Kumar Manish, Bansal Nitin
PhD Research Scholar, IKG Punjab Technical University, Kapurthala, Punjab, 144603, India; Department of Pharmacology, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, 140111, India.
Department of Pharmacology, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, 140111, India.
Behav Brain Res. 2018 Oct 1;351:4-16. doi: 10.1016/j.bbr.2018.05.024. Epub 2018 May 25.
Restoration of PI3-kinase signaling portrays therapeutic potential in Alzheimer's disease (AD). Hyperactive Rho-kinase in AD negatively modulates PI3-kinase pathway, thereby cause cognitive decline. Fasudil is a Rho-kinase inhibitor that has shown therapeutic benefits in brain disorders. The present study is aimed to decipher the role of PI3-kinase pathway in neuroprotective activity of fasudil using STZ-ICV model of AD. MWM and NORT showed that fasudil (300 μg/kg, ICV) averted the STZ-ICV (3 mg/kg) induced memory dysfunctions in rats. Wortmannin (5 μg/rat) or l-NAME (20 mg/kg) attenuated the memory restorative function of fasudil in STZ treated rats. However, l-Arginine (50 mg/kg) group exhibited marked improvement in memory functions. Markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-α, eNOS and NFκB were measured in whole brain of rats. STZ-ICV group exhibited significant elevation in brain oxidative stress, AChE activity, TNF-α, NFκB expression and decrease in eNOS level. These effects of STZ were effectively ameliorated by administration of fasudil for 21 days. Wortmannin (PI3-kinase inhibitor) or l-NAME (NOS blocker) attenuated the antioxidative, anti-inflammatory and cholinergic activities of fasudil. Although brain nitrite content was decreased by l-NAME and wortmannin, the l-NAME group depicted rise in eNOS content (not activity) and NFκB expression, whereas, decrease in same was observed in wortmannin group. l-Arginine lowered the brain oxidative stress, inflammation, AChE activity, eNOS expression (not activity), NFκB levels and elevated nitrite content. In STZ-ICV rat model of AD, fasudil (Rho-kinase inhibitor) ameliorated the AD symptoms by reinstating PI3-kinase mediated upregulation of eNOS and control over brain NFκB activity.
PI3激酶信号通路的恢复在阿尔茨海默病（AD）中显示出治疗潜力。AD中过度活跃的Rho激酶对PI3激酶通路产生负向调节作用，从而导致认知功能下降。法舒地尔是一种Rho激酶抑制剂，已在脑部疾病中显示出治疗益处。本研究旨在利用AD的STZ-ICV模型来阐明PI3激酶通路在法舒地尔神经保护活性中的作用。水迷宫实验和新物体识别实验表明，法舒地尔（300μg/kg，脑室内注射）可避免STZ-ICV（3mg/kg）诱导的大鼠记忆功能障碍。渥曼青霉素（5μg/只大鼠）或L-硝基精氨酸甲酯（20mg/kg）减弱了法舒地尔对STZ处理大鼠的记忆恢复功能。然而，L-精氨酸（50mg/kg）组的记忆功能有显著改善。在大鼠全脑中检测了氧化应激标志物（丙二醛、谷胱甘肽、超氧化物歧化酶、过氧化氢酶）、亚硝酸盐、乙酰胆碱酯酶、肿瘤坏死因子-α、内皮型一氧化氮合酶和核因子κB。STZ-ICV组脑氧化应激、乙酰胆碱酯酶活性、肿瘤坏死因子-α、核因子κB表达显著升高，内皮型一氧化氮合酶水平降低。连续21天给予法舒地尔可有效改善STZ的这些作用。渥曼青霉素（PI3激酶抑制剂）或L-硝基精氨酸甲酯（一氧化氮合酶抑制剂）减弱了法舒地尔的抗氧化、抗炎和胆碱能活性。尽管L-硝基精氨酸甲酯和渥曼青霉素降低了脑内亚硝酸盐含量，但L-硝基精氨酸甲酯组内皮型一氧化氮合酶含量（而非活性）升高且核因子κB表达增加，而渥曼青霉素组则观察到相反情况。L-精氨酸降低了脑氧化应激、炎症、乙酰胆碱酯酶活性、内皮型一氧化氮合酶表达（而非活性）、核因子κB水平，并提高了亚硝酸盐含量。在AD的STZ-ICV大鼠模型中，法舒地尔（Rho激酶抑制剂）通过恢复PI3激酶介导的内皮型一氧化氮合酶上调以及控制脑内核因子κB活性，改善了AD症状。
