PDF(Pubmed)
Abstract：
Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced \"decision making\" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β1-42 (Aβ1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.
摘要：
众所周知，高血压和衰老都会增加大脑对神经血管损伤的脆弱性，导致认知障碍。本研究调查了抗高血压药物氯沙坦对自发性高血压大鼠（SHR）的年龄和高血压相关认知功能下降的疗效及其作用的可能机制。服用氯沙坦（10mg/kg，i.p.19天）至3个月和14个月大的SHRs。年龄匹配的Wistar大鼠用作对照。工作记忆,短期物体识别，使用Y迷宫评估空间记忆，目标识别测试（ORT）和径向臂迷宫（RAM）测试。与衰老相关的标志物的表达，氧化应激，在额叶皮质(FC)和海马中评估记忆相关信号。在24小时内测量的运动活动在组间没有差异。在第一次Y迷宫测试中，经过媒介处理的中年SHR在自发交替行为（SAB）和活动方面的表现比年轻的SHR差。这表明与年龄相关的减少了在新环境中的“决策”和反应性。氯沙坦改善了ORT和第二次Y迷宫测试中测量的年龄和高血压引起的短期识别和空间记忆的下降，特别是在中年老鼠身上，但对年轻的成年大鼠无效。在海马中观察到记忆和与年龄相关的标志物的变化，例如cAMP反应元件结合蛋白（CREB）和淀粉样蛋白-β1-42（Aβ1-42）以及氧化应激的增加，但在年轻成年人和中年人之间的FC中未观察到。与媒介物处理的SHR相比，氯沙坦在中年SHR中增加CREB表达，同时降低Aβ1-42水平和伴随的氧化应激。总之,我们的研究强调了高血压之间复杂的相互作用，老化，和认知障碍。这表明使用血管紧张素II1型受体阻滞剂进行治疗干预的关键时间窗。
