We have previously reported that casein hydrolysate, CH-3, from bovine milk and casein-derived tripeptide Met-Lys-Pro (MKP) has ACE inhibitory activity and reduces blood pressure. In this study, we investigated the therapeutic effects of MKP in a hypertensive rat model (7-week-old male SHRSP/Izm rats). For long term evaluation, rats were fed either a diet containing CH-3 or normal diet. The survival rate of SHRSP rats was significantly improved by intake of CH-3 for 181 days. For short term evaluation, rats were orally administered synthetic tripeptide MKP or distilled water for 4 weeks. MRI study demonstrated that hemorrhagic lesions were observed in two of five rats in the control group, while no hemorrhagic lesions were observed in the MKP group. Volumetric analysis using MRI revealed that MKP administration inhibited atrophy of diencephalic regions. Histological examinations revealed that hemorrhage areas and astrogliosis in the hippocampus and cerebral cortex were lower in the MKP group than in the control group. Gene expression analysis indicated that MKP administration reduced expression of genes related to cerebral circulation insufficiency such as immune responses (Cd74 and Prkcd), response to hypoxia (Ddit4, Apold1, and Prkcd), reactive oxygen species metabolic process (Ddit4 and Pdk4), and apoptotic process (Ddit4, Prkcd, and Sgk1), suggesting that MKP administration prevented cerebral ischemia associated with hypertension. In addition, some genes encoding responses to hormone stimulus (Fos, Dusp1, and Sik1) were also downregulated. Serum aldosterone and corticosterone levels were also significantly decreased following MKP administration. The present study indicates that MKP shows neuroprotective effects in SHRSP rats by regulating cerebral circulation insufficiency and corticoid levels. MKP administration may therefore be a potential therapeutic strategy for hypertensive brain diseases such as cerebrovascular disease.

中文翻译：

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酪蛋白衍生肽 Met-Lys-Pro (MKP) 在高血压模型中的神经保护作用

我们之前曾报道过来自牛奶和酪蛋白衍生的三肽 Met-Lys-Pro (MKP) 的酪蛋白水解物 CH-3 具有 ACE 抑制活性并降低血压。在这项研究中，我们研究了 MKP 在高血压大鼠模型（7 周龄雄性 SHRSP/Izm 大鼠）中的治疗效果。对于长期评估，大鼠喂食含有 CH-3 的饮食或正常饮食。通过摄入CH-3 181天，SHRSP大鼠的存活率显着提高。对于短期评估，大鼠口服合成三肽 MKP 或蒸馏水 4 周。MRI研究表明，对照组5只大鼠中有2只观察到出血性病变，而MKP组未观察到出血性病变。使用 MRI 的体积分析显示，MKP 给药抑制了间脑区域的萎缩。组织学检查显示，MKP组海马和大脑皮层的出血面积和星形胶质细胞增生低于对照组。基因表达分析表明，MKP 给药降低了与脑循环不足相关基因的表达，如免疫反应（Cd74 和 Prkcd）、缺氧反应（Ddit4、Apold1 和 Prkcd）、活性氧代谢过程（Ddit4 和 Pdk4），以及凋亡过程（Ddit4、Prkcd 和 Sgk1），表明 MKP 给药可预防与高血压相关的脑缺血。此外，一些编码对激素刺激反应的基因（Fos、Dusp1 和 Sik1）也被下调。MKP 给药后，血清醛固酮和皮质酮水平也显着降低。本研究表明 MKP 通过调节脑循环功能不全和皮质激素水平对 SHRSP 大鼠显示神经保护作用。因此，MKP 给药可能是高血压脑疾病（如脑血管疾病）的潜在治疗策略。