Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia.
Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia.
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DOI：
10.3389/fncel.2022.869710
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发表时间：
2022
影响因子：
5.3
通讯作者：
Venkat, Poornima
中科院分区：
文献类型：
--
作者：
Culmone, Lauren;Powell, Brianna;Landschoot-Ward, Julie;Zacharek, Alex;Gao, Huanjia;Findeis, Elizabeth L.;Malik, Ayesha;Lu, Mei;Chopp, Michael;Venkat, Poornima
关键词：
血管性痴呆（VaD）是一种影响认知和记忆的复杂神经退行性疾病。目前还缺乏专门针对VaD的药物治疗方法。在这项研究中，我们研究了一种Tie2受体激动剂AV-001对VaD多发微梗死（MMI）模型中年大鼠的治疗作用。选用10-12月龄雄性Wistar大鼠。采用Sham、MMI、MMI+1 μg/Kg AV-001、MMI+3 μg/Kg AV-001、MMI+6 μg/Kg AV-001实验组。AV-001治疗于MMI后1天开始，每天1次通过腹腔注射给药。研究者对实验组进行了一系列神经认知测试，包括改良神经严重程度评分（mNSS）测试、新物体识别测试、新气味识别测试、三室社会互动测试和莫里斯水迷宫测试。MMI后6周处死大鼠。注射1、3、6 μg/Kg AV-001后，中年MMI大鼠未见死亡。与基线值或MMI对照组相比，AV-001治疗（1、3或6 μg/Kg）在MMI后6周没有显著改变血压或心率。与Sham或MMI对照组相比，1或3 μg/Kg AV-001治疗MMI组的体重没有显著变化。与Sham和MMI对照组相比，6 μg/Kg AV-001治疗组的体重明显降低，但在MMI开始治疗后第1天体重减轻明显，与MMI后第0天或第1天的基线值相比无显著差异。与MMI对照组相比，AV-001治疗显著降低血清丙氨酸转氨酶、血清肌酐和血清肌钙蛋白I水平；但是，所有值都在正常范围内。MMI在中年大鼠中引起轻度神经功能缺损，表现为低mNSS评分（0-18评分<6）。与MMI对照组相比，1 μg/Kg AV-001处理组mNSS评分无显著差异，而3和6 μg/Kg AV-001处理组mNSS评分分别在MMI后第21-42天和第14-42天显著降低。与假对照大鼠相比，中年大鼠的MMI可引起显著的认知障碍，包括短期记忆丧失、长期记忆丧失、社会新奇性偏好降低和空间学习记忆障碍。与MMI大鼠相比，1 μg/Kg AV-001显著改善了大鼠的短期和长期记忆，增加了对社会新奇事物的偏好，改善了空间学习和记忆。与MMI大鼠相比，3 μg/Kg AV-001处理可改善短期记忆和社会新奇偏好，但对长期记忆和空间学习记忆没有改善。与MMI大鼠相比，6 μg/Kg AV-001治疗仅改善长期记忆。因此，选择1 μg/Kg AV-001为最佳剂量。与对照组相比，1 μg/Kg AV-001处理MMI中年大鼠，可显著增加胼胝体轴突密度、髓磷脂密度和髓磷脂厚度，增加皮层突触蛋白表达、神经元分支和树突棘密度、皮层和纹状体少突胶质细胞和少突胶质细胞祖细胞数量，促进室下区神经发生。在本研究中，我们提出AV-001作为一种新的治疗剂，可以改善中年VaD MMI模型大鼠的认知功能，减少白质损伤。以1 μg/Kg AV-001治疗MMI可显著改善中年大鼠的认知功能，增加脑轴突密度、髓鞘再生和神经可塑性。
Vascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. There is a lack of approved pharmacological treatments specifically for VaD. In this study, we investigate the therapeutic effects of AV-001, a Tie2 receptor agonist, in middle-aged rats subjected to a multiple microinfarct (MMI) model of VaD. Male, 10–12 month-old, Wistar rats were employed. The following experimental groups were used: Sham, MMI, MMI+1 μg/Kg AV-001, MMI+3 μg/Kg AV-001, MMI+6 μg/Kg AV-001. AV-001 treatment was initiated at 1 day after MMI and administered once daily via intraperitoneal injection. An investigator blinded to the experimental groups conducted a battery of neuro-cognitive tests including modified neurological severity score (mNSS) test, novel object recognition test, novel odor recognition test, three chamber social interaction test, and Morris water maze test. Rats were sacrificed at 6 weeks after MMI. There was no mortality observed after 1, 3, or 6 μg/Kg AV-001 treatment in middle-aged rats subjected to MMI. AV-001 treatment (1, 3, or 6 μg/Kg) does not significantly alter blood pressure or heart rate at 6 weeks after MMI compared to baseline values or the MMI control group. Treatment of MMI with 1 or 3 μg/Kg AV-001 treatment does not significantly alter body weight compared to Sham or MMI control group. While 6 μg/Kg AV-001 treated group exhibit significantly lower body weight compared to Sham and MMI control group, the weight loss is evident starting at 1 day after MMI when treatment was initiated and is not significantly different compared to its baseline values at day 0 or day 1 after MMI. AV-001 treatment significantly decreases serum alanine aminotransferase, serum creatinine, and serum troponin I levels compared to the MMI control group; however, all values are within normal range. MMI induces mild neurological deficits in middle-aged rats indicated by low mNSS scores (<6 on a scale of 0–18). Compared to control MMI group, 1 μg/Kg AV-001 treatment group did not exhibit significantly different mNSS scores, while 3 and 6 μg/Kg AV-001 treatment induced significantly worse mNSS scores on days 21–42 and 14–42 after MMI, respectively. MMI in middle-aged rats induces significant cognitive impairment including short-term memory loss, long-term memory loss, reduced preference for social novelty and impaired spatial learning and memory compared to sham control rats. Rats treated with 1 μg/Kg AV-001 exhibit significantly improved short-term and long-term memory, increased preference for social novelty, and improved spatial learning and memory compared to MMI rats. Treatment with 3 μg/Kg AV-001 improves short-term memory and preference for social novelty but does not improve long-term memory or spatial learning and memory compared to MMI rats. Treatment with 6 μg/Kg AV-001 improves only long-term memory compared to MMI rats. Thus, 1 μg/Kg AV-001 treatment was selected as an optimal dose. Treatment of middle-aged rats subjected to MMI with 1 μg/Kg AV-001 significantly increases axon density, myelin density and myelin thickness in the corpus callosum, as well as increases synaptic protein expression, neuronal branching and dendritic spine density in the cortex, oligodendrocytes and oligodendrocyte progenitor cell number in the cortex and striatum and promotes neurogenesis in the subventricular zone compared to control MMI rats. In this study, we present AV-001 as a novel therapeutic agent to improve cognitive function and reduce white matter injury in middle aged-rats subjected to a MMI model of VaD. Treatment of MMI with 1 μg/Kg AV-001 significantly improves cognitive function, and increases axon density, remyelination and neuroplasticity in the brain of middle-aged rats.
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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
影响因子：
3.6
作者：
An L;Chopp M;Zacharek A;Shen Y;Chen Z;Qian Y;Li W;Landschoot-Ward J;Liu Z;Venkat P
通讯作者：
Venkat P
影响因子：
15.1
作者：
Kuempers, Philipp;Gueler, Faikah;Shushakova, Nelli
通讯作者：
Shushakova, Nelli
影响因子：
8.3
作者：
Bieber, Michael;Gronewold, Janine;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
影响因子：
6.3
作者：
Kynast, Jana;Lampe, Leonie;Schroeter, Matthias L.
通讯作者：
Schroeter, Matthias L.