endothelin-1 and Dementia--Vascular

Alzheimer's disease (AD) and vascular dementia are the major causes of cognitive disorders worldwide. They are characterized by cognitive impairments along with neuropsychiatric symptoms, and that their pathogeneses show overlapping multifactorial mechanisms. Although AD has long been considered the most common cause of dementia, individuals afflicted with AD commonly exhibit cerebral vascular abnormalities. The concept of mixed dementia has emerged to more clearly identify patients with neurodegenerative phenomena exhibiting both AD and cerebral vascular pathologies-vascular damage along with β-amyloid (Aβ)-associated neurotoxicity and τ-hyperphosphorylation. Cognitive impairment has long been commonly explained through a 'neuro-centric' perspective, but emerging evidence has shed light over the important roles that neurovascular unit dysfunction could have in neuronal death. Moreover, accumulating data have been demonstrating astrocytes being the essential cell type in maintaining proper central nervous system functioning. In relation to dementia, the roles of astrocytes in Aβ deposition and clearance are unclear. This article emphasizes the multiple events triggered by ischemia and the cytotoxicity exerted by Aβ either alone or in association with endothelin-1 and receptor for advanced glycation end products, thereby leading to neurodegeneration in an 'astroglio-centric' perspective.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Brain Ischemia; Dementia, Vascular; Endothelin-1; Humans

To explore the new progress of the experimental study of traditional Chinese medicine in the treatment of vascular. Consulted the relevant papers and integrated the elementary theory, we summarized the virtue of Chinese medicine in the treatment of vascular dementia and insufficient and future development of the experimental study of it. It was confirmed that the traditional Chinese medicine has a lot of target spots in the brain and less ill-effect, it could ameliorate several phenotypes of pathophysiology of vascular dementia and improve the ability of learning and memory of animals with vascular dementia.

Topics: Animals; Apoptosis; Dementia, Vascular; Drugs, Chinese Herbal; Endothelin-1; Excitatory Amino Acids; Free Radicals; Glutamic Acid; Learning; Memory; Neuroprotective Agents; Nitric Oxide Synthase; Phytotherapy; Plants, Medicinal

To determinate the clinical effect of butyphthalide combined with idebenone in the treatment of vascular dementia (VD) and the influence on inflammatory cytokines and vascular endothelial functions.. Clinical comparative study.. Department of Neurology, Baoding First Central Hospital, from June 2017 to June 2018.. Eighty-eight VD patients were divided into observation group (44 cases) and control group (44 cases) at random. Idebenone was given to the control group, and butyphthalide combined with idebenone was given to the observation group for 12 weeks. C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected before and after the treatment to evaluate the level of serum inflammatory factors. Peripheral blood endothelial microparticles (EMPs), endothelin (ET-1), and vascular endothelial growth factor (VEGF) were detected to evaluate vascular endothelial functions. Mini-mental state examination (MMSE), clinical dementia scale (CDR), and ability of daily life (ADL), were used to evaluate cognitive function, dementia degree, and self-care ability in daily life. The occurrences of adverse reactions were recorded.. Before the treatment, the comparison differences in the indexes of both groups had no statistical significance (p>0.05). After the treatment, the scores of CD62E+, VEGF, and MMSE of observation group rose obviously, compared with those before the treatment, and were significantly higher than those of control group (p <0.05). After the treatment, the scores of IL-6, CRP, TNF-α, IL-1β, CD31+, CDl44+, ET-1, CDR and ADL of observation group significantly lowered, compared with those before the treatment, and were significantly lower than those of control group (p <0.05). The differences in the adverse reactions of both groups had no statistical significance (p >0.05).. Butyphthalide combined with idebenone can effectively reduce serum inflammatory factor level of VD patients, regulate vascular endothelial functions, relieve dementia degree, and improve cognitive function and daily activity ability.

Topics: Activities of Daily Living; Aged; Antioxidants; Benzofurans; C-Reactive Protein; Cytokines; Dementia, Vascular; Drug Therapy, Combination; Endothelin-1; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Ubiquinone; Vascular Endothelial Growth Factor A

To observe the effect of Sancaijiangtang powders on plasma nitric oxide and endothelin-1 levels. We sought to identify the common pathological link and mechanism of action for Traditional Chinese medicine in type 2 diabetes mellitus and vascular dementia, and to explicate the material basis for treating the different diseases with the same method in Traditional Chinese Medicine.. In total, 168 patients with type 2 diabetes mellitus and vascular dementia were enrolled in the study, and randomly divided into two groups by simple randomization. Patients in the treatment group received oral Sancaijiangtang powders with pioglitazone hydrochloride three times daily, while patients in the control group received pioglitazone hydrochloride alone. The treatment course was for 12 weeks. Mini-mental state examinations (Chinese version) and Montreal Cognitive Assessments (Beijing version) were performed, and fasting plasma glucose, fasting insulin, hemoglobin A1c, homeostasis model assessment of insulin resistance, plasma nitric oxide and endothelin-1 levels were measured before and after the treatment.. The post-treatment levels for all measurements in both groups were better than pre-treat- ment levels (P < 0.05). The post-treatment levels for all measurements in the treatment group were better than the levels measured in the control group (P < 0.05).. Type 2 diabetes mellitus and vascular dementia have common pathological mechanisms for insulin resistance and endothelium dysfunction. Sancaijiangtang powders could improve the release of nitric oxide and inhibit the secretion of endothelin-1. Therefore, the material basis exists for treating the different diseases with the same method in Traditional Chinese Medicine.

Topics: Aged; Dementia, Vascular; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Endothelin-1; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Nitric Oxide; Single-Blind Method

Cellular senescence plays a pivotal role in the aging and progression of neurodegenerative diseases, including vascular cognitive impairment and dementia (VCID). In postmortem brains from individuals with VCID, endothelin-1 (ET-1) levels closely correlate with blood barrier breakdown and cerebral hypoperfusion. Brain microvascular endothelial cells (BMVECs), previously thought to have exclusively endothelin B receptors, also possess endothelin A (ETA) receptors; however, the functional significance of this receptor in BMVECs is not known. We hypothesize that ETA receptors mediate BMVEC senescence. Serum-starved human BMVECs (HBEC5i) were incubated with ET-1 (1 µmol/L) in the presence/absence of ETA receptor antagonist BQ-123 (20 µmol/L). Cells were collected for Western blot and quantitative real-time PCR analyses. Treatment of ET-1 increased protein expression of ETA receptor, while it was prevented by the ETA receptor antagonist. ET-1 increased p21, p16, p53, LIF1 and cyclin D1 protein levels, and β-galactosidase accumulation, which were prevented in the presence of ETA blockade. While there was no change in tight junction proteins, ET-1 decreased adherent junction protein vascular endothelial cadherin (VE-cadherin) levels. In conclusion, ET-1 upregulates ETA receptors in BMVECs in an autocrine manner and triggers the activation of senescence. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of endothelial senescence in VCID.

Topics: Brain; Dementia, Vascular; Endothelial Cells; Endothelin-1; Humans; Receptor, Endothelin A

This study tried to investigate the dynamic changes of Beclin-1 in the hippocampus of male mice with vascular dementia (VD) at different time points. The mouse model of VD was established by the four-vessel blocking method. Then, the VD mice were randomly divided into five groups (n = 12) according to the disease duration: the 0.1-day model group, 0.5-day model group, 1-day model group, 3-day model group, 5-day model group and 14-day model group. In addition, all surgical procedures were the same in the sham group as those in the model groups, except the mice in the sham group were not subjected to clipping. The expression of Beclin-1, LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP and ET-1 mRNA were determined by RT-PCR; the expression of Beclin-1 was detected by Western blot and immunofluorescence; the pathological characteristics of the hippocampus were observed by haematoxylin-eosin (HE) staining; and the correlation of Beclin-1 with other VD-related proteins was analysed by Pearson's correlation. Compared with that in the sham group, the expression of Beclin-1, LC3B, Bax, BACE1, GFAP, MBP and ET-1 mRNA was increased in the VD mice at different time points (0.1 day, 0.5 day, 1 day, 3 days, 5 days and 14 days) (P < 0.05) and then remained relatively stable in the 0.5-day VD mice, whereas the p62 and Bcl-2 mRNA levels decreased (P < 0.05). Beclin-1 protein expression was significantly increased in the VD mice at different time points (P < 0.05). The hippocampus showed a certain degree of neuronal damage in the VD mice at different time points (P < 0.05). Additionally, certain correlations among LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP, ET-1 and Beclin-1 were observed in this study. In conclusion, the results described above demonstrated that neuronal damage and dynamic stability of Beclin-1 expression were established in the VD male mice after 0.5 day by the four-vessel blocking method.

Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; bcl-2-Associated X Protein; Beclin-1; Dementia, Vascular; Endothelin-1; Glial Fibrillary Acidic Protein; Hippocampus; Male; Mice; Mice, Inbred ICR; Microtubule-Associated Proteins; Myelin Basic Protein; Proto-Oncogene Proteins c-bcl-2; Sequestosome-1 Protein

Little is known about the contributors and physiological responses to white matter hypoperfusion in the human brain. We previously showed the ratio of myelin-associated glycoprotein to proteolipid protein 1 in post-mortem human brain tissue correlates with the degree of ante-mortem ischaemia. In age-matched post-mortem cohorts of Alzheimer's disease (n = 49), vascular dementia (n = 17) and control brains (n = 33) from the South West Dementia Brain Bank (Bristol), we have now examined the relationship between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and several other proteins involved in regulating white matter vascularity and blood flow. Across the three cohorts, white matter perfusion, indicated by the ratio of myelin-associated glycoprotein to proteolipid protein 1, correlated positively with the concentration of the vasoconstrictor, endothelin 1 (P = 0.0005), and negatively with the concentration of the pro-angiogenic protein, vascular endothelial growth factor (P = 0.0015). The activity of angiotensin-converting enzyme, which catalyses production of the vasoconstrictor angiotensin II was not altered. In samples of frontal white matter from an independent (Oxford, UK) cohort of post-mortem brains (n = 74), we confirmed the significant correlations between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and both endothelin 1 and vascular endothelial growth factor. We also assessed microvessel density in the Bristol (UK) samples, by measurement of factor VIII-related antigen, which we showed to correlate with immunohistochemical measurements of vessel density, and found factor VIII-related antigen levels to correlate with the level of vascular endothelial growth factor (P = 0.0487), suggesting that upregulation of vascular endothelial growth factor tends to increase vessel density in the white matter. We propose that downregulation of endothelin 1 and upregulation of vascular endothelial growth factor in the context of reduced ratio of myelin-associated glycoprotein to proteolipid protein 1 are likely to be protective physiological responses to reduced white matter perfusion. Further analysis of the Bristol cohort showed that endothelin 1 was reduced in the white matter in Alzheimer's disease (P < 0.05) compared with control subjects, but not in vascular dementia, in which endothelin 1 tended to be elevated, perhaps reflecting abnormal regulation of white matter perfusion in vascular dementia. Our findings

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cohort Studies; Dementia, Vascular; Endothelin-1; Factor VIII; Female; Humans; Male; Middle Aged; Myelin-Associated Glycoprotein; Nerve Fibers, Myelinated; Peptidyl-Dipeptidase A; Vascular Endothelial Growth Factor A

Subcortical white matter stroke is a common stroke subtype but has had limited pre-clinical modeling. Recapitulating this disease process in mice has been impeded by the relative inaccessibility of the subcortical white matter arterial supply to induce white matter ischemia in isolation. In this report, we detail a subcortical white matter stroke model developed in the mouse and its characterization with a comprehensive set of MRI, immunohistochemical, neuronal tract tracing and electron microscopic studies. Focal injection of the vasoconstrictor endothelin-1 into the subcortical white matter produces an infarct core that develops a maximal MRI signal by day 2, which is comparable in relative size and location to human subcortical stroke. Immunohistochemical studies indicate that oligodendrocyte apoptosis is maximal at day 1 and apoptotic cells extend away from the stroke core into the peri-infarct white matter. The amount of myelin loss exceeds axonal fiber loss in this peri-infarct region. Activation of microglia/macrophages takes place at 1 day after injection near injured axons. Neuronal tract tracing demonstrates that subcortical white matter stroke disconnects a large region of bilateral sensorimotor cortex. There is a robust glial response after stroke by BrdU pulse-labeling, and oligodendrocyte precursor cells are initiated to proliferate and differentiate within the first week of injury. These results demonstrate the utility of the endothelin-1 mediated subcortical stroke in the mouse to study post-stroke repair mechanisms, as the infarct core extends through the partially damaged peri-infarct white matter and induces an early glial progenitor response.

Topics: Animals; Apoptosis; Cell Proliferation; Dementia, Vascular; Disease Models, Animal; Endothelin-1; Gliosis; Macrophages; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Regeneration; Neural Pathways; Oligodendroglia; Recovery of Function; Stem Cells; Stroke; Vasoconstrictor Agents; Wallerian Degeneration

Topics: Alzheimer Disease; Brain; Dementia, Vascular; Endothelin-1; Humans; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Regional Blood Flow; Risk Factors; Up-Regulation

Endothelin-1 is known to exist in the nervous system. A notable increase of plasma endothelin-1 is associated with acute stroke. This study was designed to measure plasma endothelin-1 levels in Binswanger's disease and explore the relationship between endothelin-1 and this disorder.. Plasma levels of endothelin-1 were-examined by radioimmunoassay in 31 patients with Binswanger's disease and in three groups of control subjects. The ratio of the plasma concentration of endothelin-1 in the internal jugular vein to that in the antecubital vein was calculated as an indicator of endothelin-1 level in cerebral circulation.. Endothelin-1 ratio devation was seen more often in patients with Binswanger's disease than in acute stroke patients. Endithelin-1 ratios were significantly negatively correlated with Hasegawa's Dementia Scale scores is subjects with Binswanger's disease.. Abnormalities is vasoactive factors may make an important contribution to the pathophysiology of Binswanger's disease. Endothelin-1 might be involved in the pathogenesis of this illness.

Topics: Aged; Cerebrovascular Disorders; Dementia, Vascular; Endothelin-1; Female; Humans; Male; Middle Aged