Mani Vasudevan, Jaafar Siti Murnirah, Azahan Nur Syamimi Mohd, Ramasamy Kalavathy, Lim Siong Meng, Ming Long Chiau, Majeed Abu Bakar Abdul
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia; Brain Degeneration and Therapeutics Group, Pharmaceutical & Life Sciences CoRe, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia; Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia.
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia.
Life Sci. 2017 Jul 1;180:23-35. doi: 10.1016/j.lfs.2017.05.013. Epub 2017 May 10.
The present study is aimed to investigate the ability of ciproxifan, a histamine H receptor antagonist to inhibit β-amyloid (Aβ)-induced neurotoxicity in SK-N-SH cells and APP transgenic mouse model.
In vitro studies was designed to evaluate the neuroprotective effects of ciproxifan in Aβ - induced SK-N-SH cells. For the in vivo study, ciproxifan (1 and 3mg/kg, i.p.) was administrated to transgenic mice for 15days and behaviour was assessed using the radial arm maze (RAM). Brain tissues were collected to measure Aβ levels (Aβ and Aβ), acetylcholine (ACh), acetylcholinesterase (AChE), nitric oxide (NO), lipid peroxidation (LPO), antioxidant activities, cyclooxygenases (COX) and cytokines (IL-1α, IL-1β and IL-6), while plasma was collected to measure TGF-1β.
The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Aβ-induced SK-N-SH cells. Ciproxifan significantly improved the behavioural parameters in RAM. Ciproxifan however, did not alter the Aβ levels in APP transgenic mice. Ciproxifan increased ACh and showed anti-oxidant properties by reducing NO and LPO levels as well as enhancing antioxidant levels. The neuroinflammatory analysis showed that ciproxifan reduced both COX-1 and COX-2 activities, decreased the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6 and increased the level of anti-inflammatory cytokine TGF-1β.
This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.
本研究旨在探讨组胺H受体拮抗剂西普罗沙芬抑制β-淀粉样蛋白（Aβ）诱导的SK-N-SH细胞神经毒性及在APP转基因小鼠模型中的作用。
体外研究旨在评估西普罗沙芬对Aβ诱导的SK-N-SH细胞的神经保护作用。体内研究中，给转基因小鼠腹腔注射西普罗沙芬（1和3mg/kg），持续15天，并用放射状臂迷宫（RAM）评估行为。收集脑组织测量Aβ水平（Aβ和Aβ）、乙酰胆碱（ACh）、乙酰胆碱酯酶（AChE）、一氧化氮（NO）、脂质过氧化（LPO）、抗氧化活性、环氧化酶（COX）和细胞因子（IL-1α、IL-1β和IL-6），同时收集血浆测量转化生长因子-1β（TGF-1β）。
体外研究表明，西普罗沙芬可提高Aβ诱导的SK-N-SH细胞的活力并抑制活性氧（ROS），具有神经保护作用。西普罗沙芬显著改善了放射状臂迷宫中的行为参数。然而，西普罗沙芬并未改变APP转基因小鼠的Aβ水平。西普罗沙芬增加了ACh水平，并通过降低NO和LPO水平以及提高抗氧化水平表现出抗氧化特性。神经炎症分析表明，西普罗沙芬降低了COX-1和COX-2的活性，降低了促炎细胞因子IL-1α、IL-1β和IL-6的水平，并提高了抗炎细胞因子TGF-1β的水平。
本研究为西普罗沙芬通过抗氧化和胆碱能途径治疗阿尔茨海默病提供了科学依据。
