%0 Journal Article
%T Effect of a CNS-Sensitive Anticholinesterase Methane Sulfonyl Fluoride on Hippocampal Acetylcholine Release in Freely Moving Rats
%A Tamotsu Imanishi
%A Muhammad Mubarak Hossain
%A Tadahiko Suzuki
%A Ping Xu
%A Itaru Sato
%A Haruo Kobayashi
%J Advances in Pharmacological Sciences
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/708178
%X Anticholinesterases (antiChEs) are used to treat Alzheimer¡¯s disease. The comparative effects of two antiChEs, methanesulfonyl fluoride (MSF) and donepezil, on the extracellular levels of ACh in the hippocampus were investigated by in vivo microdialysis in freely moving rats. MSF at 1 and 2£¿mg/kg produced a dose-dependent increase in ACh efflux from 10£¿min to at least 3£¿hrs after injection. At 2£¿mg/kg, the increase was still present at 24£¿hr. Donepezil at 1£¿mg/kg showed a similar but smaller effect, and, paradoxically, 2£¿mg/kg showed no consistent effect. MSF at 1 and 2£¿mg/kg decreased acetylcholinesterase activity in the hippocampus to 54.8 and 20.1% of control, respectively. These results suggest that MSF is a suitable candidate for the treatment of Alzheimer¡¯s disease. 1. Introduction Alzheimer¡¯s disease (AD) is a slowly progressive neurodegenerative illness characterized by the presence of senile plaques containing ¦Â-amyloid protein (A¦Â) in brain tissue, tau-neurofibrillary tangles in neurons and, the loss of different transmitter-containing axons, especially cholinergic nerves [1, 2]. Unfortunately, therapeutic strategies targeting amyloid plaques with plaque-removing vaccines or gamma-secretase modulators have been disappointing [3, 4]. It is generally accepted that progressive neurodegeneration of the cholinergic system underlies, at least in part, the cognitive deterioration of Alzheimer¡¯s disease (AD) [5¨C7]. This hypothesis is supported by findings of encouraging symptomatic improvements in clinical trials by the use of AChE inhibitors [8, 9], theoretically by enhancing central cholinergic function by permitting acetylcholine (ACh) to remain in the synaptic cleft longer. Interestingly, some AChE inhibitors have also been reported to be effective also in diminishing amyloid plaques [10, 11]. Methanesulfonyl fluoride (MSF), a long-acting and highly specific inhibitor of brain AChE [12, 13], has been proposed as a safe and effective palliative treatment for senile dementia of the Alzheimer type [14] as well as a method to attenuate stroke-induced deficits in a simple learning and memory task [13]. Therefore, the main aim of this study was to compare MSF-induced increases in extracellular ACh in the hippocampus, one of the target regions for the treatment of AD, with the effects of donepezil, a reference drug widely used for symptomatic treatment of AD. For this purpose, the present study was carried out by measuring extracellular ACh in the hippocampus by in vivo microdialysis in freely moving rats following administration of MSF and donepezil. 2.
%U http://www.hindawi.com/journals/aps/2012/708178/