Bilateral Common Carotid Artery Occlusion Research Articles

Molecular mechanism of Epimedium in the treatment of vascular dementia based on network pharmacology and molecular docking.

Backgroud: Vascular dementia is the second most common cause of dementia after Alzheimer’s disease, accounting for an estimated 15% of cases. Recently, Epimedium has attracted great attention for its potential neuroprotective benefit. However, the direct role and mechanism of Epimedium on vascular dementia still lack systematic research. To systematically explore the possible pharmacological mechanism of Epimedium for the treatment of vascular dementia, network pharmacology, molecular docking, combined with experiment validation were conducted.Methods: The bioactive compounds and targets of Epimedium were obtained from the TCMSP database. The potential targets of vascular dementia were identified from the DrugBank, OMIM, Genecards, Therapeutic Target Database, and DisGeNET databases. GO and KEGG pathway analyses were performed. Molecular docking was applied to validate the interaction between active components and hub targets. The bilateral common carotid artery occlusion (BCCAO) method was used for construction of a vascular dementia model in mice. The effects of Epimedium on learning and memory ability were examined by behavioral tests. The mechanisms of the cerebral protective effects of Epimedium were evaluated by WB, RT-PCR, and immunofluorescence.Results: A total of 23 Epimedium active ingredients, and 71 intersecting targets of Epimedium against vascular dementia were obtained. The top five hub targets AKT1, TNF, IL1β, IL6, and MMP9 were identified, and molecular docking showed good binding. GO enrichment showed a total of 602 enrichment results, with 458 (80.56%) key targets mainly focused on biological processes (BP). The response to hypoxia, positive regulation of nitric oxide biosynthetic process, aging, inflammatory response, cellular response to lipopolysaccharide, negative regulation of apoptotic process were well ranked. KEGG pathway enrichment analysis identified the TNF signaling pathway as an important pathway, with the MAPK/extracellular signal-regulated kinase (ERK) and NF-κB signaling pathways as the key pathways involved. Consistently, in vivo experiments showed that Epimedium treatment improved learning and memory functions in mice with vascular dementia. In addition, Epimedium attenuated the activation of microglia and astrocytes in the hippocampal region after BCCAO. RT-qPCR and Western blot analysis showed that Epimedium not only affected the expression of AKT, TNF, IL1β, IL6, and MMP9, but also suppressed the TNF signaling pathway.Conclusion: Epimedium may exert a protective effect against vascular dementia through the alleviation of oxidative stress, neuroinflammation, BBB dysfunction, apoptosis through TNF signaling pathway. This study explored the mechanism of Epimedium on vascular dementia systematically through network pharmacological and in vivo experiment approach, which provides insight into the treatment of vascular dementia.

Ligustilide Improves Cognitive Impairment via Regulating the SIRT1/IRE1α/XBP1s/CHOP Pathway in Vascular Dementia Rats.

Vascular dementia (VaD), the second cause of dementia, is caused by chronic cerebral hypoperfusion, producing progressive damage to cerebral cortex, hippocampus, and white matter. Ligustilide (LIG), one of the main active ingredients of Angelica sinensis, exerts the neuroprotective effect on neurodegenerative diseases. However, the mechanism remains unclear. An in vivo model of bilateral common carotid artery occlusion and in vitro model of oxygen glucose deprivation (OGD) were employed in this study. LIG (20 or 40 mg/kg/day) was intragastrically administered to the VaD rats for four weeks. The results of the Morris water maze test demonstrated that LIG effectively ameliorated learning and memory deficiency in VaD rats. LIG obviously relieved neuronal oxidative stress damage by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) and decreasing the level of malondialdehyde (MDA) in VaD rats. Nissl staining showed that LIG increased the number of the Nissl body in VaD rats. After LIG administration, the apoptotic-related protein, Bax, was decreased and Bcl-2 was increased in the hippocampus of VaD rats. Moreover, the expressions of sirtuin 1 (SIRT1) and protein disulfide isomerase (PDI) were decreased, binding immunoglobulin protein (BIP) and phospho-inositol-requiring enzyme-1α (P-IRE1α), X-box binding protein 1 (XBP1s), and C/EBP-homologous protein (CHOP) were increased in VaD rats. After LIG treatment, these changes were reversed. The immunofluorescence results further showed that LIG upregulated the expression of SIRT1 and downregulated the expression of P-IRE1α in VaD rats. In addition, in vitro experiment showed that EX-527 (SIRT1 inhibitor) partly abolished the inhibitory effect of LIG on the IRE1α/XBP1s/CHOP pathway. In conclusion, these studies indicated that LIG could improve cognitive impairment by regulating the SIRT1/IRE1α/XBP1s/CHOP pathway in VaD rats.

Chronic Cerebral Hypoperfusion Aggravates Parkinson's Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism.

Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson's disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and Morris water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of α-Syn and Aβ in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson's disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.

Resveratrol reduces inflammatory response and detrimental effects in chronic cerebral hypoperfusion by down-regulating stimulator of interferon genes/TANK-binding kinase 1/interferon regulatory factor 3 signaling.

Inflammatory responses induced by chronic cerebral hypoperfusion (CCH) play a critical role in the progression of vascular dementia. Stimulator of interferon genes (STING) signaling function as a key mediator of inflammation and immunological responses in the central nervous system (CNS), and resveratrol (RES) exerts potent anti-inflammatory effects. However, the role of STING signaling and the relationship between RES and STING signaling in persistent hypoperfusion-induced cerebral inflammation remain unclear. In this study, Sprague–Dawley rats were subjected to either Sham or bilateral common carotid artery occlusion (2VO) surgery and received RES or vehicle daily by intraperitoneal injection for 4 or 8 weeks. Morris’s water maze was used for the analysis of cognitive function. The neuroinflammatory responses in white matter and hippocampus of the rat brain were assessed by Western blot, Immunofluorescence staining, and qRT-PCR analyses. Myelin integrity, neutrophil infiltration, and microglia proliferation were assessed by Immunohistochemistry and histologic analysis. We demonstrated that after CCH, neurons, microglia, and astrocyte under endoplasmic reticulum (ER) stress upregulated the expression of STING, TANK-binding kinase 1 (TBK1), and the transcription factor interferon regulatory factor 3 (IRF3), as well as translocation of IRF3 into the nucleus. These were accompanied by infiltration of neutrophils, activation of microglia, and overproduction of proinflammatory mediators. Improvements in cognitive deficits were related to reduced hippocampal neuronal cell death and increased myelin integrity in RES-treated rats. The neuroprotective effects of RES were associated with suppression of the expression of tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), VCAM-1, interferon-β (IFN-β), and IL-1β, likely through mitigation of the STING/TBK1/IRF3 pathway. These inhibitory effects exerted by RES also inhibited the levels of myeloperoxidase, reduced excess expression of reactive astrocytes, and activated microglia. In conclusion, the STING/TBK1/IRF3 axis may be critical for proinflammatory responses in cerebral tissue with persistent hypoperfusion, and RES exerts its anti-inflammatory effects by suppressing STING/TBK1/IRF3 signaling.

Gardenia jasminoides J. Ellis extract GJ-4 attenuates hyperlipidemic vascular dementia in rats via regulating PPAR-γ-mediated microglial polarization

BackgroundGJ-4 is extracted from Gardenia jasminoides J. Ellis (Fructus Gardenia) with crocin composition and has been demonstrated to improve memory deficits in several dementia models in our previous studies.ObjectiveThis study aimed to evaluate the effects of GJ-4 on hyperlipidemic vascular dementia (VD) and explore the underlying mechanisms.DesignIn the current study, we employed a chronic hyperlipidemic VD rat model by permanent bilateral common carotid arteries occlusion (2-VO) based on high-fat diet (HFD), which is an ideal model to mimic the clinical pathogenesis of human VD.ResultsOur results showed that GJ-4 could significantly reduce serum lipids level and improve cerebral blood flow in hyperlipidemic VD rats. Additionally, treatment with GJ-4 remarkedly ameliorated memory impairment and alleviated neuronal injury. Mechanistic investigation revealed that the neuroprotective effects of GJ-4 might be attributed to the inhibition of microglia-mediated neuro-inflammation via regulating the M1/M2 polarization. Our data further illustrated that GJ-4 could regulate the phenotype of microglia through activating the peroxisome proliferator-activated receptor-γ (PPAR-γ) and subsequently inhibited nuclear factor-κB (NF-κB) nuclear translocation and increased CCAAT/enhancer-binding protein β (C/EBPβ) expression.ConclusionOur results implied that GJ-4 might be a promising drug to improve VD through the regulation of microglial M1/M2 polarization and the subsequent inhibition of neuro-inflammation.

Deeper cerebral hypoperfusion leads to spatial cognitive impairment in mice

BackgroundVascular cognitive impairment (VCI) is the second-leading cause of dementia worldwide, which is caused by cerebrovascular diseases or relevant risk factors. However, there are no appropriate animal models, which can...

Qinzhi Zhudan formula improves memory and alleviates neuroinflammation in vascular dementia rats partly by inhibiting the TNFR1-mediated TNF pathway

The Qinzhi Zhudan formula (QZZD) exhibits a prominent therapeutic effect in the treatment of vascular dementia (VaD). This study combined a network pharmacology approach and experimental validation to identify the underlying biological mechanism of QZZD against VaD. Male Wistar rats received bilateral common carotid artery occlusion (BCCAO) surgery, and after 4 weeks of intragastric administration of QZZD, the therapeutic effect was assessed using the Morris water maze test and cerebral blood flow (CBF) assessment. Hematoxylin and eosin staining, Nissl staining, and electron microscopy were used to measure the histopathological changes in the neurons of rats. The effect of QZZD treatment on hippocampal neurotransmitters was assessed by high-performance liquid chromatography with electrochemical detection and liquid chromatography mass spectrometry. Immunofluorescence was used to observe VaD-induced microglia activation. The inflammatory cytokine levels were assessed by enzyme linked immunosorbent assay. Western blot was used to examine the TNFR1-mediated TNF pathway, which was screened out by network pharmacology analysis. QZZD treatment alleviated pathological changes and neuronal damage in VaD rats and attenuated their cognitive impairment. In addition, QZZD increased CBF and the expression of acetylcholine and 5-hydroxytryptamine in the hippocampal region. Notably, QZZD inhibited microglial activation and the expression of IL-6 and TNF-α. Network pharmacology and western blot indicated that QZZD inhibited the levels of TNFR1, NF-κBp65, p-ERK, TNF-α, and IL-6, which are related to the TNFR1-mediated TNF signaling pathway. QZZD clearly improved learning and memory function, reduced brain pathological damage, elevated CBF and hippocampal neurotransmitter levels, and alleviated neuroinflammation of VaD rats partly by inhibiting the TNFR1-mediated TNF pathway, indicating its potential value in the clinical therapy of VaD.

Neuroprotective Potential of Indian Propolis and in Combination with Curcumin against Bilateral Common Carotid Artery Occlusion Induced Vascular Dementia in Rats

Vascular dementia (VaD) is associated with chronic brain ischemia and gradual memory loss which is increasing gradually but limited treatments are available as therapeutic moieties to combat the VaD. Hence in this study Indian propolis alone or in combination with curcumin was explored as a treatment modality to alleviate the VaD. VaD model was induced by bilateral common carotid artery occlusion (BCCAO). Indian propolis (200 mg/kg), curcumin (200 mg/kg) individually, and the combination of Indian propolis (100 mg/kg) with curcumin (100 mg/kg) were administered in BCCAO model followed by an estimation of behavioral (neurological score, hanging and open field test) and biochemical parameters (reduced glutathione, catalase, malondialdehyde, and acetylcholine esterase). In this study it was found that there were no changes in the locomotor activity while the neurological score was reduced and the hanging time was increased in the drug treated group which clearly depicts the neuroprotective potential of curcumin, Indian propolis individually and the combination of Indian propolis with curcumin. The combination of Indian propolis with curcumin was much better in terms of neuroprotective activity than Indian propolis and curcumin treated group as depicted by the results of behavioural and biochemical parameters. Moreover, haematoxylin and eosin (H and E) staining was performed, and was found that a combination of Indian propolis(100 mg/kg) with curcumin (100 mg/kg) attenuated better histological alterations of the hippocampus in BCCAO model group than in other treated groups. Hence these findings provided that Indian propolis in combination with curcumin has great potential as a neuroprotective agent on the cognitive deficits of VaD rats.

Preclinical Evaluation of Neuroprotective Activity of Piper nigrum L. in Cerebral Ischemic Reperfusion Induced Oxidative Stress

Introduction: Stroke is a potentially fatal condition that is defined by the fast development of clinical symptoms of ischemia. Numerous flavonoids have been demonstrated in animal models to ameliorate brain ischemia-reperfusion damage. Piperine is a flavonoid derived from Piper nigrum L. that exhibits a variety of pharmacological effects. The purpose of this research was to determine if Piper nigrum L. has a protective effect against the brain damage caused by bilateral common carotid artery occlusion (BCCAO) in rats. Materials and Methods: The animal study was certified by Institutional Animal Ethics Committee (IAEC) under research project no. RKCP/COI/RP/12/28. Numerous parameters were evaluated to ascertain the extent of oxidative stress and eventual protection of Piper nigrumL. including glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), lipid peroxidation (LPO), brain protein, and calcium levels in brain homogenate. The preventive effect of P. nigrum was evaluated and compared with quercetin as a standard using histopathology and the region of cerebral infarction. Results: In our research, we observed a substantial rise in superoxide dismutase (SOD), catalase, glutathione, and brain protein levels and a fall in lipid peroxidation and calcium levels in the P. nigrum and quercetin treated groups with the level of significance (p value) less than 0.05, confirming the protective effect against brain injury. Additionally, P. nigrum was shown to provide less protection compared to quercetin. Conclusion: As a result of these data, we hypothesise that P. nigrummay have a considerable neuroprotective effect in the brain against ischemic/ reperfusion-induced oxidative damage.

Retinal Oxygen Delivery and Metabolism Response to Hyperoxia During Bilateral Common Carotid Artery Occlusion in Rats.

PurposeThe purpose of the current study was to test the hypothesis that responses of total retinal blood flow (TRBF), inner retinal oxygen delivery (DO2), metabolism (MO2), and extraction fraction (OEF) to hyperoxia are higher after minutes of bilateral common carotid artery occlusion (BCCAO) as compared to days of BCCAO.MethodsTwenty-eight rats were subjected to BCCAO for 30 minutes (n = 12), 1 day (n = 8), or 3 days (n = 8). Eight of the 12 rats were also evaluated at baseline, prior to BCCAO. During room air breathing (RA) and 100% O2 inspiration (hyperoxia), blood flow and phosphorescence lifetime imaging were performed to measure TRBF and vascular O2 contents, respectively. DO2, MO2, and OEF were calculated from these measurements.ResultsAfter 30 minutes or 3 days of BCCAO, TRBF did not differ between RA and hyperoxia conditions (P ≥ 0.14) but decreased under hyperoxia after 1 day (P = 0.01). Compared to RA, DO2 and MO2 were increased under hyperoxia after 30 minutes of BCCAO (P ≤ 0.02). Additionally, MO2 was decreased under hyperoxia after 1 day of BCCAO (P = 0.04). OEF was decreased under hyperoxia compared to RA (P < 0.001). Under hyperoxia, TRBF and DO2 were reduced after all BCCAO durations compared to baseline (P ≤ 0.04), whereas MO2 did not differ from baseline after 30 minutes of BCCAO (P = 1.00).ConclusionsThe findings indicate that hyperoxia introduced minutes after ischemia can reduce DO2 impairments and potentially return MO2 to approximately normal values. This information contributes to the knowledge of the effect of supplemental oxygen intervention on TRBF, DO2, MO2, and OEF outcomes after variable durations of ischemia.

P38 MAPK Endogenous Inhibition Improves Neurological Deficits in Global Cerebral Ischemia/Reperfusion Mice.

Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

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.

Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood–brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

Hemodynamic changes and neuronal damage detected by 9.4 T MRI in rats with chronic cerebral ischemia and cognitive impairment

IntroductionThe bilateral common carotid artery occlusion (BCCAO) rat model is an ideal animal model for simulating the pathology of chronic brain hypoperfusion in humans. However, dynamic changes in neuronal activity, cellular edema, and neuronal structural integrity in vivo after BCCAO have rarely been reported. The purpose of this study is to use a 9.4 T MRI to explore the pathophysiological mechanisms of vascular dementia.Materials and MethodsTwelve Sprague–Dawley (SD) rats were randomly divided into two groups: the sham group and the model group (n = 6 for each group). Rats were subjected to MRI using T2*WI, diffusion tensor imaging (DTI), and DWI sequences by MRI at the following six time points: presurgery and 6 h, 3 days, 7 days, 21 days, and 28 days postsurgery. Then, the T2*, fractional anisotropy (FA), and average apparent diffusion coefficient (ADC) values were measured in the bilateral cortices and hippocampi. After MRI scanning, all rats in both groups were subjected to the Y‐maze test, novel object recognition test, and open‐field test to assess their learning, memory, cognition, and locomotor activity.ResultsThe T2*, FA, and ADC values in the cerebral cortex and hippocampus decreased sharply at 6 h after BCCAO in the model group compared with those of the sham group. By Day 28, the T2* and ADC values gradually increased to close to those in the sham group, but the FA values changed little, and the rats in the model group had worse learning, memory, and cognition and less locomotor activity than the rats in the sham group.ConclusionsThe BCCAO is an ideal rat model for studying the pathophysiological mechanisms of vascular dementia.

Endovascular Intervention in a Narrowing Vessel of the Left Vertebral Artery with Bilateral Common Carotid Artery Occlusion and Aneurysm Rupture and Hemorrhage in the V4 Segment of the Right Vertebral Artery.

In this study, a case of bilateral common carotid artery occlusion and aneurysm in the V4 segment of the right vertebral artery with constriction of the left vertebral artery is presented. By improving digital subtraction angiography, an elderly female patient with subarachnoid haemorrhage (SAH) was diagnosed with a V4 segment of right vertebral artery aneurysm, a microaneurysm at the beginning of basilar aneurysms, bilateral common carotid artery occlusion, and narrowing vessel of left vertebral artery (DSA). Through the compensation of the basilar artery, the bilateral vertebral arteries provide intracranial and extracranial blood. Because the vertebral artery is narrowed, the right vertebral artery has priority in intracranial and extracranial blood delivery. Many members of the patient's immediate family have vasculitis, which has yet to be proven by appropriate laboratory testing but is thought to be the major cause of big artery occlusion. After cerebral angiography, the major source of this subarachnoid haemorrhage was determined to be a V4 segment of right vertebral artery aneurysm. Endovascular stent-assisted coil embolization was used to treat a V4 section of the right vertebral artery aneurysm. Because the basilar aneurysm was distal to the artery, interventional embolization was difficult to do, and it was not the major cause of the subarachnoid haemorrhage, the patient was advised to have follow-up surveillance, and she recovered well following the procedure. The combination of endovascular intervention of bilateral common carotid artery blockage and V4 segment of right vertebral artery aneurysm yielded excellent clinical outcomes in this instance. Endovascular treatment of a bilateral common carotid artery blockage paired with a V4 segment of a right vertebral artery aneurysm yielded excellent clinical outcomes in this patient, although long-term follow-up is necessary.

Neuroprotective Effects of Theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion.

Cerebral hypoperfusion (CH) is a common underlying mechanism of dementia disorders linked to aberrations in the neurovascular unit. Hemodynamic disturbances adversely affect cellular energy homeostasis that triggers a sequence of events leading to irrevocable damage to the brain and neurobehavioral discrepancies. Theobromine is a common ingredient of many natural foods consumed by a large population worldwide. Theobromine has shown health benefits in several studies, attributed to regulation of calcium homeostasis, phosphodiesterase, neurotransmission, and neurotrophins. The current study evaluated the neuroprotective potential of theobromine against CH in the permanent bilateral common carotid artery occlusion (BCCAO) prototype. Wistar rats were distributed in Sham-operated (S), S + T100, CH, CH + T50, and CH + T100 groups. Animals received permanent BCCAO or Sham treatment on day 1. Theobromine (50, 100mg/kg) was given orally in animals subjected to BCCAO for 14 days daily. CH caused neurological deficits (12-point scale), motor dysfunction, and memory impairment in rats. Treatment with theobromine significantly attenuated neurological deficits and improved sensorimotor functions and memory in rats with CH. In biochemistry investigation of the entire brain, findings disclosed reduction in brain oxidative stress, inflammatory intermediaries (tumor necrosis factor-α, interleukin-1β and - 6, nuclear factor-κB), markers of cell demise (lactate dehydrogenase, caspase-3), acetylcholinesterase activity, and improvement in γ-aminobutyric acid quantity in rats that were given theobromine for 14 days daily after CH. Histopathological analysis substantiated attenuation of neurodegenerative changes by theobromine. The findings of this study indicated that theobromine could improve neurological scores, sensorimotor abilities, and memory in CH prototype.

Triad3A-Dependent TLR4 Ubiquitination and Degradation Contributes to the Anti-Inflammatory Effects of Pterostilbene on Vascular Dementia.

Pterostilbene, a methylated stilbene derived from many plant foods, has significant anti-inflammatory activity. Meanwhile, vascular dementia (VaD) is the second most common subtype of dementia, in which inflammation is one of the major pathogenic contributors. However, the protective effect of pterostilbene on VaD is not well understood. In this work, we investigated the effect of pterostilbene on VaD and explored its underlying mechanisms using in vivo and in vitro models. Y-maze and Morris water maze tests showed pterostilbene-attenuated cognitive impairment in mice with bilateral common carotid artery occlusion (BCCAO). The hippocampal neuronal death and microglial activation in BCCAO mice were also reduced by pterostilbene treatment. Further, pterostilbene inhibited the expression of TLR4 and downstream inflammatory cytokines in these mice, with similar results observed in an oxygen-glucose deprivation and reperfusion (OGD/R) BV-2 cell model. In addition, its anti-inflammatory effect on OGD/R BV-2 cells was partially blocked by TLR4 overexpression. Moreover, Triad3A-TLR4 interactions were increased by pterostilbene following enhanced ubiquitination and degradation of TLR4, and the inhibitory effect of pterostilbene on inflammation was blocked by Triad3A knockdown in OGD/R-stimulated BV-2 cells. Together, these results reveal that pterostilbene could reduce vascular cognitive impairment and that Triad3A-mediated TLR4 degradation might be the key target.

Cerebrolysin® and Environmental Enrichment, Alone or in Combination, Ameliorate Anxiety- and Depressive-Like Behaviors in a Post-Ischemic Depression Model in Mice

ObjectivesThis study examined the beneficial effects of cerebrolysin (CBL) and enriched environment (EE), alone or in combination, on the neurobehavioral and molecular changes in the post-ischemic depression (PID) model in mice. Materials and MethodsPID was induced in male Balb/c mice (25–30 g) by combining the transient bilateral common carotid artery occlusion (bCCAO), twice for 5 min at the interval of 10 min, with spatial restraint stress (2 h/day) for 2 weeks, started 48 h following the establishment of bCCAO model. Animals in the treatment groups received CBL (2.5 ml/kg) and/or were housed in EE (2 h/day) for two weeks. Anxiety- and depressive-like behaviors and sociability were evaluated the day after the last experiment. Changes in the serum corticosterone level, the hippocampal oxidative stress status, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element-binding protein (p-CREB)/CREB ratio were also detected. ResultsPID model induced anxiety- and depressive-like behaviors and impaired social behavior. These behavioral changes were accompanied by increased serum corticosterone level, increased lipid peroxidation, decreased antioxidant enzyme activities, reduced BDNF levels and p-CREB/CREB ratio, and increased protein levels of NF-κB and Iba-1 in the hippocampus. However, treatment with CBL and/or EE reversed behavioral and molecular changes induced by PID. ConclusionOur findings imply that the model mimics many manifestations of human PID, and CBL and EE treatments, separately or in combination, are beneficial in reducing anxiety- and- depressive-like behaviors in this model.

Transanethole protects against Global Cerebral Ischemia through its Anti-inflammatory and Anti apoptotic activity

Aim and Objective: In this research study, transanethole at a dose of 250 and 500mg/kg p.o was investigated for its potency against Bilateral Common Carotid Artery occlusion (BCCAO) for 1 hr accompanied by 22 hrs reperfusion. Method: Healthy Albino Wistar rats (200–250gm) were divided randomly into 4 groups (n=9). Group I was considered as sham control, received 2% tween 80p.o, group II was considered as ischemic- reperfusion (disease control) and received 2% tween 80p.o and group III and IV were considered as prophylactic treatment groups and received transanethole at doses of 250mg/kg, p.o and 500mg/kg, p.o. respectively. After pretreatment with transanethole for14 days, rats were subjected to bilateral common carotid artery occlusion (BCCAO) for 1 hour accompanied by 22 hr reperfusion (I/R). After 22 hrs of reperfusion, motor coordination, behavioral assessment, infarct area, brain water content, excitatory mediators, inflammatory and apoptotic markers were determined. Results: Transanethole improved the motor coordination, lowered the brain water content, infarction volume and attenuated the levels of excitatory mediators. Western blotting analysis was performed to identify the proinflammatory mediators (TNF α, p38 MAPK), anti-inflammatory cytokine IL 10 and apoptotic marker proteins (Caspase 3, Bcl-2 and Bax) in brain tissue. Prophylactic treatment with trans anethole significantly down regulated the expressions of TNF-α, caspase 3, Bax, dephosphorylated p38 MAPK and upregulated the expressions of Bcl-2, IL 10 in a dose dependent manner in comparison with disease control group. Conclusion: An anti-inflammatory and anti- apoptotic activity of transanethole protected from cerebral ischemia reperfusion injury.