Riluzole ameliorates learning and memory deficits in Ab25-35- induced rat model of Alzheimer’s disease and is independent of cholinoceptor activation Zahra Mokhtari a , Tourandokht Baluchnejadmojarad a,b, *, Farnaz Nikbakht a , Monireh Mansouri b , Mehrdad Roghani c, ** a Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran b Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran c Neurophysiology Research Center, Shahed University, Tehran, Iran A R T I C L E I N F O Article history: Received 17 August 2016 Received in revised form 5 December 2016 Accepted 16 December 2016 Keywords: Riluzole Alzheimer’s disease Ab 25–35 Learning and memory Oxidative stress Cholinergic receptor Acetylcholinesterase A B S T R A C T Alzheimer’s disease (AD) is a major global public health concern and social care problem that is associated with learning, memory, and cognitive deficits. Riluzole is a glutamate modulator which has shown to improve memory performance in aged rats and may be of benefit in Alzheimer's disease. In the present study, its beneficial effect on attenuation of learning and memory deficits in Ab 25-35 -induced rat model of AD was assessed. Riluzole administration at a dose of 10 mg/kg/day p.o. improved spatial memory in Morris water maze and retention and recall in passive avoidance task and its protective effect was not neutralized following intracerebroventricular microinjection of muscarinic or nicotinic receptor antagonists. Further biochemical analysis showed that riluzole pretreatment of intrahippocampal Ab- microinjected rats is able to attenuate hippocampal AChE activity and lower some oxidative stress markers, i.e. MDA and nitrite, with no significant change of the defensive enzyme catalase. Furthermore, riluzole prevented hippocampal CA1 neuronal loss and reduced 3-nitrotyrosine immunoreactivity. It is concluded that riluzole could exert a protective effect against memory decline induced by intrahippocampal Ab 25-35 through anti-oxidative, anti-cholinesterase, and neuroprotective potential and its beneficial effect is possibly independent of cholinoceptor activation. © 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder and is considered as the most prevalent form of dementia. The World Health Organization (WHO) reports that 47.5 million people were afflicted with dementia in March 2015 and 7.7 million new cases are reported each year due to accelerated population aging and a higher life expectancy [1]. The clinical symptoms of AD comprise a progressive decline in cognitive and behavioral performance, finally leading to memory deterioration, confusion, agitation, and difficulty in performing the daily activities. AD-associated disabili- ty and dependence impose a high social and economic burden on the health systems [2]. There is still no decisive cure for AD and currently used treatments are moderately effective in early stages of its pathologic process [2]. Although main pathologic hallmarks of AD focus on protein accumulation such as amyloid beta (Ab) plaque and neurofibrillary tangles in the affected brain, however, other pathologies including enhanced inflammation and oxidative stress, cholinergic dysfunction, and synaptic atrophy are also observed [3]. A decrease in the number of nicotinic and muscarinic acetylcholine receptors as a result of severe degeneration of cholinergic neurons extending from the basal forebrain to the cortical and hippocampal areas are also acknowledged as one of the prominent features of AD [4,5]. In addition to degradation and dysfunction of cholinergic receptors, an inappropriate change in activity and level of acetylcholinesterase (AChE) is also strongly involved in cognitive deficits associated with AD and for this reason AChE inhibitors may be of benefit for management of mild to moderate AD [6]. Soluble oligomers of Ab in the brain lead to neurodegeneration and impairment of synaptic function through interaction with glutamatergic signaling pathways [7,8]. Gluta- mate is responsible for most of excitatory neurotransmissions in * Corresponding author at: Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. ** Corresponding author. E-mail addresses: tmojarad@yahoo.com (T. Baluchnejadmojarad), mehjour@yahoo.com (M. Roghani). http://dx.doi.org/10.1016/j.biopha.2016.12.067 0753-3322/© 2016 Elsevier Masson SAS. All rights reserved. Biomedicine & Pharmacotherapy 87 (2017) 135–144 Available online at ScienceDirect www.sciencedirect.com