Protective Effect of Telmisartan Against Progressive Oxidative Brain Damage and Synuclein Phosphorylation in Stroke-resistant Spontaneously Hypertensive Rats

• Published in: Journal of stroke and cerebrovascular diseases Vol. 23; no. 6; pp. 1545 - 1553
• Main Authors: Fukui, Yusuke, BS, Yamashita, Toru, MD, PhD, Kurata, Tomoko, MD, Sato, Kota, MD, Lukic, Violeta, MD, Hishikawa, Nozomi, MD, Deguchi, Kentaro, MD, Abe, Koji, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2014
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Benzoates - pharmacology; Benzoates - therapeutic use; Blood Pressure - drug effects; Brain - drug effects; Brain - metabolism; Cardiovascular; Hypertension - metabolism; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; oxidative stress; Oxidative Stress - drug effects; peroxisome proliferator–activated receptor gamma; phosphorylated α-synuclein; Phosphorylation - drug effects; Rats; Rats, Inbred SHR; Rats, Wistar; Reactive Oxygen Species - metabolism; Stroke-resistant spontaneously hypertensive rat; Synucleins - metabolism; telmisartan; telmisartan; phosphorylated α-synuclein; oxidative stress; peroxisome proliferator–activated receptor gamma; Stroke-resistant spontaneously hypertensive rat
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2013.12.052

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.