A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction
A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction
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DOI：
10.1124/jpet.118.254854
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发表时间：
2019-04-01
影响因子：
3.5
通讯作者：
Konhilas, John P.
中科院分区：
文献类型：
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作者：
Hay, Meredith;Polt, Robin;Konhilas, John P.
越来越多的证据表明，脑血流量减少、活性氧（ROS）产生增加和促炎机制加速了神经退行性疾病的进展，如在血管对认知障碍和痴呆（VOID）以及阿尔茨海默病和相关痴呆的贡献中所见。临床上迫切需要安全有效的疗法来治疗和预防已知在患有VCID和慢性炎性疾病如心力衰竭（HF）、高血压和糖尿病的患者中发生的认知损害。本研究使用我们的VCID/HF小鼠模型来测试我们的新型糖基化血管紧张素-（1-7）肽Ang-1-6-O-Ser-Glc-NH 2（PNA 5）作为治疗VCID的疗法，并研究可能涉及的循环炎症生物标志物。我们证明，PNA 5具有更大的脑渗透相比，天然血管紧张素-（1-7）肽。此外，在以1.0/mg/kg，s.c.，持续21天，PNA 5在我们的VCID/HF小鼠中表现出长达10天的持续认知保护作用，其持续超过肽半衰期。PNA 5逆转了VCID/HF小鼠的物体识别障碍，并挽救了空间记忆障碍。PNA 5激活Mas受体导致人内皮细胞中ROS的剂量依赖性抑制。最后，PNA 5治疗降低了VCID/HF诱导的脑小胶质细胞/巨噬细胞的活化，并抑制了循环肿瘤坏死因子α、白细胞介素（IL）-7和粒细胞刺激因子血清水平，同时增加了抗炎细胞因子IL-10的水平。这些结果表明，PNA 5是治疗VCID和其他炎症相关脑疾病的优秀候选者和“一流”疗法。
Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VOID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor alpha , interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.