Vasudevan Mani1, Siti Murnirah Jaafar2, Nur Syamimi Mohd Azahan2, Kalavathy Ramasamy3, Siong Meng Lim3, Long Chiau Ming4, Abu Bakar Abdul Majeed5. 1. 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. Electronic address: V.SAMY@qu.edu.sa. 2. Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia. 3. Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia; Collaborative Drug Discovery Research (CDDR) Group, Pharmaceutical & Life Sciences CoRe, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia. 4. 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; Unit for Medication Outcomes Research and Education (UMORE), Pharmacy, School of Medicine, University of Tasmania, Hobart, Australia. 5. 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.
Abstract
AIM: The present study is aimed to investigate the ability of ciproxifan, a histamine H3 receptor antagonist to inhibit β-amyloid (Aβ)-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 Aβ25-35 - 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 Aβ levels (Aβ1-40 and Aβ1-42), 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. RESULTS: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Aβ25-35-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. CONCLUSION: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.
AIM: The present study is aimed to investigate the ability of ciproxifan, a histamine H3 receptor antagonist to inhibit β-amyloid (Aβ)-induced neurotoxicity in SK-N-SH cells and APP transgenicmouse model. MATERIALS AND METHODS: In vitro studies was designed to evaluate the neuroprotective effects of ciproxifan in Aβ25-35 - 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 Aβ levels (Aβ1-40 and Aβ1-42), 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. RESULTS: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Aβ25-35-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. CONCLUSION: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.
Authors: Victoria O Polyakova; Igor M Kvetnoy; George Anderson; Jessica Rosati; Gianluigi Mazzoccoli; Natalya S Linkova Journal: Front Physiol Date: 2018-03-12 Impact factor: 4.566