A New Way of Data Interpretation for Cognition Tests in Rats Used to Characterise Six Choline Esterase Inhibitors with Heterocyclic Nitrogen Bridgehead Structure

Abstract

Six new tri- and tetracyclic nitrogen bridgehead compounds known to be moderate to potent inhibitors of acetylcholinesterase (AChE) and butyrylcholin-esterase (BChE) in vitro were tested in vivo as experimental therapeutics for treatment of Alzheimer’s disease. Cognitive impairment in rats was reversibly induced by scopolamine (CAS 51-34-3). The effect of the new substances was evaluated in an eight-arm radial maze and run times (1), errors (2), correct choices (3), correct choices per second (4), speed (5), and running distance (6) were recorded. For optimisation of data analysis a new strategy was used: A score was created on the basis of the 6 parameters described with score 1 for controls and score 4 for scopolamine rats. Scores above 4 indicate an impairment of cognition function compared to scopolamine. After equimo-lar dosage compared to the reference drug rivastigmine (CAS 123441-03-2), two of the new substances slightly improved cognition in rats, but only to a significantly lower degree compared to the irreversible inhibitor rivastigmine. Surprisingly, the other four compounds did not improve or even worsened the scopolamine effect on working memory.

Key words

Acetylcholine - Acetylcholinesterase - Butyrylcholinesterase - Choline esterase inhibitors, data analysis, effect on memory - heterocyclic nitrogen bridgehead structure, radial maze, rat - Cognitive impairment, rat, scopolamine induced

• References

• 1 Ni JW, Matsumoto K, Li HB, Murakami Y, Watanabe H. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res. 1995; 673: 290-296
• 2 Francis PT, Palmer AM, Snape A, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999; 66: 137-147
• 3 Giacobini E. Drugs that target cholinesterases. In Buccafusco JJ. ed Cognitive Enhancing Drugs. Basle-Boston-Berlin: Birkhäuser; 2004. p 11-36
• 4 Holzgrabe U, Kapkova P, Alptuezuen V, Scheiber J, Kugelmann E. Targeting acetylcholinesterase to treat neu-rodegeneration. Expert Opin Therap Targets. 2007; 11: 161-179
• 5 Nordberg A. Mechanisms behind the neuroprotective actions of Cholinesterase inhibitors in Alzheimer’s disease. Alzheimer Dis Assoc Disorders. 2006; 20: S12-S18
• 6 Messer Jr JS. Drugs that target muscarinic cholinergic receptors. In: Buccafusco JJ. ed Cognitive Enhancing Drugs. Basle-Boston-Berlin: Birkhäuser; 2004. p 37-49
• 7 Ellis JM. Cholinesterase inhibitors in the treatment of dementia. JAOA. 2005; 105: 145-158
• 8 Johnson G, Moore SW. The peripheral anionic site of acetylcholinesterase: Structure, functions and potential role in rational drug design. Curr Pharmaceut Design. 2006; 12: 217-225
• 9 Park CH, Lee Y-J, Lee SH, Choi SH, Kim H-S, Jeong S-J et al. Dehydroevodiamine HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance. J Neurochem. 2000; 74: 244-253
• 10 Tulyaganov N, Sadritdinov FS, Suleimanova GA. The pharmacological characteristics of desoxypeganine hydrochloride. Farmakol Toksikol. 1986; 49: 37-40
• 11 Decker M. Novel inhibitors of acetyl- and butyrylcholinest-erase derived from the alkaloids dehydroevodiamine and rutaecarpine. Eur J Med Chem. 2005; 40: 305-313
• 12 Decker M, Krauth F, Lehmann I. Novel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as Cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorg Med Chem. 2006; 14: 1966-1977
• 13 Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinestrase in dementia. Int J Neuropharmacol. 2006; 9: 101-124
• 14 Decker M. Homobivalent quinazolinimines as novel nano-molar inhibitors of cholinesterases with dirigible selectivity toward butyrylcholinesterase. J Med Chem. 2006; 49: 5411-5413
• 15 Fisher A, Hanin I. Potential animal models for senile dementia of Alzheimer’s type, with emphasis on AF64A-induced cholinotoxicity. Ann Rev Pharmacol Toxicol. 1986; 26: 161-181
• 16 Wirsching BA, Beninger RJ, Jhamandas K, Boegman RJ, El Defrawy S R. Differential effects of scopolamine on working and reference memory of rats in the radial maze. Pharmacol Biochem Behav. 1984; 20: 659-662
• 17 Appenroth D, Decker M, Lehmann J, Fleck C. In vivo investigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: Scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage. Pflügers Arch Eur J Physiol. 2008; 455: 895-901
• 18 Rawlins JNP, Deacon RMJ. Further developments of maze procedures. In Sahgal A. ed Behavioural Neuroscience. Vol. I Oxford: IRL Press; 1993. p 95-122
• 19 Eckerman DA, Gordon WA, Edwards JD, McPhail R, Gage MI. Effects of scopolamine, pentobarbital, and amphetamine on radial arm maze performance in the rat. Pharmacol Biochem Behav. 1980; 12: 595-602
• 20 Rush DK. Scopolamine amnesia of passive avoidance: a deficit of information acquisition. Behav Neural Biol. 1988; 50: 255-274
• 21 Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP et al. Neurochemical correlates of dementia severity in Alzheimer’s disease: relative importance of the cholinergic deficits. J Neurochem. 1995; 64: 749-760
• 22 Wang T, Tang XC. Reversal of scopolamine-induced deficits in radial-arm maze performance by (-)huperizine A: comparison with E2020 and tacrine. Eur J Pharmacol. 1998; 349: 137-142
• 23 Bassant MH, Jazat-Poindessous F, Lamour Y. Effects of metrifonate, a cholinesterase inhibitor, on local cerebral glucose utilization in young and aged rats. J Cereb Blood Flow Metab. 1996; 16: 1014-1025
• 24 Ni JW, Ohta H, Matsumoto K, Watanabe H. Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats. Brain Res. 1994; 653: 231-236
• 25 Tanaka K, Mizukawa K, Ogawa N, Mori A. Post-ischemic administration of the acetylcholinesterase inhibitor ENA-713 prevents delayed neuronal death in the gerbil hippocampus. Neurochem Res. 1995; 20: 663-667
• 26 Fisher A, Bar-Ner RHN, Kligal-Spatz M, Naton N, Sonego H, Marcovitch I et al. AF150(S) and AF267B: Ml muscarinic agonists as innovative therapies for Alzheimer’s disease. J Mol Neurosci. 2002; 19: 145-153
• 27 Terry AV jr, Buccafusco JJ, Borsini F, Leusch A. Memory-related task performance by aged rhesus monkeys administered the muscarinic M₁-preferring agonist, talsaclidine. Psychopharmacol. 2002; 162: 292-300
• 28 Wanibuchi F, Nishida T, Yamashita H, Hidaka K, Koshiya K, Tsukamoto S et al. Characterization of a novel muscarinic receptor agonist, YM796; comparison with Cholinesterase inhibitors in in vivo pharmacological studies. Eur J Pharmacol. 1994; 265: 151-158
• 29 Kords H, Lüllmann H, Ohnesorge FK, Wassermann O. Reduction in the toxicity of diisopropylfluorophosphate (DFP) by atropine and derivatives of hexane-bis-ammonium. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1968; 260: 157-158