504
Views
22
CrossRef citations to date
0
Altmetric
SPECIAL FOCUS: Alzheimer's Disease Therapy - Review

Pharmacological approaches for Alzheimer’s disease: neurotransmitter as drug targets

, , , &

References

  • Vassallo N, Scerri C. Mediterranean diet and dementia of the Alzheimer type. Curr Aging Sci 2013;6:150-62
  • Reed TT, Pierce WM, Maresbery WR, Butterfield DA. Proteomic Identification of HNE bound proteins in early Alzheimer’s disease: insight into the role of lipid peroxidationin the progression of AD. Brain Res 2009;1274:66-76
  • Vellas B, Andrieu S, Sampaio C, Wilcock G. Disease-modifying trials in Alzheimer’s disease: a European task force consensus. Lancet Neurol 2007;6:56-62
  • WHO. Dementia: A Public Health Priority. WHO; Geneva: 2012. 112
  • Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement 2012;8:131-68
  • Barnes DE, Yaffe K. The Projected Impact of Risk Factor Reduction on Alzheimer’s Disease Prevalence. Lancet Neurol 2011;10:819-28
  • Practico D. Evidence of oxidative stress in Alzheimer’s disease brain and antioxidant therapy: lights and shadows. Ann N Y AcadSci 2008;1147:70-8
  • Michon A. The concept of mild cognitive impairment: relevance and limits in Clinical practice. Front Neurol Neurosci 2009;24:12-29
  • Bernardi DA, De Jager PL, Leurgans SE, et al. Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles. Neurology 2009;72:1495-503
  • Placanica L, Zhu L, Li YM. Gender- and age-dependent γ-secretase activity in mouse brain and its implication in sporadic Alzheimer disease. PLoS One 2009;4:e5088
  • Thal DR, von Arnim C, Griffin WS, et al. Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 2013;263(Suppl 2):S137-45
  • Ramirez-Bermudez J. Alzheimer’s disease: critical notes on the history of a medical concept. Arch Med Res 2012;43:595-9
  • Levenga J, Krishnamurthy P, Rajamohamedsait H, et al. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. Acta Neuropathol Commun 2013;1:34
  • Reinikainen KJ, Soininen H, Riekkinen PJ. Neurotransmitter changes in Alzheimer’s disease: implications to diagnostics and therapy. J Neurosci Res 1990;27:576-86
  • Drachman DA, Leavitt J. Human memory and the cholinergic system. Arch Neurol 1974;30:113-21
  • Rissman RA, Bennett DA, Armstrong DM. Subregional analysis of GABA(A) receptor subunit mRNAs in the hippocampus of older persons with and without cognitive impairment. J Chem Neuroanat 2004;28:17-25
  • Francis PT. Lifting the lid: post-mortem brain analysis and Alzheimer’s disease. The Journal of Quality Research in Dementia 2014;4
  • Martorana A, Mori F, Esposito Z, et al. Dopamine Modulates Cholinergic Cortical Excitability in Alzheimer’s Disease Patients. Neuropsychopharmacology 2009;34:2323-8
  • Limon A, Reyes-Ruiz JM, Miledi R. Loss of functional GABA(A) receptors in the Alzheimer diseased brain. Proc Natl Acad Sci U S A 2012;109:10071-6
  • Borbély E, Scheich B, Helyes Z. Neuropeptides in learning and memory. Neuropeptides 2013;6:439-50
  • Paris JJ, Eans SO, Mizrachi E, et al. Central administration of angiotensin IV rapidly enhances novel object recognition among mice. Neuropharmacol 2013;70:247-53
  • Motawaj M, Burban A, Davenas E, et al. Activation of brain histaminergic neurotransmission: a mechanism for cognitive effects of memantine in Alzheimer’s disease. J Pharmacol Exp Ther 2011;336:479-87
  • Chen C, Magee JC, Marcheselli V, et al. Attenuated LTP in hippocampal dentate gyrus neurons of mice deficient in the PAF receptor. J Neurophysiol 2001;85:384-90
  • Diógenes MJ, Costenla AR, Lopes LV, et al. Enhancement of LTP in Aged Rats is Dependent on Endogenous BDNF. Neuropsychopharmacology 2011;36:1823-36
  • Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacol 2014;76(Pt A):27-50
  • Norimoto H, Mizunuma M, Ishikawa D, et al. Muscarinic receptor activation disrupts hippocampal sharp wave-ripples. Brain Res 2012;1461:1-9
  • Parsons CG, Danysz W, Dekundy A, et al. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer’s disease. Neurotox Res 2013;3:358-69
  • Kato G, Agid Y. Acetylcholine receptors (author’s transl.). Nouv Presse Med 1979;8:2407-11
  • Paterson D, Nordberg A. Neuronal nicotinic receptors in the human brain. Prog Neurobiol 2000;61:75-111
  • Garduno J, Charles LG, Rodríguez JJ, et al. Presynaptic42 Nicotinic Acetylcholine Receptors Increase Glutamate Release and Serotonin Neuron Excitability in the Dorsal Raphe Nucleus. J Neurosci 2012;32:15148-57
  • Buckingham SD, Jones AK, Brown LA, et al. Nicotinic Acetylcholine Receptor Signalling: roles in Alzheimer’s Disease and Amyloid Neuroprotection. Pharmacol Rev 2009;61:39-61
  • Schröder H, Giacobini E, Struble RG, et al. Nicotinic cholinoceptive neurons of the frontal cortex are reduced in Alzheimer’s Disease. Neurobiol Aging 1991;12:259-62
  • Levin ED, Perkins A, Brotherton T, et al. Chronic underactivity of medial frontal cortical β2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:296-302
  • Tsang SW, Lai MK, Kirvell S, et al. Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer’s disease. Neurobiol Aging 2006;27:1216-23
  • Heo YM, Shin MS, Lee JM, et al. Treadmill exercise ameliorates short-term memory disturbance in scopolamine-induced amnesia rats. Int Neurol J 2014;18:16-22
  • Higgins JP, Flicker L. Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev 2003;CD001015
  • Penry JT, Manore M. Choline: an important micronutrient for maximal endurance-exercise performance? Int J Sport Nutr Exerc Metab 2008;18:191-203
  • Wurtman RJ, Cansev M, Ulus IH. Choline and Its Products Acetylcholine and Phosphatidylcholine. Handbook of Neurochemistry and Molecular Neurobiology. Springer; US: 2010. pp 443-501
  • Cohen EL, Wurtman RJ. Brain acetylcholine: increase after systemic choline administration. Life Sci 1975;16:1095-102
  • Cohen EL, Wurtman RJ. Brain acetylcholine: control by dietary choline. Science 1976;191:561-2
  • Amenta F, Tayebati SK. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr Med Chem 2008;15:488-98
  • Lanctôt KL, Rajaram RD, Herrmann N. Therapy for Alzheimer’s disease: how effective are current treatments? Ther Adv Neurol Disord 2009;2:163-80
  • Barar FSK. Essentials of Pharmacotherapeutics, Antiparkinsonian drugs. 4th Edition. S. Chand and Company Ltd; New Delhi: 2007. 169
  • Farlow M, Veloso F, Moline M, et al. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer’s disease. BMC Neurol 2011;11:57
  • Akasofu S, Kimura M, Kosasa T, et al. Study of neuroprotection of donepezil, a therapy for Alzheimer’s disease. Chem Biol Interact 2008;175:222-6
  • Takada Y, Yonezawa A, Kume T, et al. Nicotinic acetycholine receptor mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther 2003;306:772-7
  • Fisher A. Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease. Neurotherapeutics 2008;5:433-42
  • Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 2006;49:671-82
  • Hock C, Maddalena A, Raschig A, et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer’s disease. Amyloid 2003;10:1-6
  • Heinrich JN, Butera JA, Carrick T, et al. Pharmacological comparisons of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol 2009;605:53-6
  • Sadashiva CT, Chandra JN, Kavitha CV, et al. Synthesis and pharmacological evaluation of novel N-alkyl/aryl substituted thiazolidinone arecoline analogues as muscarinic receptor 1 agonist in Alzheimer’s dementia models. Eur J Med Chem 2009;44:4848-54
  • Malviya M, Kumar YC, Mythri RB, et al. Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models. Bioorg Med Chem 2009;17:5526-34
  • Malviya M, Kumar YC, Asha D, et al. Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models. Bioorg Med Chem 2008;16:7095-101
  • Kumar YC, Malviya M, Chandra JN, et al. Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models. Bioorg Med Chem 2008;16:5157-63
  • Dunbar GC, Inglis F, Kuchibhatla R, et al. Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI). J Psychopharmacol 2007;21:171-8
  • Baker JD, Lenz RA, Locke C, et al. ABT-089, a neuronal nicotinic receptor partial agonist, reverses scopolamine-induced cognitive deficits in healthy normal subjects. Alzheimers Dement 2009;5(4 suppl 1):P325
  • Nie H, Wang Z, Zhao W, et al. New nicotinic analogue ZY-1 enhances cognitive functions in a transgenic mice model of Alzheimer’s disease. Neurosci Lett 2013;537:29-34
  • Dajas-Bailador F, Wonnacott S. Nicotinic acetylcholine receptors and the regulation of neuronal signalling. Trends Pharmacol Sci 2004;25:317-24
  • Broide RS, Leslie FM. The α7 nicotinic acetylcholine receptor in neuronal plasticity. Mol Neurobiol 1999;20:1-16
  • Berg DK, Conroy WG. Nicotinic α7 receptors: synaptic options and downstream signaling in neurons. J Neurobiol 2002;53:512-23
  • Hashimoto K, Hattori E, Part II. Candidate Gene and Models. 4. Neurotransmission. In: Neurogenetics of Psychiatric Disorders. Sawa A, McInnis MG, Editors Informa Healthcare; New York: 2007. pp. 81-100
  • Ikonomovic MD, Wecker L, Abrahamson EE, et al. Cortical alpha7 nicotinic acetylcholine receptor and beta-amyloid levels in early Alzheimer disease. Arch Neurol 2009;66:646-51
  • Ni R, Marutle A, Nordberg A. Modulation of α7 nicotinic acetylcholine receptor and fibrillar amyloid-β interactions in Alzheimer’s disease brain. J Alzheimers Dis 2013;33:841-51
  • Oz M, Lorke DE, Yang KH, et al. On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr Alzheimer Res 2013;10:618-30
  • Liu QS, Kawai H, Berg DK. β-Amyloid peptide blocks the response of α7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci USA 2001;48:4734-9
  • Pettit DL, Shao Z, Yakel JL. β-Amyloid1-42 peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 2001;21(RC120):1-5
  • Lee DH, Wang HY. Differential physiologic responses of α7 nicotinic acetylcholine receptors to β-amyloid1-40 and β-amyloid1-42. J Neurobiol 2003;55:25-30
  • Wang HY, Lee DH, Davis CB, et al. Amyloid peptide Aβ1-42 binds selectively and with pico-molar affinity to α7 nicotinic acetylcholine receptors. J Neurochem 2000;75:1155-61
  • Kem WR. The brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21). Behav Brain Res 2000;113:169-81
  • Zawieja P, Kornprobst JM, Métais P. 3-(2,4-dimethoxybenzylidene)-anabaseine: a promising candidate drug for Alzheimer’s disease? Geriatr Gerontol Int 2012;12:365-71
  • Vicens P, Ribes D, Heredia L, et al. Motor and anxiety effects of PNU-282987, an alpha7 nicotinic receptor agonist, and stress in an animal model of Alzheimer’s disease. Curr Alzheimer Res 2013;10:516-23
  • Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 1957;58:193-201
  • Kallarackal AJ, Kvarta MD, Cammarata E, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci 2013;33:15669-74
  • Butterfield DA, Pocernich CB. The Glutamatergic System and Alzheimer’s Disease. CNS Drugs 2003;17:641-52
  • Huganir RL, Nicoll RA. AMPARs and Synaptic Plasticity: the Last 25 Years. Neuron 2013;80:704-17
  • Filliat P, Blanchet G. Effects of TCP on spatial memory: comparison with MK-801. Pharmacol Biochem Behav 1995;51:429-34
  • Hynd M, Scott H, Dodd P. Glutamate mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 2004;45:583-95
  • Henry WQ, Frank ML. Alzheimer’s disease: the mechanism of disease. N Engl J Med 2010;362:329-44
  • Wilkinson D, Wirth Y, Goebel C. Memantine in Patients with Moderate to Severe Alzheimer’s Disease: meta-Analyses Using Realistic Definitions of Response. Dement Geriatr Cogn Disord 2013;37:71-85
  • Jarvis B, Figgitt DP. Memantine. Drugs Aging 2003;20:465-76
  • Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs 2011;25:765-81
  • Meltzer CC, Smith G, DeKosky ST, et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 1998;18:407-30
  • Bajwa A, Patel H, Pan ML. Christopher Liang and Jogeshwar Mukherjee. Evaluation of serotonin 5HT1A receptors in postmortem Alzheimer’s disease brains. J Nucl Med 2013;54:1791
  • Lai MKP, Tsang SWY, Francis PT, et al. Postmortem serotoninergic correlates of cognitive decline in Alzheimer’s disease. Neurreport 2002;13:1175-8
  • Whitford GM. Alzheimer’s Disease and Serotonin: a Review. Pharmacopsychiatry 1986;15:3-4
  • Hardy J, Adolfsson R, Alafuzoff I, et al. Transmitter deficits in Alzheimer’s disease. Neurochem Int 1985;7:545-63
  • Hoyer D, Martin G. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacol 1997;36:419-28
  • Yunqi Xu, Junqiang Yan, Peng Zhou. Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 2012;97:1-13
  • Schechter LE, Dawson LA, Harder JA. The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease. Curr Pharm Des 2002;8:139-45
  • Schechter LE, Smith DL, Rosenzweig-Lipson S, Sukoff SJ. Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive enhancing properties. J Pharmacol Exp Ther 2005;314:1274-89
  • Patat A, Parks V, Raje S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects. Br J Clin Pharmacol 2009;67:299-308
  • Upton N, Chuang TT, Hunter AJ, et al. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 2008;5:458-69
  • Marazziti D, Baroni S, Pirone A, et al. Serotonin receptor of type 6 (5-HT6) in human prefrontal cortex and hippocampus post-mortem: an immunohistochemical and immunofluorescence study. Neurochem Int 2012;62(2):182-8
  • Schechter LE, Lin Q, Smith DL, et al. Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 2008;33:1323-35
  • West PJ, Marcy VR, Marino MJ, et al. Activation of the 5-HT (6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neurosci 2009;164:692-701
  • Codony X, Vela JM, Ramírez MJ. 5-HT (6) receptor and cognition. Curr Opin Pharmacol 2011;11:94-100
  • Martorana A, Di Lorenzo F, Esposito Z, et al. Dopamine D2-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacol 2013;64:108
  • Sesack SR, Grace AA. Cortico-Basal Ganglia Reward Network: microcircuitry. Neuropsychopharmacology REVIEWS 2010;35:27-47
  • Zhang L, Doyon WM, Clark JJ, et al. Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum. Mol Pharmacol 2009;76:2-396-404
  • Hosp JA, Molina-Luna K, Hertler B, et al. Dopaminergic modulation of motor maps in rat motor cortex: an in vivo study. Neurosci 2009;159:692-700
  • Molina-Luna K, Pekanovic A, Röhrich S, et al. Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One 2009;4:7082
  • McCormick AV, Wheeler JM, Guthrie CR, et al. Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry 2013;73:464-71
  • Sesack SR, Grace AA. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 2010;35:27-47
  • Cytril G, Valerio M, Marc L, et al. Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev 2009;S60:43-56
  • Eduardo EB. GABAB receptors Structure, functions, and clinical implications. Neurology 2012;78:578-84
  • Zarrindast MR, Bakhsha A, Rostami P, et al. Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats. J Psychopharmacol 2002;16:313-19
  • Oblak AL, Gibbs TT, Blatt GJ. Decreased GABAB receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem 2010;114:1414-23
  • Froestl W, Gallagher M, Jenkins H, et al. SGS742: the first GABAB receptor antagonist in clinical trials. Biochem Pharm 2004;68:1479-87
  • Helm KA, Haberman RP, Dean SL, et al. GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus. Neuropharmacol 2005;48:956-64
  • Berta S, Ki-Shuk S, Gunyong A, et al. Hippocampal levels of phosphorylated protein kinase a (phosphor-S96) are linked to spatial memory enhancement by SGS742. Hippocampus 2009;19:90-8
  • Craig MT, Mayne EW, Bettler B, et al. Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity. J Physiol 2013;591:835-43
  • Marcade M, Bourdin J, Loiseau N, et al. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J Neurochem 2008;106:392-404
  • Nuutinen S, Panula P. Histamine in neurotransmission and brain diseases. Adv Exp Med Biol 2011;709:95-107
  • Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001;63:637-72
  • Medhurst AD, Roberts JC, Lee J, et al. Characterization of histamine H3 receptors in Alzheimer’s Disease brain and amyloid over-expressing TASTPM mice. Br J Pharmacol 2009;157:130-8
  • Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983;28:832-7
  • Chazot PL. Therapeutic potential of histamine H3 receptor antagonists in dementias. Drug News Perspect 2010;23:99-103
  • Da Silveira CK, Furini CR, Benetti F, et al. The role of histamine receptors in the consolidation of object recognition memory. Neurobiol Learn Mem 2013;103:64-71
  • Ligneau X, Perrin D, Landais L. 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 2007;320:365-75
  • Soares H, Wagner T, Schmidt A. H3 receptor antagonism increases methylhistamine level in the cerebrospinal fluid of dogs and healthy human volunteers. in International Conference on Alzheimer’s Disease (ICAD). 2009. Vienna
  • Iannone R, Renger J, Potter W, et al. The relationship between brain receptor occupancy (RO) and alerting effects in humans support MK-0249 and MK-3134 as inverse agonists at the histamine subtype-3 pre-synaptic receptor (H3R). 48th Meeting of the ACNP Hollywood; 2009. Florida
  • Medhurst A, Atkins A, Beresford I, 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 2007;321:1032-45
  • Brioni JD, Esbenshade TA, Garrison TR, et al. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer’s disease. J Pharmacol Exp Ther 2011;336:38-46
  • Othman AA, Haig G, Florian H. Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers. Br J Clin Pharmacol 2013;75:1299-311
  • Nathan PJ, Boardley R, Scott N, et al. The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H3 receptor antagonist in patients with mild to moderate Alzheimer’s disease: a preliminary investigation. Curr Alzheimer Res 2013;10:240-51
  • Griebel G, Pichat P, Pruniaux MP, et al. SAR110894, a potent histamine H3-receptor antagonist, displays procognitive effects in rodent. Pharmacol Biochem Behav 2012;102:203-14
  • Van Ruitenbeek P, Mehta MA. Potential enhancing effects of histamine H1 agonism/H3 antagonism on working memory assessed by performance and bold response in healthy volunteers. Br J Pharmacol 2013;170:144-55
  • Rapoport SI. Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fatty Acids 2008;79:153-6
  • Choi SH, Bosetti F. Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging (Albany NY) 2009;1:234-44
  • Kaufmann WE, Worley PF, Pegg J, et al. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996;93:2317-21
  • Kumar P, Kalonia H, Kumar A. Role of LOX/COX pathways in 3-nitropropionic acid-induced Huntington’s Disease-like symptoms in rats: protective effect of licofelone. Br J Pharmacol 2011;164(2b):644-54
  • Ryu JK, Franciosi S, Sattayaprasert P, et al. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 2004;48:85-90
  • Androsova LV, Mikhaîlova NM, Zozulia SA, et al. Inflammatory markers in Alzheimer’s disease and vascular dementia. Zh Nevrol Psikhiatr Im S S Korsakova 2013;113:49-53
  • Fujimi K, Noda K, Sasaki K, et al. Altered expression of COX-2 in subdivisions of the hippocampus during aging and in Alzheimer’s disease: the Hisayama Study. Dement Geriatr Cogn Disord 2007;23:423-31
  • Manev H, Chen H, Dzitoyeva S, et al. Cyclooxygenases and 5-lipoxygenase in Alzheimer’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 2011;35:315-19
  • Scali C, Giovannini MG, Prosperi C, et al. The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo. Neurosci 2003;117:909-19
  • Choi SH, Aid S, Caracciolo L, et al. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 2013;124:59-68
  • Lim GP, Yang F, Chu T, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000;20:5709-14
  • Zurita MP, Muñoz G, Sepúlveda FJ, et al. Ibuprofen inhibits the synaptic failure induced by the amyloid-β peptide in hippocampal neurons. J Alzheimers Dis 2013;35:463-73
  • Côté S, Carmichael PH, Verreault R, et al. Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer’s disease. Alzheimers Dement 2012;8:219-26
  • Wright JW, Harding JW. Harding. Brain renin-angiotensin—A new look at an old system. Prog Neurobiol 2011;95:49-67
  • Littlejohn NK, Siel RBJr, Ketsawatsomkron P, et al. Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regul Integr Comp Physiol 2013;304:R818-28
  • Barnes NM, Champaneria S, Costall B, et al. Cognitive enhancing actions of DuP 753 detected in a mouse habituation paradigm. Neuroreport 1990;1(3-4):239-42
  • Singh B, Sharma B, Jaggi AS, et al. Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s disease type: possible involvement of PPAR-γ agonistic property. J Renin Angiotensin Aldosterone Syst 2013;14:124-36
  • Yonkov D, Georgiev V, Kambourova T. Further evidence for the GABAergic influence on memory. Interaction of GABAergic transmission with angiotensin II on memory processes. Methods Find Exp Clin Pharmacol 1989;11:603-6
  • Wilson WL, Munn C, Ross RC, et al. The role of the AT4 and cholinergic systems in the Nucleus Basalis Magnocellularis (NBM): effects on spatial memory. Brain Res 2009;1272:25-31
  • Wright JW, Stubley L, Pederson ES, et al. Contributions of the brain angiotensin IV–AT4 receptor subtype system to spatial learning. J Neurosci 1999;19:3952-61
  • Chai SY, Bastias MA, Clune EF, et al. Distribution of angiotensin IV binding sites (AT4 receptor) in the human forebrain, midbrain and pons as visualised by in vitro receptor autoradiography. J Chem Neuroanat 2000;20:339-48
  • Olson ML, Olson EA, Qualls JH, et al. Norleucine1 Angiotensin IV alleviates mecamylamine-induced spatial memory deficits. Peptides 2004;2:233-41
  • Paul V, Ekambaram P. Involvement of nitric oxide in learning & memory processes. Indian J Med Res 2011;133:471-8
  • Harooni HE, Naghdi N, Sepehri H, et al. The role of hippocampal nitric oxide on learning and immediate short and long-term memory retrieval in inhibitory avoidance task in male adult rats. Behav Brain Res 2009;201:166-72
  • Zhihui Q. Modulating nitric oxide signaling in the CNS for Alzheimer’s disease therapy. Future Med Chem 2013;5:1451-68
  • Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, et al. Nitric oxide: target for therapeutic strategies in Alzheimer’s disease. Curr Pharm Des 2010;16:2837-50
  • Xu X, Russel T, Bazner J, et al. NMDA receptor antagonist AP5 and nitric oxide synthase inhibitor 7-NI affect different phase of learning and memory in gold fish. Brain Res 2001;889:274-7
  • Yildiz Akar E, Ulak G, Tanyer P, et al. 7-nitroindazole, a neuronal nitric oxide synthase inhibitor impairs passive-avoidance and elevated plus-maze memory performance in rats. Pharmacol Biochem Behav 2007;87:434-43
  • Sweatt JD. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 2004;14:311-17
  • Calissano P, Matrone C, Amadoro G. Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Dev Neurobiol 2010;70:372-83
  • Venero JL, Knusel B, Beck KD, et al. Expression of neurotrophin and trk receptor genes in adult rats with fimbria transections: effect of intraventricular nerve growth factor and brain-derived neurotrophic factor administration. Neurosci 1994;59:797-815
  • Weissmiller AM, Wu C. Current advances in using neurotrophic factors to treat neurodegenerative disorders. Translational Neurodegeneration 2012;1:14
  • Nabeshima T. Nerve growth factor strategy and preparation of animal model for Alzheimer-type senile dementia. Yakugaku Zasshi 1995;115:499-512
  • Caraci F, Spampinato S, Sortino MA, et al. Dysfunction of TGF-β1 signaling in Alzheimer’s disease: perspectives for neuroprotection. Cell Tissue Res 2012;347:291-301
  • Caraci F, Battaglia G, Busceti C, et al. TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway. Neurobiol Dis 2008;30:234-42
  • Sortino MA, Chisari M, Merlo S, et al. Glia mediates the neuroprotective action of estradiol on beta-amyloid induced neuronal death. Endocrinology 2004;145:5080-6
  • Goeldner C, Ballard TM, Knoflach F, et al. Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target. Neuropharmacol 2013;64:337-46
  • Caraci F, Battaglia G, Bruno V, et al. TGF-β1 pathway as a new target for neuroprotection in Alzheimer’s disease. CNS Neurosci Ther 2011;17:237-49
  • Vollmar P, Haghikia A, Dermietzel R, et al. Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model. Int J Neuropsychopharmacol 2008;11:111-17
  • Alcalay RN, Giladi E, Pick CG, et al. Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze. Neurosci Lett 2004;361:128-31
  • Gozes I, Divinski I, Piltzer I. NAP and D-SAL: neuroprotection against the beta amyloid peptide (1-42). BMC Neurosci 2008;9(Suppl 3):S3
  • Fernandez-Montesinos R, Torres M, Baglietto-Vargas D, et al. Activity-dependent neuroprotective protein (ADNP) expression in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease. J Mol Neurosci 2010;41:114-20
  • Brenneman DE, Gozes I. A femtomolar-acting neuroprotective peptide. J Clin Invest 1996;97:2299-307
  • Glazner GW, Boland A, Dresse AE, et al. Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress-induced death. J Neurochem 1999;73:2341-7
  • Blondel O, Collin C, McCarran WJ, et al. A glia-derived signal regulating neuronal differentiation. J Neurosci 2000;20:8012-20
  • Bassan M, Zamostiano R, Davidson A, et al. Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 1999;72:1283-93
  • Gozes I, Zaltzman R, Hauser J, et al. The expression of activity-dependent neuroprotective protein (ADNP) is regulated by brain damage and treatment of mice with the ADNP derived peptide, NAP, reduces the severity of traumatic head injury. Curr Alzheimer Res 2005;2:149-53
  • Vulih-Shultzman I, Pinhasov A, Mandel S, et al. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther 2007;323:438-49
  • Divinski I, Mittelman L, Gozes I. A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication. J Biol Chem 2004;279:28531-8
  • Visochek L, Steingart RA, Vulih-Shultzman I, et al. PolyADP-ribosylation is involved in neurotrophic activity. J Neurosci 2005;25:7420-8
  • Mironov SL, Ivannikov MV, Johansson M. [Ca2+]i signaling between mitochondria and endoplasmic reticulum in neurons is regulated by microtubules. From mitochondrial permeability transition pore to Ca2+-induced Ca2+ release. J Biol Chem 2005;280:715-21
  • Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task. Proc Natl Acad Sci U S A 1995;92:5047-51
  • Hu XL, Xiao HM, Hu XW, et al. Influence of PAF receptors on long term potentiation attenuated by aluminium in hippocampal CA3 area of rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2004;20:161-5
  • Packard MG, Teather LA, Bazan NG. Effects of intrastriatal injections of platelet-activating factor and the PAF antagonist BN 52021 on memory. Neurobiol Learn Mem 1996;66:176-82
  • Singh N, Sharma A, Singh M. Effects of BN-50730 (PAF receptor antagonist) and physostigmine (AChE inhibitor) on learning and memory in mice. Methods Find Exp Clin Pharmacol 1997;19:585-8
  • Van Dam D, Van Dijck A, Janssen L, et al. Neuropeptides in Alzheimer’s Disease: from Pathophysiological Mechanisms to Therapeutic Opportunities. Curr Alzheimer Res 2013;10:449-68
  • Tiwari SK, Chaturvedi RK. Peptide therapeutics in neurodegenerative disorders. Curr Med Chem 2014;21(23):2610-31
  • Pan YF, Jia XT, Wang XH, et al. Arginine vasopressin remolds the spontaneous discharges disturbed by amyloid β protein in hippocampal CA1 region of rats. Regul Pept 2013;183C:7-12
  • Pan YF, Chen XR, Wu MN, et al. Arginine vasopressin prevents against Abeta (25-35)-induced impairment of spatial learning and memory in rats. Horm Behav 2010;57:448-54
  • Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: A 2014 update. Mol Cell Endocrinol 2014;389(1-2):7-12
  • Yin QQ, Pei JJ, Xu S, et al. Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats. 2013;10:1371
  • Sørensen AT, Kanter-Schlifke I, Lin EJ, et al. Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in the subiculum. Mol Cell Neurosci 2008;39:229-37
  • Flood JF, Baker ML, Hernandez EN, et al. Modulation of memory retention by neuropeptide K. Brain Res 1990;520:284-90
  • Medicines in Development for Neurological Disorders, A Report on Disorders of the Brain, Spinal Cord and Nerves presented by America’s biopharmaceutical research companies; 2013 report. Available from: www.phrma.org/sites/default/files/Alzheimer’s%202013.pdf
  • Medicines in Development for Older Americans, The Medicare Population and Leading Chronic Diseases presented by America ’s biopharmaceutical research companies. 2013 report
  • Wildburger NC, Lin-Ye A, Baird MA, et al. Neuroprotective effects of blockers for T-type calcium channels. Mol Neurodegener 2009;4:44
  • Barret MJ. Calcium channel blockers and Parkinson disease. Medscape.boards.forum. Data retrieved on 8 June 2014
  • Huang BR, Chang PC, Yeh WL, et al. Anti-neuroinflammatory effects of the calcium channel blocker nicardipine on microglial cells: implications for neuroprotection. PLoS One 2014.9:3. Available from: www.plosone.org
  • A Phase III Trial of Nilvadipine to Treat Alzheimer’s Disease (NILVAD). Available from: http://clinicaltrials.gov/show/NCT02017340
  • Watt AD, Crespi GA, Down RA, et al. Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target? Acta Neuropathol 2014;127:803-10
  • Panza F, Frisardi V, Imbimbo BP, et al. Monoclonal antibodies against β-amyloid (Aβ) for the treatment of Alzheimer’s disease: the Aβ target at a crossroads. Expert Opin Biol Ther 2011;11:679-86
  • Okun I, Tkachenko SE, Khvat A, et al. From anti-allergic to anti-Alzheimer’s: molecular pharmacology of Dimebon. Curr Alzheimer Res 2010;2:97-112
  • Editorial. Mechanism matters. Nat Med 2010;16:4
  • Yun H, Rhim H. The Serotonin-6 Receptor as a Novel Therapeutic Target. ExpNeurobiol 2011;20:159-68
  • Study of Lu AE58054 in Patients With Mild - Moderate Alzheimer’s Disease Treated With Donepezil (STARSHINE). 2014. Available from: http://www.clinicaltrials.gov/show/NCT01955161
  • Bi BT, Lin HB, Cheng YF, et al. Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer’s disease. Neurochem Int 2012;60:257-66
  • Erratum The BACE race is on. Nat Rev Drug Discov 2014;13:165
  • Lilly. Available from: www.lilly.com/Pages/Home.aspx
  • Freiherr J, Hallschmid M, Frey WH, et al. Intranasal Insulin as a Treatment for Alzheimer’s Disease: a Review of Basic Research and Clinical Evidence. CNS Drugs 2013;27:505-14
  • Takeda and Zinfandel Pharmaceuticals Initiate Phase 3 TOMMORROW Trial of AD-4833 for the Delay of Onset of Mild Cognitive Impairment Due to Alzheimer’s Disease in Subjects Selected Using a Genetic-Based Biomarker Risk Assignment Algorithm. Takeda Pharmaceutical Company Limited Zinfandel Pharmaceuticals, Inc. 2013; Data retrieved on 5 June 2014
  • 3-monnths study of MSDC-0160 Effects on Brain Glucose Utilization, Cognition and Safety in Subjects with Alzheimer’s disease. Available from: http://clinicaltrials.gov/show/NCT01374438
  • EVP-6124 for Treating Alzheimer’s Disease. Available from: www.nia.nih.gov/alzheimers/clinical-trials/evp-6124-treating-alzheimersdisease [Last accessed on 10 Jun 2014]
  • Masangkay EG. Mitsubishi Tanabe And EnVivo Kickstart Phase III Trial Of Alzheimer’s Disease Treatment MT-4666. Available from: www.outsourcedpharma.com [Last accessed on 8 Jun 2014]
  • Astrazeneca. Available from: www.astrazeneca.com
  • TARGACEPT. Available from: www.targacept.com
  • Abbvie. Available from: www.abbvie.com
  • ADAMAS. Available from: www.adamaspharma.com
  • Actavis. Available from: www.frx.com/
  • Gsk. Available from: www.gsk.com
  • Lundbeck. Available from: www.lundbeck.com
  • Otsuka. Available from: www.otsuka.com
  • Avineuro. Available from: www.avineuro.com
  • Nanotherapeutics. Available from: www.nanotherapeutics.com
  • Roche. Available from: www.roche.com
  • SANOFI. Available from: http://en.sanofi.com/
  • Aphios. Available from: www.aphios.com/
  • Pfizer. Available from: www.pfizer.com
  • QR Pharma. Available from: www.qrpharma.com
  • GENERVON. Available from: www.genervon.com
  • RESVERLOGIX. Available from: www.resverlogix.com
  • Accera. Available from: www.accerapharma.com/
  • Janimm. Available from: www.janimm.com
  • Sunovion. Available from: www.sunovion.com
  • Takeda. Available from: www.takeda.com
  • T3D Therapeutics. Available from: http://www.t3dtherapeutics.com/
  • Janssen. Available from: www.janssenrnd.com
  • Affiris. Available from: www.affiris.com
  • Archer Pharmaceuticals. Available from: www.archerpharma.com
  • Astellas. Available from: www.astellas.com
  • Janssen Pharmaceuticals, Inc. Available from: www.janssenpharmaceuticalsinc.com
  • SHIONOGI INC. Available from: www.shionogi.com
  • Eisai. Available from: www.eisai.com
  • Biogenidec. Available from: www.biogenidec.com
  • Bristol-Myers Squibb. Available from: www.bms.com
  • NOVARTIS. Available from: www.novartis.com/
  • MERCK. Available from: www.merck.com
  • XEL Pharmaceuticals. Available from: www.xelpharmaceuticals.com
  • Vivus. Available from: www.vivus.com
  • TransTech Pharma. Available from: www.ttpharma.com
  • FUJI FILM. Available from: www.toyama-chemical.co.jp
  • Sonexa. Available from: www.sonexa.com
  • SGC Pharma. Available from: www.sgcpharma.com
  • Navidea. Available from: www.navidea.com
  • Allon therapeutics. Available from: www.allontherapeutics.com
  • Forum Pharmaceuticals. Available from: www.envivopharma.com
  • Proteo Tech. Available from: www.proteotech.com
  • SIEMENS. Available from: www.usa.healthcare.siemens.com
  • GE Healthcare. Available from: www.gehealthcare.com
  • Baxter. Available from: http://baxter.com/
  • Highpointpharma. Available from: www.highpointpharma.com
  • GRIFOLS. Available from: www grifols.com
  • KAREUS Therapeutics; SA. Available from: www.kareustherapeutics.com
  • TAU Rx Therapeutics. Available from: www.taurx.com
  • Amarantus. Available from: www.amarantus.com
  • AB-SCIENCE. Available from: www.ab-science.com
  • Mithridion. Available from: www.mithridion.com
  • Metabolic Solutions Development Company. Available from: www.msdrx.com
  • Humanetics. Available from: www.humaneticscorp.com

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.