Department of Neurology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikatacho, Okayama, 700-8558, Japan.
Transl Stroke Res. 2012 Dec;3(4):466-72. doi: 10.1007/s12975-012-0205-6. Epub 2012 Aug 14.
Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor /insulin receptor substrate 1(IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Zucker fatty rats (8 weeks) were treated with vehicle (0.5 % methyl cellulose in physiological saline, p.o.), amlodipine (3 mg/kg/day, p.o.), atorvastatin (10 mg/kg/day, p.o.), or the combination of amlodipine plus atorvastatin (3 + 10 mg/kg/day, p.o.) for 28 days, and anti-insulin-like growth factor 1 (IGF-1)/IRS-1/PI3K/Akt pathways were evaluated. Our present immunohistochemical study first demonstrated that a combination of amlodipine plus atorvastatin treatment prevented an arteriosclerotic process compared to the single treatment with amlodipine or atorvastatin with strong recoveries of pTyr IRS-1, pPI3K, and pAkt expressions and with remarkable restraints of IGF-1 and pSer IRS-1. As a result, combination therapy with amlodipine plus atorvastatin showed a strong synergistic effect to prevent atherosclerotic processes. The present study newly suggests a synergistic benefit of combination therapy with amlodipine plus atorvastatin for strong prevention of atherosclerotic processes, which could reduce the clinical risk of cerebrovascular events for obesity patients.
肥胖是代谢综合征和动脉粥样硬化性心脑血管疾病的主要危险因素，它会导致胰岛素抵抗，表现为胰岛素对胰岛素受体/胰岛素受体底物 1（IRS-1）/磷酸肌醇 3-激酶（PI3K）/Akt 通路的功能障碍。给予 Zucker 肥胖大鼠（8 周） vehicle（0.5%甲基纤维素生理盐水，po）、氨氯地平（3mg/kg/天，po）、阿托伐他汀（10mg/kg/天，po）或氨氯地平加阿托伐他汀（3+10mg/kg/天，po）治疗 28 天，评估抗胰岛素样生长因子 1（IGF-1）/IRS-1/PI3K/Akt 通路。本研究首次通过免疫组化研究表明，与单一治疗相比，氨氯地平和阿托伐他汀联合治疗可预防动脉粥样硬化过程，pTyr IRS-1、pPI3K 和 pAkt 表达明显恢复，IGF-1 和 pSer IRS-1 明显受到抑制。因此，氨氯地平加阿托伐他汀联合治疗具有很强的协同作用，可预防动脉粥样硬化过程。本研究提示氨氯地平加阿托伐他汀联合治疗具有协同作用，可强力预防动脉粥样硬化过程，从而降低肥胖患者发生脑血管事件的临床风险。
