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 β-amyloid protein (Aβ) 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) [5–7]. 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.
References
[1]
H. Braak and E. Braak, “Neuropathological stageing of Alzheimer-related changes,” Acta Neuropathologica, vol. 82, no. 4, pp. 239–259, 1991.
[2]
D. R. Thal, U. Rüb, M. Orantes, and H. Braak, “Phases of Aβ-deposition in the human brain and its relevance for the development of AD,” Neurology, vol. 58, no. 12, pp. 1791–1800, 2002.
[3]
P. E. Potter, “Investigational medications for treatment of patients with Alzheimer disease,” Journal of the American Osteopathic Association, vol. 110, supplement 8, pp. S27–S36, 2010.
[4]
D. W. Ethell, “An amyloid-notch hypothesis for Alzheimer's disease,” Neuroscientist, vol. 16, no. 6, pp. 614–617, 2010.
[5]
P. Davies and A. J. F. Maloney, “Selective loss of central cholinergic neurons in Alzheimer's disease,” The Lancet, vol. 2, no. 8000, p. 1403, 1976.
[6]
E. J. Mufson, A. D. Kehr, B. H. Wainer, and M. M. Mesulam, “Cortical effects of neurotoxic damage to the nucleus basalis in rats: persistent loss of extrinsic cholinergic input and lack of transsynaptic effect upon the number of somatostatin-containing, cholinesterase-positive, and cholinergic cortical neurons,” Brain Research, vol. 417, no. 2, pp. 385–388, 1987.
[7]
P. J. Whitehouse, D. L. Price, A. W. Clark, J. T. Coyle, and M. R. DeLong, “Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis,” Annals of Neurology, vol. 10, no. 2, pp. 122–126, 1981.
[8]
Y. Q. Liang and X. C. Tang, “Comparative studies of huperzine A, donepezil, and rivastigmine on brain acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats,” Acta Pharmacologica Sinica, vol. 27, no. 9, pp. 1127–1136, 2006.
[9]
H. Sugimoto, H. Ogura, Y. Arai, Y. Iimura, and Y. Yamanishi, “Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor,” Japanese Journal of Pharmacology, vol. 89, no. 1, pp. 7–20, 2002.
[10]
M. Rosini, E. Simoni, M. Bartolini et al., “Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush,” Journal of Medicinal Chemistry, vol. 51, no. 15, pp. 4381–4384, 2008.
[11]
H. Sugimoto, “The new approach in development of anti-Alzheimer's disease drugs via the cholinergic hypothesis,” Chemico-Biological Interactions, vol. 175, no. 1–3, pp. 204–208, 2008.
[12]
D. E. Moss, H. Kobayashi, G. Pacheco, R. Paracios, and R. G. Perez, “Methanesulfonyl fluoride: a CNS selective inhibitor,” in Current Research in Alzheimer Theory: Cholinesterase Inhibitors, E. Giacobini and R. Becher, Eds., pp. 305–314, Taylor and Francis, New York, NY, USA, 1988.
[13]
G. Pacheco, R. Palacios-Esquivel, and D. E. Moss, “Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase,” Journal of Pharmacology and Experimental Therapeutics, vol. 274, no. 2, pp. 767–770, 1995.
[14]
D. E. Moss, P. Berlanga, M. M. Hagan, H. Sandoval, and C. Ishida, “Methanesulfonyl fluoride (MSF): a double-blind, placebo-controlled study of safety and efficacy in the treatment of senile dementia of the Alzheimer type,” Alzheimer Disease and Associated Disorders, vol. 13, no. 1, pp. 20–25, 1999.
[15]
M. M. Hossain, T. Suzuki, I. Sato, T. Takewaki, K. Suzuki, and H. Kobayashi, “The modulatory effect of pyrethroids on acetylcholine release in the hippocampus of freely moving rats,” NeuroToxicology, vol. 25, no. 5, pp. 825–833, 2004.
[16]
G. L. Ellman, K. D. Courtney, V. Andres, and R. M. Featherstone, “A new and rapid colorimetric determination of acetylcholinesterase activity,” Biochemical Pharmacology, vol. 7, no. 2, pp. 88–95, 1961.
[17]
H. Kobayashi, T. Nakano, D. E. Moss, and T. Suzuki, “Effects of a central anticholinesterase, methanesulfonyl fluoride on the cerebral cholinergic system and behavior in mice: comparison with an organophosphate DDVP,” Journal of Health Science, vol. 45, no. 4, pp. 191–202, 1999.
[18]
K. Isomae, M. Ishikawa, M. Ohta et al., “Effects of T-82, a new quinoline derivative, on cholinesterase activity and extracellular acetylcholine concentration in rat brain,” Japanese Journal of Pharmacology, vol. 88, no. 2, pp. 206–212, 2002.
[19]
T. Kosasa, Y. Kuriya, and Y. Yamanishi, “Effect of donepezil hydrochloride (E2020) on extracellular acetylcholine concentration in the cerebral cortex of rats,” Japanese Journal of Pharmacology, vol. 81, no. 2, pp. 216–222, 1999.
[20]
E. Shearman, S. Rossi, B. Szasz et al., “Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study,” Brain Research Bulletin, vol. 69, no. 2, pp. 204–213, 2006.
[21]
K. Takashina, T. Bessho, R. Mori, J. Eguchi, and K. I. Saito, “MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats,” Journal of Neural Transmission, vol. 115, no. 7, pp. 1027–1035, 2008.
[22]
K. Yano, K. Koda, Y. Ago et al., “Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice,” British Journal of Pharmacology, vol. 156, no. 1, pp. 173–180, 2009.
[23]
M. ？ivin and P. Pregelj, “Prolonged treatment with donepezil increases acetylcholinesterase expression in the central nervous system,” Psychiatria Danubina, vol. 20, no. 2, pp. 168–173, 2008.
