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Perindopril ameliorates experimental Alzheimer's disease progression: role of amyloid β degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling.
Inflammopharmacology ( IF 4.6 ) Pub Date : 2020-06-01 , DOI: 10.1007/s10787-020-00724-4
Basim A S Messiha 1 , Mohammed R A Ali 1 , Mahmoud M Khattab 2 , Amira M Abo-Youssef 1
Affiliation  

Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with β-amyloid (Aβ) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer’s disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4 weeks following d-galactose injection (150 mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5 mg/kg/day, p.o.) was administered on a daily basis for 30 days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aβ1–42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood–brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and β-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.



中文翻译:

培哚普利改善了实验性阿尔茨海默氏病的进展:淀粉样β蛋白降解,中央雌激素受体和高脂血脂筏信号传导的作用。

越来越多的证据表明,过度刺激血管紧张素转化酶1(ACE1)的活性与β-淀粉样蛋白(Aβ)和磷酸化tau(p-tau)诱导的凋亡,氧化亚硝化神经炎性应激和神经变性有关。 )。或者,ACE2,金属蛋白酶中性溶酶(中性内肽酶; NEP)和胰岛素降解酶(IDE)的激活可能与ACE1激活的作用相反。我们旨在调查高脂血症AD模型中ACE1 / ACE2 / NEP / IDE与淀粉样蛋白生成/高脂血症-脂筏信号之间的关系。AD的诱导去卵巢的雌性大鼠4周后下列高脂肪高果糖饮食(HFFD)将执行d-半乳糖注射液(150 mg / kg)。每天服用可穿透脑的ACE1抑制剂培哚普利(0.5 mg / kg /天,口服)30天。培哚普利显着降低ACE1的海马表达并增加ACE2,NEP和IDE的表达。培哚普利显着降低Aβ1–42,改善脂质谱并改善脂质筏蛋白标记小窝蛋白1(CAV1)和弗洛蒂林1(FLOT1)。这伴随着p-tau蛋白表达的降低和胆碱能神经传递的增强,氧化亚硝化神经炎性应激的降低,血脑屏障(BBB)功能的增强和凋亡标记物胶质纤维酸性蛋白(GFAP)的表达降低, Bax和β-微管蛋白。此外,培哚普利分别改善了莫里斯水迷宫,Y迷宫,新颖物体识别和强迫游泳测试的组织病理学损伤,并改善了学习,认知和识别障碍以及抑郁行为。结论是培哚普利可以改善AD大鼠的认知缺陷,

更新日期:2020-06-01
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