Mani_2017_Life.Sci_180_23

AIM: The present study is aimed to investigate the ability of ciproxifan, a histamine H3 receptor antagonist to inhibit beta-amyloid (Abeta)-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 Abeta25-35 - 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 Abeta levels (Abeta1-40 and Abeta1-42), acetylcholine (ACh), acetylcholinesterase (AChE), nitric oxide (NO), lipid peroxidation (LPO), antioxidant activities, cyclooxygenases (COX) and cytokines (IL-1alpha, IL-1beta and IL-6), while plasma was collected to measure TGF-1beta.
RESULTS: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Abeta25-35-induced SK-N-SH cells. Ciproxifan significantly improved the behavioural parameters in RAM. Ciproxifan however, did not alter the Abeta 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-1alpha, IL-1beta and IL-6 and increased the level of anti-inflammatory cytokine TGF-1beta. CONCLUSION: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.