Naringin Abrogates Cisplatin-Induced Cognitive Deficits and Cholinergic Dysfunction Through the Down-Regulation of AChE Expression and iNOS Signaling Pathways in Hippocampus of Aged Rats
Naringin Abrogates Cisplatin-Induced Cognitive Deficits and Cholinergic Dysfunction Through the Down-Regulation of AChE Expression and iNOS Signaling Pathways in Hippocampus of Aged Rats
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DOI：
10.1007/s12031-015-0547-0
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发表时间：
2015-06-01
影响因子：
3.1
通讯作者：
Fetoui, Hamadi
中科院分区：
文献类型：
--
作者：
Chtourou, Yassine;Gargouri, Brahim;Fetoui, Hamadi
化疗相关的认知缺陷是一个主要的神经学问题，但其潜在机制尚不清楚。然而，很少有研究着眼于预防这种由压力引起的缺陷的可能方法。因此，我们研究了顺铂(Cisplatin，Cis)暴露于乙酰胆碱酯酶、ATPase、氧化应激生物标志物与老年大鼠行为能力受损的关系，以及植物来源的黄酮类化合物--柚皮苷(Nar)可能的保护机制。实验程序分为两组实验。实验分为4组：赋形剂组、NAR 25 mg/kg组、NAR 50 mg/kg组、NAR 100 mg/kg组。第2组动物随机分为4组：顺式(5 mg kg-1)周(-1)连续5周，顺式+NAR(25 mg/kg)，顺式+NAR(50 mg/kg)，顺式+NAR(100 mg/kg)。结果表明，顺铂暴露可导致大鼠海马乙酰胆碱酯酶表达增加，同时海马区乙酰胆碱酯酶和诱导型一氧化氮合酶(INOS)的表达水平显著升高。此外，海马膜结合的ATPase酶活性以及酶和非酶类抗氧化活性降低，丙二醛(MDA)、蛋白质羰基(PCO)、亚硝酸盐(NO)和活性氧(ROS)水平升高。此外，顺式反应诱导的神经元改变被行为能力减退所证实。在用顺铂治疗的老年大鼠中，NAR治疗显著地和剂量依赖地阻止了所有的行为、生化和分子改变。因此，本研究的结果表明氧化应激介导的炎症信号可能参与了顺式诱导的认知功能障碍，并提示柚皮苷在预防化疗诱导的周围神经病变中的认知功能障碍方面的有效性。
Chemotherapy-related cognitive deficits are a major neurological problem, but the underlying mechanisms are unclear. However, very few studies have looked at the possible ways of preventing this stress-induced deficit. Thus, we investigated the relationship between cisplatin (Cis) exposure to acetylcholinesterase, ATPase, oxidative stress biomarkers, and impaired behavior performance and the possible protecting mechanism of naringin (Nar), a plant-derived flavonoid, in aged rats. The experimental procedures were divided in two sets of experiments. In the first, the animals were divided into four groups: vehicle, Nar 25 mg/kg, Nar 50 mg/kg, and Nar 100 mg/kg. In the second, the animals were divided into four groups: Cis (5 mg kg(-1) week(-1) for five consecutive weeks), Cis plus Nar (25 mg/kg), Cis plus Nar (50 mg/kg), and Cis plus Nar (100 mg/kg). Results showed that Cis exposure leads to the increase in acetylcholinesterase associated with a significant increase in mRNA levels of acetylcholinesterase and the inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, a decrease in membrane-bound ATPase enzyme activities and enzymatic and nonenzymatic antioxidant activities in the hippocampus and an increase in the levels of malondialdehyde (MDA), protein carbonyls (PCO), nitrite formation (NO), and reactive oxygen species (ROS) levels were found. Further, Cis-induced neuronal alterations were evidenced by impairment behavioral performance. Treatment with Nar significantly and dose-dependently prevented all the behavioral, biochemical, and molecular alterations in aged rats treated with cisplatin. Thus, findings from the current study demonstrate the possible involvement of oxidative-stress-mediated inflammatory signaling in Cis-induced cognitive dysfunction and also suggests the effectiveness of naringin in preventing cognitive deficits in chemotherapy-induced peripheral neuropathy.