Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.
Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.
复制标题
DOI：
10.3389/fnagi.2023.1180913
复制
发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
血管性痴呆（VaD）是指由脑血管疾病和/或大脑血流量减少引起的痴呆，是继阿尔茨海默病之后第二常见的痴呆形式。我们先前发现，在经历VaD的多发性微梗塞（MMI）模型的中年大鼠中，与对照MMI大鼠相比，用AV-001（Tie 2受体激动剂）治疗显著改善了短期记忆、长期记忆以及改善了对社会新奇性的偏好。在这项研究中，我们测试了AV-001对VaD大鼠炎症和胶质淋巴功能的早期治疗作用。将接受MMI的雄性中年Wistar大鼠（10-12 m）随机分配至MMI和MMI + AV-001治疗组。包括假手术组作为参考组。通过向颈内动脉注射800 ± 200，70-100 μm大小的胆固醇晶体来诱导MMI。将动物用AV-001（lyg/Kg，i. p.）MMI后24 h开始每日1次。MMI后14天，评价脑脊液（CSF）和脑中的炎症因子表达。免疫组织化学染色评价脑内白色物质完整性、血管周围间隙（PVS）和血管周围水通道蛋白4（AQP 4）表达。制备另外一组大鼠以测试胶质淋巴功能。MMI后第14天，将50 μL 1%四甲基罗丹明（3 kD）和FITC结合葡聚糖（500 kD）以1：1的比例注射到CSF中。在示踪剂输注开始后30分钟、3小时和6小时处死大鼠（4-6只/组/时间点），并使用激光扫描共聚焦显微镜对脑冠状切片成像以评价脑中的示踪剂强度。用AV-001治疗MMI在MMI后14天显著改善胼胝体中的白色物质完整性。与Sham大鼠相比，MMI诱导PVS显著扩张，降低AQP 4表达并损害胶质淋巴功能。与MMI大鼠相比，AV-001治疗显著降低PVS，增加血管周围AQP 4表达并改善胶质淋巴功能。MMI显著增加CSF中炎性因子（肿瘤坏死因子-α（TNF-α）、趋化因子配体9）和抗血管生成因子（内皮抑素、纤溶酶原激活物抑制剂-1、P-选择素）的表达，而AV-001显著降低CSF中炎性因子（TNF-α、趋化因子配体9）和抗血管生成因子（内皮抑素、纤溶酶原激活物抑制剂-1、P-选择素）的表达。MMI显著增加，而AV-001显著降低脑组织内皮抑制素、凝血酶、TNF-α、派-1、CXCL 9和白细胞介素-6（IL-6）的表达。与MMI大鼠相比，MMI的AV-001治疗显著减少PVS扩张并增加血管周围AQP 4表达，这可能有助于改善胶质淋巴功能。AV-001治疗显著降低CSF和脑中的炎性因子表达，这可能有助于AV-001治疗诱导的白色完整性和认知功能的改善。
Vascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer’s disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD. Male, middle-aged Wistar rats (10–12 m), subjected to MMI, were randomly assigned to MMI and MMI + AV-001 treatment groups. A sham group was included as reference group. MMI was induced by injecting 800 ± 200, 70–100 μm sized, cholesterol crystals into the internal carotid artery. Animals were treated with AV-001 (1 μg/Kg, i.p.) once daily starting at 24 h after MMI. At 14 days after MMI, inflammatory factor expression was evaluated in cerebrospinal fluid (CSF) and brain. Immunostaining was used to evaluate white matter integrity, perivascular space (PVS) and perivascular Aquaporin-4 (AQP4) expression in the brain. An additional set of rats were prepared to test glymphatic function. At 14 days after MMI, 50 μL of 1% Tetramethylrhodamine (3 kD) and FITC conjugated dextran (500 kD) at 1:1 ratio were injected into the CSF. Rats (4–6/group/time point) were sacrificed at 30 min, 3 h, and 6 h from the start of tracer infusion, and brain coronal sections were imaged using a Laser scanning confocal microscope to evaluate tracer intensities in the brain. Treatment of MMI with AV-001 significantly improves white matter integrity in the corpus callosum at 14 days after MMI. MMI induces significant dilation of the PVS, reduces AQP4 expression and impairs glymphatic function compared to Sham rats. AV-001 treatment significantly reduces PVS, increases perivascular AQP4 expression and improves glymphatic function compared to MMI rats. MMI significantly increases, while AV-001 significantly decreases the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), chemokine ligand 9) and anti-angiogenic factors (endostatin, plasminogen activator inhibitor-1, P-selectin) in CSF. MMI significantly increases, while AV-001 significantly reduces brain tissue expression of endostatin, thrombin, TNF-α, PAI-1, CXCL9, and interleukin-6 (IL-6). AV-001 treatment of MMI significantly reduces PVS dilation and increases perivascular AQP4 expression which may contribute to improved glymphatic function compared to MMI rats. AV-001 treatment significantly reduces inflammatory factor expression in the CSF and brain which may contribute to AV-001 treatment induced improvement in white matter integrity and cognitive function.
登录
查看更多内容
DOI：
10.1186/s13054-017-1851-6
发表时间：
2017-11-13
期刊：
Critical care (London, England)
影响因子：
--
作者：
Gutbier B;Jiang X;Dietert K;Ehrler C;Lienau J;Van Slyke P;Kim H;Hoang VC;Maynes JT;Dumont DJ;Gruber AD;Weissmann N;Mitchell TJ;Suttorp N;Witzenrath M
通讯作者：
Witzenrath M
DOI：
10.1016/j.jalz.2016.04.006
发表时间：
2016-08
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Corrada MM;Sonnen JA;Kim RC;Kawas CH
通讯作者：
Kawas CH
影响因子：
4.3
作者：
Gyengesi, Erika;Rangel, Alejandra;Muench, Gerald
通讯作者：
Muench, Gerald
影响因子：
5.1
作者：
Cumurciuc, R;Guichard, JP;Chabriat, H
通讯作者：
Chabriat, H
脑膜淋巴系统：神经生理学的新玩家。
影响因子：
16.2
作者：
Da Mesquita S;Fu Z;Kipnis J
通讯作者：
Kipnis J