Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 5 (2007), No 2, p 57-70




Pharmacological aspects of cognitive impairment: past, present and future of drugs in dementia

Kathleen Isensee, Georg Petroianu, Holger Stark

Address: Georg Petroianu, United Arab Emirates University, Faculty of Medicine and Health Sciences, Department of Pharmacology and Therapeutics, P. O. Box 17666, Al-Ain, United Arab Emirates
h.stark@pharmchem.uni-frankfurt.de

Received 24th April 2007.
Revised 26th April 2007.
Published online 18th May 2007.

Full text article (pdf)
Full text article (html)

SUMMARY
Cognitive impairment is a dramatically increasing problem affecting many individuals as well as the health system. As we have no causal treatment for the loss of memory, symptomatic treatment is needed. Influencing the ACh system is a generally accepted approach, although other therapeutic treatments are in various stages of development. The multiple target drug approach using hybrid compounds may be another optimized move forward for the treatment of cognitive disorders. Since the complex neuronal regulation is slowly being decoded, there is hope that ways will be found to stop neuronal loss and to generate new synapses.

KEY WORDS
cholin esterase inhibitors; NMDA; receptor antagonist; histaminergic neurotransmission; beta-amyloid peptide; tau-protein; therapy; animal models; H3 receptor; histamine H3


REFERENCES
Apelt J, Grassmann S, Ligneau X, Pertz HH, Ganellin CR, Arrang JM, Schwartz JC, Schunack W, Stark H: Search for histamine H3 receptor antagonists with combined inhibitory potency at N-methyltransferase: Ether derivatives. Pharmazie 60:79-106, 2005.

Arrang J, Garbarg M, Lancelot J, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC: Highly potent and selective ligands for histamine H3-receptors. Nature 327:117-123, 1987.

Bacciottini L, Mannaioni PF, Chiappetta M, Giovannini MG, Blandina P: Acetylcholine release from hippocampus of freely moving rats is modulated by thioperamide and cimetidine. Inflamm Res 48:63-64, 1999.

Bacciottini L, Giovannelli L, Passani MB, Schunack W, Mannaioni PF, Blandina P: Endogenous histamine in the medial septumdiagonal band complex increases the release of acetylcholine from the hippocampus: A dualprobe microdialysis study in the freely moving rat. Eur J Neurosci 15:1669-1680, 2002.

Bamford MJ, Dean DK, Sehmi SS, Wilson DM, Witherington J: Benzodiazepine derivatives for the treatment of neurological disorders. WO 2004/056369, 2004.

Barbier AJ, Berridge C, Dugovic C, Laposky AD, Wilson SJ, Boggs J, Aluisio L, Lord B, Mazur C, Pudiak CM, Langlois X, Xiao W: Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br J Pharmacol 143:649-661, 2004.

Bekkers JM: Enhancement by histamine of NMDAmediated synaptic transmission in the hippocampus. Science 261:104-106, 1993.

Blandina P, Giorgetti M, Bartolini L, Cecchi M, Timmerman H, Leurs R, Pepeu G, Giovannini MG: Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol 119:1656-1564, 1996.

Block W: Galantamine: Revives memory and helps fight Alzheimer's. www.galantamine.cc/articles/galantaminearticles- 5.htm (accessed on April 19, 2007).

Bonaventure P, Letavic M, Dugovic C, Wilson S, Aluisio L, Pudiak C, Lord B, Mazur C, Kamme F, Nishino S, Carruthers N, Lovenberg T: Histamine H3 receptor antagonists: From target indentification to drug leads. Biochem Pharmacol 73:1084-1096, 2007.

Brown RE, Stevens DR, Haas HL: The physiology of brain histamine. Prog Neurobiol 63:637-672, 2001.

Bullock R: Future directions in the treatment of Alzheimer's disease. Expert Opin Investig Drugs 13:303-314, 2004.

Burns A, O’Brien J: Clinical practice with antidementia drugs: a consensus statement from British Association for Psychopharmacology. J Psychopharmacol 20:732-755, 2006.

Cecchi M, Giorgetti M, Bacciottini L, Giovannini MG, Blandina P: Increase of acetylcholine release from cortex of freely moving rats by administration of histamine into the nucleus basalis magnocellularis. Inflamm Res 47:32-33, 1998.

Chotard C, Ouimet T, Morisset S, Sahm U, Schwartz JC, Trottier S: Effects of histamine H3 receptor agonist and antagonist on histamine co-transmitter expression in rat brain. J Neural Transm 109:293-306, 2002.

Coge F, Guenin SP, Rique H, Boutin JA, Galizzi JP: Structure and expression of the human histamine H4 receptor gene. Biochem Biophys Res Commun 284:301-309, 2001.

Cowart M, Faghih R, Gfesser G, Curtis M, Pratt JK, Bennani Y, Fox GB, Esbenshade TA, Hancock AA: The medicinal chemistry of novel H3 antagonists. Inflamm Res 53:69-70, 2004a.

Cowart M, Pratt JK, Stewart AO, Bennani YL, Esbenshade TA, Hancock AA: A new class of potent non-imidazole H3 antagonists: 2- aminoethylbenzofurans. Bioorg Med Chem Lett 14:689-693, 2004b.

Cumming P, Vincent SR: Inhibition of histamine- N-methyltransferase (HNMT) by fragments of 9-amino-1,2,3,4-tetrahydroacridine (Tacrine) and by beta-carbolines. Biochem Pharmacol 44:989-992, 1992.

Cummings JL: Cholinesterase inhibitors; a new class of psychotropic compounds. Am J Psychiatry 157:4-15, 2000.

Decker JLM, McGaugh JL: The role of interactions between the cholinergic system and other neuromodulatory systems in learing and memory. Synapse 7:151-168, 1991.

Delagarza VW: Pharmacologic treatment of Alzheimer’s disease: An update. Am Fam Physician 68:1365-1372, 2003.

Esbenshade TA, Krueger KM, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Fox GB, Faghih R, Bennani YL, Williams M, Hancock AA: Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects. J Pharmacol Exp Ther 305:887-896, 2003.

Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan JB, Faghih R, Bennani Y et al.: Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist. Biochem Pharmacol 68:933-945, 2004.

Everitt BJ, Robbins TW: Central cholinergic systems and cognition. Annu Rev Psychol 48:649-684, 1997.

Everitt BJ, Robbins TW, Muir JL: Reversal of visual attentional dysfunction following lesions of the cholinergic basal forebrain by physostigmine and nicotine but not by the 5- HT3 receptor antagonist, ondansetron. Psychopharmacology (Berl.) 118:82-92, 1995.

Fox GB, Pan JB, Esbenshade TA, Bennani YL, Black LA, Faghih R, Hancock AA, Decker MW: Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav Brain Res 131:151-161, 2002.

Fox GB, Pan JB, Radek RJ, Lewis AM, Bitner RS, Esbenshade TA, Faghih R, Bennani YL, Williams M, Yao BB, Decker MW, Hancock AA: Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization. J Pharmacol Exp Ther 305:897-908, 2003.

Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB, Browman KE, Buckley MJ, Ballard ME, Komater VA, Miner H, Zhang M, Faghih R et al.: Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2- methylpyrrolidinyl]ethyl}-benzofuran-5- yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cogntion and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 313:176-190, 2005.

Ganellin CR, Leurquin F, Piripitsi A, Arrang JM, Garbarg M, Ligneau X, Schunack W, Schwartz JC: Synthesis of potent non-imidazole histamine H3-receptor antagonists. Arch Pharm 331:395-404: 1998.

Giorgetti M, Bacciottini L, Bianchi L, Giovannini MG, Cecchi M, Blandina P: GABAergic mechanism in histamine H3 receptor inhibition of K+-evoked release of acetylcholine from rat cortex in vivo. Inflamm Res 46:33-34, 1997.

Giorgetti M, Bacciottini L, Giovannini MG, Colivicchi MA, Goldfarb J, Blandina P.: Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats. Eur J Neurosci 12:1941-1948; 2000.

Giovannini MG, Bartolini L, Bacciottini L, Greco L, Blandina P.: Effects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia. Behav Brain Res 104:147-155, 1999.

Givens B, Sarter M: Modulation of cognitive processes by transsynaptic activation of the basal forebrain. Behav Brain Res 84:1-22, 1997.

Grassmann S, Apelt J, Sippl W, Ligneau X, Pertz HH, Zhao YH, Arrang JM, Ganellin CR, Schwartz JC, Schunack W, Stark H: Imidazole derivates as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities. Bioorg Med Chem 11:2163-2174, 2003.

Green VJ, Pirmohamed M, Kitteringham NR, Knapp MJ, Park BK: Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with Tacrine transaminitis. Br J Clin Pharmacol 39:411-415, 1995.

Hahn B, Shoaib M, Stolerman IP: Nicotine-induced enhancement of attention in the five-choice serial reaction time task: The influence of task demands. Psychopharmacology (Berl.) 162:129-137, 2002.

Hancock AA, Fox GB: Perspectives on cognitive domains, H3 receptor ligands and neurological disease. Expert Opin Investig Drugs 13:1237-1248, 2004.

Hancock AA: The challenge of drug discovery of a GPCR target: Analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists. Biochem Pharmacol 71:1103-1113, 2006.

Holmstedt B: Structure-activity relationship of the organophosphorus anticholinesterase agents. In Koelle GB (ed): Cholinesterases and Anticholinesterase Agents, Berlin, 1963, pp. 429-485.

Hough LB: Genomics meets histamine receptors: New subtypes, new receptors. Mol Pharmacol 59:415-419, 2001.

Ireland-Denny L, Parihar AS, Miller TR, Kang CH, Krueger KM, Esbenshade TA, Hancock AA: Species-related pharmacological heterogeneity of histamine H3 receptors. Eur J Pharmacol 433:141-150, 2001.

Jann MW: Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy 20:1-12, 2000.

Jia JP, Jia JM, Zhou WD, Xu M, Chu CB, Yan X, Sun YX: Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia. Chin Med J 117:1161-1164, 2004.

Julian PL, Pikl J: The complete synthesis of Physostigmine (Eserine). J Am Chem Soc 57:755-757, 1935.

Krall WJ, Sramek JJ, Cutler NR: Cholinesterase inhibitors: A therapeutic strategy for Alzheimer's disease. Ann Pharmacother 33:441-450, 1999.

LaBella FS, Queen G, Glavin G, Durant G, Stein D, Brandes LJ: H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450. Br. J Pharmacol 107:161-164, 1992.

Lane RM, Potkin SG, Enz A: Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol 9:101-124, 2006.

Leurs R, Bakker RA, Timmerman H, de Esch IJ: The histamine H3 receptor: From gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4:107-120, 2005.

Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J: Neurochemical and behavioral effects of Ciproxifan, a potent histamine H3-receptor antagonist. J Pharmacol Exp Ther 287:658-666: 1998.

Ligneau X, Morisset S, Tardivel-Lacombe J, Gbahou F, Ganellin CR, Stark H, Schunack W, Schwartz JC, Arrang JM: Distinct pharmacology of rat and human histamine H3 receptors: Role of two amino acids in the third transmembrane domain. Br J Pharmacol 131:1247-1250, 2000.

Ligneau X, Perrin D, Landais L, Camelin JC, Calmels TP, Berrebi-Bertrand I, Lecomte JM, Parmentier R, Anaclet C, Lin JS, Bertaina- Anglade V, la Rochelle CD: BF2.649 [1-{3-[3- (4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology. J Pharmacol Exp Ther 320:365-375, 2007.

Lipton SA: Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx 1:101-110, 2004.

Liu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, Pyati J, Li X, Chai W, Carruthers N, Lovenberg TW: Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol Pharmacol 59:420-426, 2001.

Lleo A, Greenberg SM, Growdon JH: Current pharmacotherapy for Alzheimer disease. Annu Rev Med 57:513-533, 2006.

Lovenberg TW, Pyati J, Chang H, Wilson SJ, Erlander MG.: Cloning of rat histamine H3 receptor reveals distinct species pharmacological profiles. J Pharmacol Exp Ther 293:771-778, 2000.

Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, Cilia J, Cluderay JE, Crook B, Davis JB, Davis RK, Davis RP et al.: GSK189254 - a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's Disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther 321:1032-1045, 2007.

Meguro KI, Yanai K, Sakai N, Sakurai E, Maeyama K, Sasaki H, Watanabe T: Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescenceaccelerated mice. Pharmacol Biochem Behav 50:321-325, 1995.

Meier G, Apelt J, Reichert U, Grassmann S, Ligneau X, Elz S, Leurquin F, Ganellin CR, Schwartz JC, Schunack W, Stark H: Influence of imidazole replacement in different structural classes of histamine H3-receptor antagonists. Eur J Pharm Sci 13:249-259, 2001.

Melnikova I: Therapies for Alzheimer’s disease. Nat Rev Drug Discov 6:341-342, 2007.

Mochizuki T, Okakura-Mochizuki K, Horii A, Yamamoto Y, Yamatodani A: Histaminergic modulation of hippocampal acetylcholine release in vivo. J Neurochem 62:2275-2282, 1994.

Monti JM: Involvement of histamine in the control of the waking state. Life Sci 53:1331-1338, 1993.

Morisset S, Traiffort E, Schwartz JC: Inhibition of histamine versus acetylcholine metabolism as a mechanism of Tacrine activity. Eur J Pharmacol 315:R1-R2, 1996.

Morphy R, Kay C, Rankovic Z: From magic bullets to designed multiple ligands. Drug Discov Today 9:641-651, 2004.

Muir JL, Everitt BJ, Robbins TW: AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function. J Neurosci 14:2313-2326, 1994.

Munoz-Torrero D, Camps P: Dimeric and hybrid anti-Alzheimer drug candidates: Curr Med Chem 13:399-422, 2006.

Neumann R, Peter HH: Insecticidal organophosphates: Nature made them first. Experientia 43:1235-1237, 1987.

Orr EL, Quay WB: The effects of castration on histamine levels and 24-hour rhythm in the male rat hypothalamus. Endocrinology 96:941-945, 1984.

Ortho-Mcneil neurologics: http://www.rxforsafety.com/news/index.htm (accessed on April 19, 2007).

Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, Relja M: Neuronal histamine deficit in Alzheimer's disease. Neuroscience 82:993-997, 1997.

Passani MB, Blandina P: Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: A parallel story. Methods Find Exp Clin Pharmacol 20:725-733, 1998.

Passani MB, Blandina P: The neuronal histaminergic system in cognition. Curr Med Chem CNS Agents 4:17-26, 2004.

Passani MB, Cangioli I, Baldi , Bucherelli C, Mannaioni PF, Blandina P: Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala. Eur J Neurosci 14:1522-1532, 2001.

Passani MB, Lin JS, Hancock A, Crochet S, Blandina P: The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci 25:618-625, 2004.

Petroianu G, Arafat K, Sasse BC, Stark H: Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Pharmazie 61:179-182, 2005.

Plaitakis A, Duvoisin RC: Homer's moly identified as Galanthus nivalis L.: Physiologic antidote to Stramonium poisoning. Clin Neuropharmacol 6:1-5, 1983.

Prast H, Fischer H, Prast M, Philippu A: In vivo modulation of histamine release by autoreceptors and muscarinic acetylcholine receptors in the rat anterior hypothalamus. Naunyn Schmiedebergs Arch Pharmacol 350:599-604, 1994.

Prast H, Fischer H, Tran MH, Grass K, Lamberti C, Philippu A: Modulation of acetylcholine release in the ventral striatum by histamine receptors. Inflamm Res 46:37-38, 1997.

Proudfoot A: The early toxicology of Physiostigmine: A tale of beans, great men and egos. Toxicol Rev 25:99-138, 2006.

Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev 9:275-308, 2003.

Roth BL, Sheffler DJ, Kroeze WK: Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia. Drug Discov Today 3:353-359, 2004.

Selbach O, Brown RE, Haas HL: Long-term increase of hippocampal excitability by histamine and cyclic AMP. Neuropharmacology 36:1539-1548, 1997.

Schlicker E, Betz R, Gothert M: Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol 337:588-590, 1988.

Schlicker E, Fink K, Detzner M, Gothert M: Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm 93:1-10, 1993.

Schlicker E, Fink K, Hinterhaner M, Gothert M: Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors. Naunyn Schmiedebergs Arch Pharmacol 340:633-638, 1989.

Schlicker E, Werthwein S, Zentner J: Histamine H3 receptor-mediated inhibition of noradrenaline release in the human brain. Fundam Clin Pharmacol 13:120-122, 1999.

Stark H: Recent advances in histamine H3/H4 receptor ligands. Expert Opin Ther Pat 13:851-865, 2004a.

Stark H: Turning from monogamy to strategic promiscuity. Drug Discov Today 9:736-737, 2004b.

Sugimoto H, Ogura H, Arai Y, Iimura Y, Yamanishi: Research and development of Donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol 89:7-20, 2002.

Summers WK: Tacrine, and Alzheimer's treatments. J Alzheimers Dis 9:439-445, 2006.

Tedford CE, Hoffmann M, Seyedi N, Maruyama R, Levi R, Yates SL, Ali SM, Phillips JG: High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models. Eur J Pharmacol 351:307-311, 1998.

Ting P, Aslanian R, Berlin MY, Boyce CW; Cao J; Mangiaracina P; Mc Cormick KD; Mutahi MW; Rosenblum SB; Shih NY; Solomon DM; Tom WC; Zeng Q: 1-(4- Piperidinyl)benzimidazolones as histamine H3 antagonists. WO-03103669, 2003.

Tuomisto L, Tuomisto J: Diurnal variations in brain and pituitary histamine and histamine-Nmethyltransferase in the rat and guinea pig. Med Biol 60:204-209, 1982.

Wada H, Inagaki N, Yamatodani A, Watanabe T: Is the histaminergic neuron system a regulatory center for whole-brain activity? Trends Neurosci 14:415-418, 1991.

Wimo A, Winblad B, Aguero-Torres H, von Strauss E: The magnitude of dementia occurrence in the world. Alzheimer Dis Assoc Disord 17:63-67, 2003.

Yang R, Hey JA, Aslanian R, Rizzo CA: Coordination of histamine H3 receptor antagonists with human adrenal cytochrome P450 enzymes. Pharmacology 66:128-135, 2002.

Yao BB, Hutchins CW, Carr TL, Cassar S, Masters JN, Bennani YL, Esbenshade TA, Hancock AA: Molecular modeling and pharmacological analysis of species-related histamine H3 receptor heterogeneity. Neuropharmacology 44:773-786, 2003.
CITED

Sander K, Kottke T, Stark H: Histamine H-3 Receptor Antagonists Go to Clinics. Biol Pharm Bull 31:2163-2181, 2008.

Isensee K, Amon M, Galaparti A, Ligneau X, Camelin J-C, Capet M, Schwartz J-C, Stark H: Fluorinated non-imidazole histamine H-3 receptor antagonists. Bioorg Med Chem Lett 19:2172-2175, 2009.

Johnson CN, Ahmed M, Miller ND: 5-HT6 receptor antagonists: Prospects for the treatment of cognitive disorders including dementia. Curr Opin Drug Discovery Dev 11:642-654, 2008.


BACK