Abstract
Aim: The present study is aimed to investigate the ability of ciproxifan, a histamine H-3 receptor antagonist to inhibit beta-amyloid (A beta)-induced neurotoxicity in SK-N-SH cells and APP transgenic mouse model.
Materials and methods: In vitro studies was designed to evaluate the neuroprotective effects of ciproxifan in A beta(25-35)-induced SK-N-SH cells. For the in vivo study, ciproxifan (1 and 3 mg/kg, i.p.) was administrated to transgenic mice for 15 days and behaviour was assessed using the radial arm maze (RAM). Brain tissues were collected to measure A beta levels (A beta(1-40) and A beta(1-42)), acetylcholine (ACh), acetylcholinesterase (AChE), nitric oxide (NO), lipid peroxidation (LPO), antioxidant activities, cyclooxygenases (COX) and cytokines (IL-1 alpha, IL-1 beta and IL-6), while plasma was collected to measure TGF-1 beta.
Results: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in A beta(25-35)-induced SK-N-SH cells. Ciproxifan significantly improved the behavioural parameters in RAM. Ciproxifan however, did not alter the iv, 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-1 alpha and IL-1 beta and increased the level of antiinflammatory cytokine TGF-1 beta.
Conclusion: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD. (C) 2017 Elsevier Inc. All rights reserved.