Fukui Yusuke, Yamashita Toru, Kurata Tomoko, Sato Kota, Lukic Violeta, Hishikawa Nozomi, Deguchi Kentaro, Abe Koji
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
J Stroke Cerebrovasc Dis. 2014 Jul;23(6):1545-53. doi: 10.1016/j.jstrokecerebrovasdis.2013.12.052. Epub 2014 Mar 28.
Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP.
此前，我们报道过，在血压正常的Wistar大鼠脑缺血后，活性氧和血管紧张素II的信号分子会产生脂质过氧化物、使蛋白质变性并损伤DNA。在此，我们研究了I型血管紧张素II受体阻滞剂替米沙坦对具有抗中风能力的自发性高血压大鼠（SHR-SR）氧化应激和α-突触核蛋白过度磷酸化积累的长期影响。3个月大时，将SHR-SR分为3个治疗组：SHR-SR溶剂对照组（SHR/Ve）、SHR-SR低剂量替米沙坦组（0.3 mg/kg/天）（SHR/low）和SHR-SR高剂量替米沙坦组（3 mg/kg/天）（SHR/high）。在6、12和18个月龄时，对这些组以及Wistar大鼠进行免疫组织学分析。与18个月龄的Wistar组相比，SHR/Ve组大脑皮层和海马中晚期糖基化终产物（AGE）、4-羟基壬烯醛（4-HNE）和磷酸化α-突触核蛋白（pSyn）阳性细胞的增加更为明显。在SHR/low组中，即使血压（BP）未降低，这些表达也有所减少，而在BP降低的SHR/high组中，表达受到显著抑制。这些数据表明，SHR-SR中的持续性高血压强烈增强了氧化损伤标志物（AGEs和4-HNE）以及pSyn的异常积累，替米沙坦在不降低和降低BP的情况下均以剂量依赖性方式对其有显著抑制作用。
