Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University, Chandigarh-160014, India.
Eur J Pharmacol. 2011 Jun 1;659(2-3):177-86. doi: 10.1016/j.ejphar.2011.03.026. Epub 2011 Apr 2.
Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus. Increasing evidence indicates that factors such as oxidative-nitrergic stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer's disease pathogenesis. Intracerebroventricular (i.c.v.) streptozotocin induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer's disease. In the present study, i.c.v. streptozotocin produced significant cognitive deficits as measured in Morris water maze and elevated plus maze task coupled with increased serum TNF-α levels and marked rise in brain acetylcholinesterase and oxidative-nitrergic stress in female Wistar rats. Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol), a potent anti-oxidant and anti-inflammatory molecule markedly improved cognitive impairment, reduced acetylcholinesterase activity, TNF-α levels and attenuated oxidative-nitrergic stress in brain of i.c.v.-streptozotocin treated rats. Administration of L-arginine (125 mg/kg i.p), a nitric oxide donor, alone to i.c.v.-streptozotocin treated rats accentuated behavioral and biochemical deficits and also abolished the protective effect of sesamol (8 mg/kg). L-NAME (10 mg/kgi.p.), a non-specific NOS inhibitor significantly restored all the behavioral and biochemical indices in i.c.v.-streptozotocin rats. Moreover, combination of L-NAME with sub-effective dose of sesamol (4 mg/kg) potentiated its protective effect. Our findings demonstrate the effectiveness of sesamol in preventing intracerebroventricular streptozotocin-induced cognitive deficits by modulating nitrergic signaling and oxido-inflammatory cascade.
阿尔茨海默病是一种神经退行性疾病，其特征是认知能力逐渐下降，大脑皮层和海马区的神经元及其突触广泛丧失。越来越多的证据表明，氧化氮应激、谷胱甘肽耗竭、蛋白质代谢受损和胆碱能不足等因素可以相互作用形成恶性循环，这是阿尔茨海默病发病机制的核心。侧脑室（i.c.v.）链脲佐菌素诱导的认知障碍已广泛用于研究阿尔茨海默病的实验模型。在本研究中，侧脑室注射链脲佐菌素可导致雌性 Wistar 大鼠在 Morris 水迷宫和高架十字迷宫任务中出现明显的认知缺陷，同时血清 TNF-α 水平升高，大脑乙酰胆碱酯酶和氧化氮应激明显升高。Sesamol（5-羟基-1,3-苯并二恶唑或 3,4-亚甲基二氧基苯酚）是一种有效的抗氧化剂和抗炎分子，可显著改善认知障碍，降低乙酰胆碱酯酶活性、TNF-α 水平，并减轻 i.c.v.-链脲佐菌素治疗大鼠的氧化氮应激。单独给予 i.c.v.-链脲佐菌素治疗大鼠 L-精氨酸（125mg/kg，腹腔注射），一种一氧化氮供体，可加重行为和生化缺陷，并消除 Sesamol（8mg/kg）的保护作用。非特异性 NOS 抑制剂 L-NAME（10mg/kg，腹腔注射）可显著恢复 i.c.v.-链脲佐菌素大鼠的所有行为和生化指标。此外，L-NAME 与 Sesamol（4mg/kg）的亚有效剂量联合使用可增强其保护作用。我们的研究结果表明，Sesamol 通过调节氮能信号和氧化炎症级联反应，可有效预防侧脑室链脲佐菌素诱导的认知障碍。
