PhD Research Scholar, IKG Punjab Technical University, Kapurthala, Punjab, 144603, India; Department of Pharmacology, ASBASJSM College of Pharmacy, Bela, Ropar, 140111, India.
Department of Pharmacology, ASBASJSM College of Pharmacy, Bela, Ropar, 140111, India.
Biomed Pharmacother. 2018 May;101:162-173. doi: 10.1016/j.biopha.2018.02.089. Epub 2018 Feb 24.
The present study was undertaken to elucidate the role of PI3-kinase signaling in memory enhancing potential of caffeic acid phenethyl ester (CAPE) against cognitive defects in rats after centrally administered streptozotocin as a model of Alzheimer's disease. The Morris water maze and elevated plus maze paradigms showed profound loss of memory in adult Wistar rats (180-200 g) injected with streptozotocin (3 mg/kg) bilaterally (STZ-ICV) on day 1 and 3. Intraperitoneal administration of CAPE (6 mg/kg, i.p., 28 days) attenuated STZ-ICV triggered memory loss in rats. Treatment with PI3-kinase inhibitor (wortmannin, 5 μg/rat, ICV) or NOS blocker (L-NAME, 20 mg/kg, i.p., 28 days) interfered with memory restorative function of CAPE in STZ treated rats. In biochemical analysis markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-α, eNOS and NFκB were measured in brain of rats on day 28. Interestingly, L-Arginine (100 mg/kg, i.p., 28 days) group exhibited moderate (p > 0.05) decline in memory functions. The brain oxidative stress, TNF-α, AChE activity and NFκB levels were elevated, and eNOS level was lowered by STZ-ICV treatment. Administration of CAPE lowered oxidative stress, AChE, nitrite and TNF-α levels in brain of rats. The eNOS level was enhanced and NFκB level was decreased by CAPE in STZ treated rats. Wortmannin injection elevated the brain oxidative stress, AChE activity and TNF-α levels, and decreased the nitrite, eNOS and NFκB level. Rise of brain oxidative stress parameters, AChE activity, TNF-α, eNOS and NFκB levels, and decline in brain nitrite content was observed in L-NAME treated group. L-Arginine administration showed modest effects (p > 0.05) on oxidative stress parameters. Brain nitrite content was enhanced although eNOS, NFκB levels, and AChE activity was decimated by L-Arginine treatment. It can be concluded that PI3-kinase mediated nitric oxide facilitation is an essential feature of CAPE action in STZ-ICV treated rats.
本研究旨在阐明 PI3-激酶信号通路在咖啡酸苯乙酯（CAPE）增强认知中的作用，咖啡酸苯乙酯可预防链脲佐菌素（STZ）脑室内注射所致大鼠认知缺陷，该模型可模拟阿尔茨海默病。水迷宫和高架十字迷宫实验表明，成年 Wistar 大鼠（180-200g）双侧脑室注射 STZ（3mg/kg）（STZ-ICV）后，记忆明显丧失。腹腔注射 CAPE（6mg/kg，腹腔注射，28 天）可减轻 STZ-ICV 引起的大鼠记忆丧失。PI3-激酶抑制剂（wortmannin，5μg/大鼠，脑室注射）或一氧化氮合酶抑制剂（L-NAME，20mg/kg，腹腔注射，28 天）处理可干扰 CAPE 对 STZ 处理大鼠的记忆修复功能。在第 28 天，测量大鼠脑中氧化应激标志物（TBARS、GSH、SOD、CAT）、亚硝酸盐、乙酰胆碱酯酶、TNF-α、eNOS 和 NFκB 的含量。有趣的是，L-精氨酸（100mg/kg，腹腔注射，28 天）组记忆功能仅出现中度（p>0.05）下降。STZ-ICV 处理后，大脑氧化应激、TNF-α、乙酰胆碱酯酶活性和 NFκB 水平升高，eNOS 水平降低。CAPE 降低了大鼠大脑中的氧化应激、乙酰胆碱酯酶、亚硝酸盐和 TNF-α水平。CAPE 处理可增强 STZ 大鼠的 eNOS 水平并降低 NFκB 水平。wortmannin 注射可升高大脑氧化应激、乙酰胆碱酯酶活性和 TNF-α水平，并降低大脑中亚硝酸盐、eNOS 和 NFκB 水平。L-NAME 处理组观察到大脑氧化应激参数、乙酰胆碱酯酶活性、TNF-α、eNOS 和 NFκB 水平升高，大脑中亚硝酸盐含量降低。L-精氨酸处理组对氧化应激参数有适度影响（p>0.05）。虽然 L-精氨酸处理降低了 eNOS、NFκB 水平和乙酰胆碱酯酶活性，但大脑中亚硝酸盐含量增加。可以得出结论，PI3-激酶介导的一氧化氮促进作用是 CAPE 在 STZ-ICV 处理大鼠中作用的重要特征。
