarily explored. mBCCAO surgery led to obvious cognitive impairment and the decrease of whole cerebral blood flow, among which the blood flow in the cortex, hippocampus and thalamus brain regions decreased more significantly. High-dose NBP (80 mg/kg) improved long-term cognitive function in mBCCAO rats, alleviated Evans blue leakage and reduced the loss of tight junction proteins (ZO-1, Claudin-5) in the early course of the disease, thereby exerting a protective effect on the blood–brain barrier. No significant changes in pericyte coverage were observed after mBCCAO. High-dose NBP improved cognitive function in mBCCAO rats. High-dose NBP protected the integrity of BBB by upregulating TJ protein expression, rather than regulating pericyte coverage ratio. NBP could be a potential drug for the treatment of VCI.

Vascular cognitive impairment: issues of diagnosis and treatment

Vascular brain diseases are one of the leading causes of death and disability in developed countries. Along with acute disturbance of cerebral circulation, chronic cerebrovascular diseases, which manifest as vascular cognitive impairment (VCI), are of great medical and social importance. VCIs include a wide range of cognitive impairments (CI) ranging from subjective CI to vascular and mixed dementia. The article discusses pathogenetic and clinical variants, approaches to the diagnosis of VCIs, and provides their modern classification. The features of CI, typical for chronic cerebrovascular insufficiency, are described, such as a slowdown in the rate of mental activity and disorders of frontal executive functions in combination with behavioral and emotional disorders. The issues of treatment of VCI are discussed, which should be comprehensive and include correction of the underlying vascular disease, non-drug (regular physical activity, smoking cessation, cognitive training) and drug treatments aimed at improving cognitive functions. The possibilities of modern neuroprotective and symptomatic therapy of CI, including the use of Cellex®, are shown.

Exploring the target and molecular mechanism of Astragalus membranaceus in the treatment of vascular cognitive impairment based on network pharmacology and molecular docking.

Astragalus membranaceus (AM) is a traditional Chinese herbal medicine extensively utilized in vascular cognitive impairment (VCI) treatment. However, due to the complex components of AM, its exact molecular mechanism remains unclear. Therefore, this study investigated the target and molecular mechanism of AM to treat VCI based on network pharmacology and molecular docking. Firstly, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, STITCH, and SwissTargetPrediction were utilized to gather the primary active ingredients of AM. The potential therapeutic targets of VCI were collected through GeneCards, OMIM, and DisGeNET databases. Secondly, the protein-protein interaction network was built using the STRING database. The enrichment analysis of gene ontology and the Kyoto Encyclopedia of Genes and Genome pathways was carried out in the R language. Finally, The network topology calculation of Cytoscape software was combined with module analysis to predict the binding properties of its active ingredients and targets. Twenty effective compounds and 733 targets were screened from AM, among which 158 targets were seen as possible targets of AM to treat VCI. MAPK3 and MMP9 were the critical targets of AM intervention in VCI. The crucial pathways include PI3K/Akt, MAPK, Rap1, and Ras signaling pathways. Besides, calycosin and quercetin might be the potential active compounds of AM for VCI treatment. AM intervenes in VCI through a multi-ingredient, multi-target, and multi-pathway coordination mechanism. These findings provide a foundation for a deeper understanding of the molecular mechanisms by which AM is effective in treating VCI.

Clinical efficacy of Danshen preparation in the treatment of vascular cognitive impairment: A systematic review and meta-analysis.

Danshen preparations are widely used in the treatment of ischaemic cerebrovascular disease. However, the clinical efficacy of such preparations remains unclear. Consequently, Danshen preparations are used to a lesser extent in vascular cognitive impairment (VCI). In this study, we aimed to systematically assess the clinical efficacy and safety of Danshen preparations in VCI. To this end, we examined and performed a meta-analysis (MA) of the evidence available from randomised controlled trials (RCTs) of Danshen preparations conducted in patients with VCI. We queried the following sources and collected all articles reporting on RCTs of Danshen preparations published prior to December 2021: PubMed, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chongqing VIP Database (CQVIP), and China Biology Medicine (CBM) disc databases. The assessment of treatments that were included in references were performed by RevMan 5.2 software based on guidelines from Cochrane Handbook for Systematic Reviews of Interventions. We included a total of 12 RCTs that included data on clinical therapeutic effects. The evaluation criteria included the following: National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Barthel Index (BI), Mini-Mental State Assessment (MMSE), Montreal Cognitive Assessment (MOCA), Activities of Daily Living Scale (ADL), treatment effect index, and incidence of adverse reaction index. In the included studies, the observation groups included 656 cases and the control groups included 660 cases. The results of the MA were as follows: the mean difference (MD) value after combining the effect size for NIHSS was -2.91, with a 95% confidence interval (CI) of -4.22 to -1.59; the combined effect quantity hypothesis test revealed that Z = 4.33 (p < 0.00001), indicating that the score pertaining to the degree of neurological deficit (NIHSS) in the observation group after treatment was significantly lower than that in the control group. This result reveals that treatment with a Danshen preparation can reduce neurological deficit in VCI patients. The MD value after combining the effect size for mRS was -0.73, with a 95% CI of -0.85 to -0.61; the result of the combined effect quantity hypothesis test revealed that Z = 12.29 (p < 0.00001). These results indicate that the degree of disability was significantly reduced after treatment in the observation group. The MD value after combining the effect size for MMSE was 2.09, with a 95% CI of 0.33-3.84; the result of the combined effect quantity hypothesis test showed that Z = 2.33 (p = 0.02). These results indicate that the cognitive function score (MMSE) of the observation group after treatment was significantly higher than that of the control group and suggests that the cognitive function of VCI patients was improved after treatment with Danshen preparations. The MD value after combining the effect size for ADL was 8.79, with a 95% CI of 3.52 to 14.06; the result of the combined effect quantity hypothesis test indicated that Z = 3.27 (p = 0.001). These results showed that the life ability (ADL scale) scores of patients in the observation group after treatment were significantly higher than those in the control group, and reveals that after treatment with Danshen preparations, patients exhibited significant improvement in life ability. The MD value after combining the effect size for high-sensitivity C-reactive protein (hs-CRP) was -3.21, with a 95% CI of -4.21 to -2.22; the result of the combined effect quantity hypothesis test showed that Z = 6.31 (p < 0.00001), indicating that the hs-CRP level in the observation group was significantly decreased after treatment. The MD value after combining the effect size for interleukin (IL)-6 was -2.95, with a 95% CI of -3.86 to -2.04; the result of the combined effect quantity hypothesis test showed that Z = 6.36 (p < 0.00001). These results showed that the IL-6 level in the observation group was significantly decreased after treatment. The existing clinical evidence shows that Danshen preparations exert significant therapeutic effects on VCI patients and can ameliorate inflammatory conditions in these patients. In addition, Danshen preparations are relatively safe.

Criteria for diagnosis and classification of vascular cognitive impairment

Vascular cognitive impairment (VCI) is a very diverse group of conditions that differ in etiopathogenesis, severity, clinical picture, dynamics and severity of functional disorders. This heterogeneity significantly complicates the development of uniform standardized recommendations for the diagnosis and treatment of VCI. The development of criteria for each clinical and pathogenetic variant for permanent practical application is a difficult task. In this article, based on the analysis of previously proposed approaches to the diagnosis of various clinical and pathogenetic variants, common diagnostic criteria and classification of VCI are presented.

Expert consensus on clinical application of Compound Congrong Yizhi Capsules in treatment of vascular dementia

Compound Congrong Yizhi Capsules is widely used in clinic for the long-term treatment and synergistic treatment of vascular cognitive impairment. After years of clinical observation, it has an obvious curative effect on the treatement of vascular cognitive impairment and has been recommended by multiple guidelines, consensuses, and series. This consensus was formulated for the treatment of vascular dementia. On the basis of summarizing the application experience of clinicians, and combined with the existing evidence-based evidence, 11 recommendations/consensus recommendations were finally reached through the nominal group method. The indications, usage and dosage, course of treatment, medication time, concomitant medication, and precautions of Congrong Yizhi Capsules in the treatment of vascular dementia were proposed, and the safety of the clinical application was described. This consensus is applicable to the use of Compound Congrong Yizhi Capsules in the treatment of patients with vascular dementia, and can be used by clinicians from the departments of encephalopathy(neurology), geriatrics, and traditional Chinese medicine in general hospitals. This consensus has been approved by China Association of Chinese Medicine, with the number of GS/CACM 298-2022.

Remote ischaemic conditioning for stroke prevention

Simple low-cost treatments to reduce the risk of stroke are needed and remote ischaemic conditioning might be such a treatment. 1 Koch S Gonzalez N Preconditioning the human brain: proving the principle in subarachnoid hemorrhage. Stroke. 2013; 44: 1748-1753 Crossref PubMed Scopus (35) Google Scholar This technique induces brief periods of ischaemia–reperfusion in a limb, with the intention of protecting a remote organ (eg, brain or heart) from injury. 2 Hess DC Khan MB Hoda N Morgan JC Remote ischemic conditioning: a treatment for vascular cognitive impairment. Brain Circ. 2015; 1: 133-139 Crossref PubMed Google Scholar Clinically, the ischaemic challenge is achieved by the transient occlusion of arterial blood flow, typically in one or both arms. With a blood pressure cuff on the arm inflated above systolic pressure, the limb becomes ischaemic, and the systemic reaction is thought to result in a combination of humoral and neuronal responses that might protect the brain and other organs from ischaemic injury—eg, by promoting cell survival and repair while inhibiting apoptosis and inflammation. 3 Stokfisz K Ledakowicz-Polak A Zagorski M Zielinska M Ischaemic preconditioning— current knowledge and potential future applications after 30 years of experience. Adv Med Sci. 2017; 62: 307-316 Crossref PubMed Scopus (50) Google Scholar Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in ChinaNo evidence was found for a difference between remote ischaemic conditioning and sham remote ischaemic conditioning in lowering the risk of ischaemic stroke in patients with symptomatic ICAS. The benefit of remote ischaemic conditioning might have been diluted by poor compliance. Future studies of remote ischaemic conditioning in this population should address challenges in patients’ compliance and assess longer term treatment. Full-Text PDF

Meta-analysis of clinical efficacy and safety of yangxuenao granules combined with cholinesterase inhibitors in the treatment of vascular cognitive impairment.

article: Meta-analysis of clinical efficacy and safety of Yangxuenao Granules combined with cholinesterase inhibitors in the treatment of vascular cognitive impairment - Minerva Medica 2022 Sep 30 - Minerva Medica - Journals

GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis.

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32/MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelin/myelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP+/Iba1+/CD68+ microglia was significantly reduced in the BCCAO rats pretreated with these three drugs compared with the vehicle group, suggesting that these drugs suppress microglial phagocytosis. No significant difference was found between the groups pretreated with metformin, rapamycin, or NMN. Our data suggest that metformin, rapamycin, or NMN could protect or attenuate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings may open a new avenue for VCI treatment.

Shengyu Decoction treating vascular cognitive impairment by promoting AKT/HIF-1α/VEGF related cerebrovascular generation and ameliorating MAPK/NF-κB mediated neuroinflammation

Ethnopharmacological relevanceShengyu Decoction (SYD), a classical Chinese medicine formula, is good at nourishing blood, promoting blood circulation, and soothe the nerves. SYD can improve cognitive ability. This decoction is suitable for treating vascular cognitive impairment (VCI). however, its active ingredients and possible mechanism have not been investigated. Aim of the studyThis study was conducted to observe the effects of SYD on improving the cognitive abilities of rats with VCI, to explore its active ingredients and mechanism. Materials and methodsThe rats with VCI model were established by bilateral common carotid artery occlusion (BCCAO), and the effects of SYD (5, 2.5 g/kg) on the cognitive abilities of VCI rats were evaluated using the Morris water maze (MWM) and neurological assessment. The pathological changes of hippocampal CA1 were observed by H &E and Nissl staining. The effect of SYD on cerebral blood flow (CBF) was evaluated by Laser Speckle Contrast Imager. The expression of CD31 in the cerebral cortex was measured by immunofluorescence (IF) to evaluate the number of cerebral micro vessels. The levels of IL-6, IL-1β, and TNF-α in the hippocampus were determined using an ELISA kit, and the active components in the plasma and brain tissues of rats after SYD administration were analyzed using UPLC-Q-TOF-MS/MS. The interaction network of the compound-target pathway was established using the SWISS Target, GO, and DAVID databases. The expression of AKT/HIF-1α/VEGF and p38 MAPK signaling pathway in the brain tissues was determined using western blotting (WB). ResultsSYD (2.5, 5 g/kg) significantly improved the cognitive abilities of VCI rats in the MWM and neurological assessment. H&E and Nissl staining showed that SYD significantly ameliorated the pathological hippocampal CA1 area and increased the number of Nissl bodies. The Laser Speckle Contrast Imager showed that the cortical CBF of VCI rats in the SYD group was significantly increased, and the IF results showed that CD31 expression was significantly increased in the SYD group. The ELISA results showed that the contents of IL-6, IL-1β, and TNF-α in SYD were significantly reduced. A total of 29 compounds were found in the plasma and brain tissues of the rats treated with SYD. Network pharmacology revealed 99 targets for the treatment of VCI. Pathway enrichment analysis showed that the HIF-1 and MAPK signaling pathways might be important for SYD to ameliorate VCI. WB showed that the expressions of AKT, HIF-1α, and VEGF in the brain tissues of rats were significantly increased; in addition, NF-κB and p38 MAPK were significantly reduced in the SYD group. ConclusionSYD can improve the cognitive abilities of VCI rats. The mechanism of action of its active ingredients improves cognitive impairment by affecting the AKT/HIF-1α/VEGF and p38 MAPK/NF-κB signaling pathways, promoting cerebrovascular generation, and ameliorating neuroinflammation.

Simvastatin Alleviates Vascular Cognitive Impairment Caused by Lacunar Cerebral Infarction Through Protein Kinase B/Nuclear Factor Erythroid 2–Related Factor 2 (AKT/Nrf2) Signaling Pathway

Lacunar cerebral infarction (LACI) is one of the main causes of vascular cognitive impairment (VCI). Herein, this study explored the potential effect of Simvastatin (Sim) on VCI secondary to LACI and Akt/Nrf2 signaling transduction and apoptosis. We established a rat model of VCI and the animals were administered with Sim (40 mg/kg and 80 mg/kg) every day for 28 days. After that, the cognition and memory abilities of rats were assessed together with analysis of morphological changes of hippocampal neurons by immunohistochemistry staining and level of anti-apoptotic related proteins and Akt and Nrf2 signaling proteins by western blot. Compared with normal saline (control group), Sim administration significantly improved the capacity spatial learning and relieved the memory impairment with an improvement in morphological defects. Importantly, Sim treatment restored the p-Akt, t-Nrf2, n-Nrf2 and HO-1 expression along with up-regulation of Bcl-2 and down-regulation of Bax. In conclusion, Sim improves cognitive and morphological disorders induced by LACI possibly through regulating Akt/Nrf2 signaling pathway. These evidence might promote the development of Sim-based treatment for VCI and LACI.