Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

Monoamines and their Derivatives on GPCRs: Potential Therapy for Alzheimer’s Disease

Author(s): Eunice D. Farfán-García, Ricardo Márquez-Gómez, Mónica Barrón-González, Teresa Pérez-Capistran, Martha C. Rosales-Hernández, Rodolfo Pinto-Almazán and Marvin A. Soriano-Ursúa*

Volume 16 , Issue 10 , 2019

Page: [871 - 894] Pages: 24

DOI: 10.2174/1570159X17666190409144558

Price: $65


Albeit cholinergic depletion remains the key event in Alzheimer’s Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.

Keywords: Monoamines, monoaminergic neuropathology, drug design, GPCR, tau-protein, amyloid beta.

Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141(7): 1917-33. (2018)
[] [PMID: 29850777]
Šimić G, Babić Leko M, Wray S, Harrington CR, Delalle I, Jovanov-Milošević N, et al. Monoaminergic neuropathology in Alzheimer’s disease. Prog Neurobiol 151: 101-38. (2017)
[] [PMID: 27084356]
Suri D, Teixeira CM, Cagliostro MK, Mahadevia D, Ansorge MS. Monoamine-sensitive developmental periods impacting adult emotional and cognitive behaviors. Neuropsychopharmacology 40(1): 88-112. (2015)
[] [PMID: 25178408]
Leanza G, Gulino R, Zorec R. Noradrenergic hypothesis linking neurodegeneration-based cognitive decline and astroglia. Front Mol Neurosci 11: 254. (2018)
Maudsley S, Martin B, Luttrell LM. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Curr Alzheimer 4(1): 3-19. (2007)
Cong X, Topin J, Golebiowski J, Class A, Class A. GPCRs: structure, Function, Modeling and Structure-based Ligand Design. Curr Pharm Des 23(29): 4390-409. (2017)
[] [PMID: 28699533]
Verma S, Kumar A, Tripathi T, Kumar A. Muscarinic and nicotinic acetylcholine receptor agonists: current scenario in Alzheimer’s disease therapy. J Pharm Pharmacol 70(8): 985-93. (2018)
[] [PMID: 29663387]
Huang Y, Todd N, Thathiah A. The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention. Curr Opin Pharmacol 32: 96-110. (2017)
[] [PMID: 28288370]
Boulton AA. Letter: amines and theories in psychiatry. Lancet 2(7871): 52-3. (1974)
[] [PMID: 4134443]
Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA 98(16): 8966-71. (2001)
[] [PMID: 11459929]
Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. Amphetamine, 3,4-methylenedioxymethamp-hetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60(6): 1181-8. (2001)
Lindemann L, Hoener MC. A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci 26(5): 274-81. (2005)
[] [PMID: 15860375]
Pei Y, Asif-Malik A, Canales JJ. Trace amines and the trace amine-associated receptor 1: pharmacology, neurochemistry, and clinical implications. Front Neurosci 10: 148. (2016)
[] [PMID: 27092049]
Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther 324(3): 948-56. (2008)
[] [PMID: 18083911]
Xie Z, Miller GM. β-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther 325(2): 617-28. (2008)
[] [PMID: 18182557]
Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, André CB, et al. Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine. Neuropsychopharmacology 37(12): 2580-92. (2012)
[] [PMID: 22763617]
Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci USA 108(20): 8485-90. (2011)
[] [PMID: 21525407]
Kato M, Ishida K, Chuma T, Abe K, Shigenaga T, Taguchi K, et al. β-Phenylethylamine modulates acetylcholine release in the rat striatum: involvement of a dopamine D(2) receptor mechanism. Eur J Pharmacol 418(1-2): 65-71. (2001)
[] [PMID: 11334866]
Ishida K, Murata M, Kato M, Utsunomiya I, Hoshi K, Taguchi K. Beta-phenylethylamine stimulates striatal acetylcholine release through activation of the AMPA glutamatergic pathway. Biol Pharm Bull 28(9): 1626-9. (2005)
[] [PMID: 16141528]
Manni ME, De Siena G, Saba A, Marchini M, Landucci E, Gerace E, et al. Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold. Br J Pharmacol 168(2): 354-62. (2013)
[] [PMID: 22889145]
Laurino A, De Siena G, Saba A, Chiellini G, Landucci E, Zucchi R, et al. In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine. Eur J Pharmacol 761: 130-4. (2015)
[] [PMID: 25941083]
Ligands and Putative Role in the Central Nervous System 151-64. (2016)
Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry 18(5): 543-56. (2013)
[] [PMID: 22641180]
Rutigliano G, Accorroni A, Zucchi R. The Case for TAAR1 as a Modulator of Central Nervous System Function. Front Pharmacol 8: 987. (2018)
[] [PMID: 29375386]
Guariento S, Tonelli M, Espinoza S, Gerasimov AS, Gainetdinov RR, Cichero E. Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 agonists. Eur J Med Chem 146: 171-84. (2018)
[] [PMID: 29407948]
Tonelli M, Espinoza S, Gainetdinov RR, Cichero E. Novel biguanide-based derivatives scouted as TAAR1 agonists: synthesis, biological evaluation, ADME prediction and molecular docking studies. Eur J Med Chem 127: 781-92. (2017)
[] [PMID: 27823885]
Martorana A, Koch G. Is dopamine involved in Alzheimer’s disease? Front Aging Neurosci 6: 252. (2014)
[] [PMID: 25309431]
Cordella A, Krashia P, Nobili A, Pignataro A. La Barbera 1, Viscomi MT, et al Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 116: 142-54. (2018)
[] [PMID: 29778899]
D’Amelio M, Puglisi-Allegra S, Mercuri N. The role of dopaminergic midbrain in Alzheimer’s disease: Translating basic science into clinical practice. Pharmacol Res 130: 414-9. (2018)
[] [PMID: 29391234]
Costa C, Parnetti L, D’Amelio M, Tozzi A, Tantucci M, Romigi A, et al. Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link? Neurobiol Aging 48: 161-71. (2016)
[] [PMID: 27701029]
Volkow ND, Fowler JS, Wang GJ, Logan J, Schlyer D, MacGregor R, et al. Decreased dopamine transporters with age in health human subjects. Ann Neurol 36(2): 237-9. (1994)
[] [PMID: 8053661]
Bäckman L, Lindenberger U, Li SC, Nyberg L. Linking cognitive aging to alterations in dopamine neurotransmitter functioning: recent data and future avenues. Neurosci Biobehav Rev 34(5): 670-7. (2010)
[] [PMID: 20026186]
Kemppainen N, Laine M, Laakso MP, Kaasinen V, Någren K, Vahlberg T, et al. Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease. Eur J Neurosci 18(1): 149-54. (2003)
[] [PMID: 12859348]
Kumar U, Patel SC. Immunohistochemical localization of dopamine receptor subtypes (D1R-D5R) in Alzheimer’s disease brain. Brain Res 1131(1): 187-96. (2007)
[] [PMID: 17182012]
Perez SE, Lazarov O, Koprich JB, Chen EY, Rodriguez-Menendez V, Lipton JW, et al. Nigrostriatal dysfunction in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 transgenic mice. J Neurosci 25(44): 10220-9. (2005)
[] [PMID: 16267229]
Melief EJ, Cudaback E, Jorstad NL, Sherfield E, Postupna N, Wilson A, et al. Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer’s disease. J Neurosci Res 93(9): 1413-22. (2015)
[] [PMID: 25824456]
Von Linstow CU, Severino M, Metaxas A, Waider J, Babcock AA, Lesch KP, et al. Effect of aging and Alzheimer’s disease-like pathology on brain monoamines in mice. Neurochem Int 108: 238-45. (2017)
[] [PMID: 28414094]
Siepel FJ, Dalen I, Grüner R, Booij J, Brønnick KS, Buter TC, et al. Loss of dopamine transporter binding and clinical symptoms in dementia with lewy bodies. Mov Disord 31(1): 118-25. (2016)
[] [PMID: 26207978]
Cools R. Chemistry of the adaptive mMind: lessons from dopamine. Neuron 104(1): 113-31. (2019)
Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 8: 14727. (2017)
[] [PMID: 28367951]
Moreno-Castilla P, Rodriguez-Duran LF, Guzman-Ramos K, Barcenas-Femat A, Escobar ML, Bermudez-Rattoni F. Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment. Neurobiol Aging 41: 187-99. (2016)
[] [PMID: 27103531]
Dalet FG, Guadalupe TF, María Del Carmen CH, Humberto GA, Antonio SU. Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes. Neural Regen Res 8(24): 2290-302. (2013)
[PMID: 25206539]
Kumar S, Chowdhury S, Kumar S. In silico repurposing of antipsychotic drugs for Alzheimer’s disease. BMC Neurosci 18(1): 76. (2017)
[] [PMID: 29078760]
Yuan Xiang P, Janc O, Grochowska KM, Kreutz MR, Reymann KG. Dopamine agonists rescue Aβ-induced LTP impairment by Src-family tyrosine kinases. Neurobiol Aging 40: 98-102. (2016)
[] [PMID: 26973108]
Zang X, Cheng ZY, Sun Y, Hua N, Zhu LH, He L. The ameliorative effects and underlying mechanisms of dopamine D1-like receptor agonist SKF38393 on Aβ1-42-induced cognitive impairment. Prog Neuropsychopharmacol Biol Psychiatry 81: 250-61. (2018)
[] [PMID: 28939187]
Shen L, Yan M, He L. D5 receptor agonist 027075 promotes cognitive function recovery and neurogenesis in a Aβ1-42-induced mouse model. Neuropharmacology 105: 72-83. (2016)
[] [PMID: 26773200]
Koch G, Di Lorenzo F, Bonnì S, Giacobbe V, Bozzali M, Caltagirone C, et al. Dopaminergic modulation of cortical plasticity in Alzheimer’s disease patients. Neuropsychopharmacology 39(11): 2654-61. (2014)
[] [PMID: 24859851]
Andersson RH, Johnston A, Herman PA, Winzer-Serhan UH, Karavanova I, Vullhorst D, et al. Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors. Proc Natl Acad Sci USA 109(32): 13118-23. (2012)
[] [PMID: 22822214]
Wu L, Feng X, Li T, Sun B, Khan MZ, He L. Risperidone ameliorated Aβ1-42-induced cognitive and hippocampal synaptic impairments in mice. Behav Brain Res 322(Pt A): 145-56 (2017).
Reeves S, McLachlan E, Bertrand J, D’Antonio F, Brownings S, Nair A, et al. Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease. Brain 140(4): 1117-27. (2017)
[] [PMID: 28334978]
Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortés A, et al. Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease. Mol Neurobiol 54(6): 4537-50. (2017)
[] [PMID: 27370794]
Liu M, Kou L, Bin Y, Wan L, Xiang J. Complicated function of dopamine in Aβ-related neurotoxicity: Dual interactions with Tyr10 and SNK(26-28) of Aβ. J Inorg Biochem 164: 119-28. (2016)
[] [PMID: 27687332]
Amato D, Canneva F, Cumming P, Maschauer S, Groos D, Dahlmanns JK, et al. A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter. Mol Psychiatry (2018)
[] [PMID: 30038229]
Kalaria RN, Andorn AC, Tabaton M, Whitehouse PJ, Harik SI, Unnerstall JR. Adrenergic receptors in aging and Alzheimer’s disease: increased beta 2-receptors in prefrontal cortex and hippocampus. J Neurochem 53(6): 1772-81. (1989)
[] [PMID: 2553864]
Lemmer B, Langer L, Ohm T, Bohl J. Beta-adrenoceptor density and subtype distribution in cerebellum and hippocampus from patients with Alzheimer’s disease. Naunyn Schmiedebergs Arch Pharmacol 347(2): 214-9. (1993)
[] [PMID: 8097284]
Vermeiren Y, De Deyn PP. Targeting the norepinephrinergic system in Parkinson’s disease and related disorders: The locus coeruleus story. Neurochem Int 102: 22-32. (2017)
[] [PMID: 27899296]
Stefani A, Olivola E, Liguori C, Hainsworth AH, Saviozzi V, Angileri G, et al. Catecholamine-based treatment in ad patients: expectations and delusions. Front Aging Neurosci 7: 67. (2015)
[] [PMID: 25999852]
Femminella GD, Leosco D, Ferrara N, Rengo G. Adrenergic drugs blockers or enhancers for cognitive decline? what to choose for alzheimer’s disease patients? CNS Neurol Disord Drug Targets 15(6): 665-71. (2016)
[] [PMID: 27189470]
Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107(13): 6058-63. (2010)
[] [PMID: 20231476]
Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Monoaminergic neurotransmitter alterations in postmortem brain regions of depressed and aggressive patients with Alzheimer’s disease. Neurobiol Aging 35(12): 2691-700. (2014)
[] [PMID: 24997673]
Szot P. Common factors among Alzheimer’s disease, Parkinson’s disease, and epilepsy: possible role of the noradrenergic nervous system. Epilepsia 53(1): 61-6. (2012)
[] [PMID: 22612810]
Chen Y, Peng Y, Che P. Gannon M, Liu Y, Li L, Bu G, et al. α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction. Proc Natl Acad Sci USA 111(48): 17296-301. (2014)
[] [PMID: 25404298]
Yu JT, Wang ND, Ma T, Jiang H, Guan J, Tan L. Roles of β-adrenergic receptors in Alzheimer’s disease: implications for novel therapeutics. Brain Res Bull 84(2): 111-7. (2011)
[] [PMID: 21129453]
Femminella GD, Rengo G, Pagano G, de Lucia C, Komici K, Parisi V, et al. β-adrenergic receptors and G protein-coupled receptor kinase-2 in Alzheimer’s disease: a new paradigm for prognosis and therapy? J Alzheimers Dis 34(2): 341-7. (2013)
[] [PMID: 23207488]
Xia M, Cheng X, Yi R, Gao D, Xiong J. The binding receptors of Aβ: an alternative therapeutic target for Alzheimer’s disease. Mol Neurobiol 53(1): 455-71. (2016)
[] [PMID: 25465238]
Cowburn RF, Vestling M, Fowler CJ, Ravid R, Winblad B, O’Neill C. Disrupted beta 1-adrenoceptor-G protein coupling in the temporal cortex of patients with Alzheimer’s disease. Neurosci Lett 155(2): 163-6. (1993)
[] [PMID: 8397350]
Branca C, Wisely EV, Hartman LK, Caccamo A, Oddo S. Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer’s disease. Neurobiol Aging 35(12): 2726-35. (2014)
[] [PMID: 25034342]
Wang D, Fu Q, Zhou Y, Xu B, Shi Q, Igwe B, et al. β2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. J Biol Chem 288(15): 10298-307. (2013)
[] [PMID: 23430246]
Amezcua-Gutierrez MA, Cipres-Flores FJ, Trujillo-Ferrara JG, Soriano-Ursua MA. Clinical implications of recent insights into the structural biology of beta2 adrenoceptors. Curr Drug Targets 13(10): 1336-46. (2012)
[] [PMID: 22812411]
Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, et al. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry 17(9): 744-51. (2009)
[] [PMID: 19700947]
Borthwick AD. Fluparoxan: a comprehensive review of its discovery, adrenergic and CNS activity and treatment of cognitive dysfunction in central neurodegenerative diseases. Mini Rev Med Chem 17(7): 572-82. (2017)
[] [PMID: 26996616]
Lương Kv, Nguyen LT. The role of Beta-adrenergic receptor blockers in Alzheimer’s disease: potential genetic and cellular signaling mechanisms. Am J Alzheimers Dis Other Demen 28(5): 427-39. (2013)
[] [PMID: 23689075]
Dobarro M, Gerenu G, Ramírez MJ. Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer’s transgenic mice. Int J Neuropsychopharmacol 16(10): 2245-57. (2013)
[] [PMID: 23768694]
Dobarro M, Orejana L, Aguirre N, Ramírez MJ. Propranolol restores cognitive deficits and improves amyloid and tau pathologies in a senescence-accelerated mouse model. Neuropharmacology 64: 137-44. (2013)
[] [PMID: 22824191]
Wang J, Ono K, Dickstein DL, Arrieta-Cruz I, Zhao W, Qian X, et al. Carvedilol as a potential novel agent for the treatment of Alzheimer’s disease. Neurobiol Aging 32(12): 2321.e1-2321.e12. (2011)
[] [PMID: 20579773]
Manthey D, Gamerdinger M, Behl C. The selective beta1-adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective abilities. Br J Pharmacol 159(6): 1264-73. (2010)
[] [PMID: 20128815]
Wang J, Wright HM, Vempati P, Li H, Wangsa J, Dzhuan A, et al. Investigation of nebivolol as a novel therapeutic agent for the treatment of Alzheimer’s disease. J Alzheimers Dis 33(4): 1147-56. (2013)
[] [PMID: 23128558]
Ardestani PM, Evans AK, Yi B, Nguyen T, Coutellier L, Shamloo M. Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer’s disease using a biased and selective beta-1 adrenergic receptor partial agonist. Neuropharmacology 116: 371-86. (2017)
[] [PMID: 28089846]
Yi B, Jahangir A, Evans AK, Briggs D, Ravina K, Ernest J, et al. Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders. PLoS One 12(7)e0180319 (2017)
[] [PMID: 28746336]
Chai GS, Wang YY, Zhu D, Yasheng A, Zhao P. Activation of β2-adrenergic receptor promotes dendrite ramification and spine generation in APP/PS1 mice. Neurosci Lett 636: 158-64. (2017)
[] [PMID: 27838449]
Gibbs ME, Maksel D, Gibbs Z, Hou X, Summers RJ, Small DH. Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist. Neurobiol Aging 31(4): 614-24. (2010)
[] [PMID: 18632189]
Nieto-Alamilla G, Márquez-Gómez R, García-Gálvez AM, Morales-Figueroa GE, Arias-Montaño JA. The histamine H3 receptor: structure, pharmacology and function. Mol Pharmacol 90(5): 649-73. (2016)
[] [PMID: 27563055]
Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4(2): 121-30. (2003)
[] [PMID: 12563283]
Cacabelos R, Yamatodani A, Niigawa H, Hariguchi S, Tada K, Nishimura T, et al. Brain histamine in Alzheimer’s disease. Methods Find Exp Clin Pharmacol 11(5): 353-60. (1989)
[PMID: 2755282]
Alvarez XA, Franco A, Fernández-Novoa L, Cacabelos R. Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. Mol Chem Neuropathol 29(2-3): 237-52. (1996)
[] [PMID: 8971699]
Mazurkiewicz-Kwilecki IM, Nsonwah S. Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients. Can J Physiol Pharmacol 67(1): 75-8. (1989)
[] [PMID: 2713757]
Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, et al. Neuronal histamine deficit in Alzheimer’s disease. Neuroscience 82(4): 993-7. (1998)
[] [PMID: 9466423]
Airaksinen MS, Paetau A, Paljärvi L, Reinikainen K, Riekkinen P, Suomalainen R, et al. Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience 44(2): 465-81. (1991)
[] [PMID: 1719449]
Nakamura S, Takemura M, Ohnishi K, Suenaga T, Nishimura M, Akiguchi I, et al. Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer’s disease. Neurosci Lett 151(2): 196-9. (1993)
[] [PMID: 8506080]
Shan L, Bossers K, Unmehopa U, Bao A-M, Swaab DF. Alterations in the histaminergic system in Alzheimer’s disease: a postmortem study. Neurobiol Aging 33(11): 2585-98. (2012)
[] [PMID: 22284987]
Yanai K, Watanabe T, Meguro K, Yokoyama H, Sato I, Sasano H, et al. Age-dependent decrease in histamine H1 receptor in human brains revealed by PET. Neuroreport 3(5): 433-6. (1992)
[] [PMID: 1633281]
Higuchi M, Yanai K, Okamura N, Meguro K, Arai H, Itoh M, et al. Histamine H(1) receptors in patients with Alzheimer’s disease assessed by positron emission tomography. Neuroscience 99(4): 721-9. (2000)
[] [PMID: 10974435]
Honrubia MA, Vilaró MT, Palacios JM, Mengod G. Distribution of the histamine H(2) receptor in monkey brain and its mRNA localization in monkey and human brain. Synapse 38(3): 343-54. (2000)
[<343:AID-SYN14>3.0.CO;2-M] [PMID: 11020238]
da Silva WC, Bonini JS, Bevilaqua LRM, Izquierdo I, Cammarota M. Histamine enhances inhibitory avoidance memory consolidation through a H2 receptor-dependent mechanism. Neurobiol Learn Mem 86(1): 100-6. (2006)
[] [PMID: 16488163]
Breitner JCS, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 16(4): 523-30. (1995)
[] [PMID: 8544901]
Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Schumacher Dimech A, Santuccione Chadha A, et al. Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol 14(8): 457-69. (2018)
[] [PMID: 29985474]
Schneider EH, Seifert R. The histamine H4-receptor and the central and peripheral nervous system: a critical analysis of the literature. Neuropharmacology 106: 116-28. (2016)
[] [PMID: 25986697]
Connelly WM, Shenton FC, Lethbridge N, Leurs R, Waldvogel HJ, Faull RL, et al. The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br J Pharmacol 157(1): 55-63. (2009)
[] [PMID: 19413571]
Bovet D, Staub AM. Action protectrice des ethers phenolque au cours de l’intoxicationhistaminique. C R Soc Biol Ses Fil 123: 547-54. (1937)
Leurs R, Vischer HF, Wijtmans M, de Esch IJP. En route to new blockbuster anti-histamines: surveying the offspring of the expanding histamine receptor family. Trends Pharmacol Sci 32(4): 250-7. (2011)
[] [PMID: 21414671]
Canto-de-Souza L, Garção DC, Romaguera F, Mattioli R. Dorsal hippocampal microinjection of chlorpheniramine reverses the anxiolytic-like effects of l-histidine and impairs emotional memory in mice. Neurosci Lett 587: 11-6. (2015)
[] [PMID: 25524405]
Ambrée O, Buschert J, Zhang W, Arolt V, Dere E, Zlomuzica A. Impaired spatial learning and reduced adult hippocampal neurogenesis in histamine H1-receptor knockout mice. Eur Neuropsychopharmacol (2014); 24(8): 1394-404.
[] [PMID: 24862254]
Carlson MC, Tschanz JT, Norton MC, Welsh-Bohmer K, Martin BK, Breitner JC. H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. Alzheimer Dis Assoc Disord (2002); 16(1): 24-30.
[] [PMID: 11882746]
Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO. Dimebon improves learning in animals with experimental Alzheimer’s disease. Bull Exp Biol Med (2000); 129(6): 544-6.
[] [PMID: 11022244]
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet 372(9634): 207-15. (2008)
[] [PMID: 18640457]
Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. From anti-allergic to anti-Alzheimer’s: molecular pharmacology of Dimebon. Curr Alzheimer Res (2010); 7(2): 97-112.
[] [PMID: 19939222]
Schmitz TW, Mur M, Aghourian M, Bedard M-A, Spreng RN. Londitudinal Alzheimer’s degeneration reflects the spatial topography of cholinergic basal forebrain projections. Cell Rep 24(1): 38-46. (2018)
[] [PMID: 29972789]
Clapham J, Kilpatrick GJ. Histamine H3 receptors modulate the release of [3H]-acetylcholine from slices of rat entorhinal cortex: evidence for the possible existence of H3 receptor subtypes. Br J Pharmacol 107(4): 919-23. (1992)
[] [PMID: 1334753]
Bitner RS, Markosyan S, Nikkel AL, Brioni JD. In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer’s disease. Neuropharmacology 60(2-3): 460-6. (2011)
[] [PMID: 21044639]
Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB, 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 cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 313(1): 176-90. (2005)
[] [PMID: 15608077]
Egan M, Yaari R, Liu L, Ryan M, Peng Y, Lines C, et al. Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res 9(4): 481-90. (2012)
[] [PMID: 22272611]
Patnaik R, Sharma A, Skaper SD, Muresanu DF, Lafuente JV, Castellani RJ, et al. Histamine H3 inverse agonist BF 2649 or antagonist with partial H4 agonist activity clobenpropit reduces amyloid beta peptide-induced brain pathology in Alzheimer’s disease. Mol Neurobiol 55(1): 312-21. (2018)
[] [PMID: 28861757]
Artigas F. Future directions for serotonin and antidepressants. ACS Chem Neurosci 4(1): 5-8. (2013)
[] [PMID: 23336036]
Gareri P, De Fazio P, De Sarro G, Dessaro G. Neuropharmacology of depression in aging and age-related diseases. Ageing Res Rev 1(1): 113-34. (2002)
[] [PMID: 12039452]
Gottfries CG. Disturbance of the 5-hydroxytryptamine metabolism in brains from patients with Alzheimer’s dementia. J Neural Transm Suppl 30: 33-43. (1990)
[] [PMID: 2202785]
Palmer AM, Wilcock GK, Esiri MM, Francis PT, Bowen DM. Monoaminergic innervation of the frontal and temporal lobes in Alzheimer’s disease. Brain Res 401(2): 231-8. (1987)
[] [PMID: 2434191]
Nazarali AJ, Reynolds GP. Monoamine neurotransmitters and their metabolites in brain regions in Alzheimer’s disease: a postmortem study. Cell Mol Neurobiol 12(6): 581-7. (1992)
[] [PMID: 1283363]
Sparks DL, Hunsaker JC III, Slevin JT, DeKosky ST, Kryscio RJ, Markesbery WR. Monoaminergic and cholinergic synaptic markers in the nucleus basalis of Meynert (nbM): normal age-related changes and the effect of heart disease and Alzheimer’s disease. Ann Neurol 31(6): 611-20. (1992)
[] [PMID: 1355334]
Garcia-Alloza M, Hirst WD, Chen CPL-H, Lasheras B, Francis PT, Ramírez MJ. Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer’s disease. Neuropsychopharmacology 29(2): 410-6. (2004)
[] [PMID: 14571255]
Chen CP, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, et al. Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlations with depression and neuroleptic medication. J Neurochem 66(4): 1592-8. (1996)
[] [PMID: 8627315]
Förstl H, Burns A, Levy R, Cairns N. Neuropathological correlates of psychotic phenomena in confirmed Alzheimer’s disease. Br J Psychiatry 165(1): 53-9. (1994)
[] [PMID: 7953058]
Chen CP, Eastwood SL, Hope T, McDonald B, Francis PT, Esiri MM. Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes. Neuropathol Appl Neurobiol 26(4): 347-55. (2000)
[] [PMID: 10931368]
Cheng AV, Ferrier IN, Morris CM, Jabeen S, Sahgal A, McKeith IG, et al. Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer’s and Parkinson’s diseases. J Neurol Sci 106(1): 50-5. (1991)
[] [PMID: 1779239]
Cross AJ. Serotonin in Alzheimer-type dementia and other dementing illnesses. Ann N Y Acad Sci 600(1): 405-15. (1990)
[] [PMID: 1701291]
Holmes C, Arranz MJ, Powell JF. Collier D a, Lovestone S. 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease. Hum Mol Genet 7(9): 1507-9. (1998)
[] [PMID: 9700207]
Lai MKP, Tsang SWY, Francis PT, Esiri MM, Keene J, Hope T, et al. Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res 974(1-2): 82-7. (2003)
[] [PMID: 12742626]
Lai MKP, Tsang SWY, Francis PT, Keene J, Hope T, Esiri MM, et al. Postmortem serotoninergic correlates of cognitive decline in Alzheimer’s disease. Neuroreport 13(9): 1175-8. (2002)
[] [PMID: 12151764]
Middlemiss DN, Palmer AM, Edel N, Bowen DM. Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain. J Neurochem 46(3): 993-6. (1986)
[] [PMID: 2419502]
Švob Štrac D, Pivac N, Mück-Šeler D. The serotonergic system and cognitive function. Transl Neurosci 7(1): 35-49. (2016)
[] [PMID: 28123820]
Buhot MC. Serotonin receptors in cognitive behaviors. Curr Opin Neurobiol 7(2): 243-54. (1997)
[] [PMID: 9142756]
Buhot MC, Martin S, Segu L. Role of serotonin in memory impairment. Ann Med 32(3): 210-21. (2000)
[] [PMID: 10821328]
Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM, et al. Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology (Berl) 179(3): 673-7. (2005)
[] [PMID: 15551121]
Giannoni P, Gaven F, de Bundel D, Baranger K, Marchetti-Gauthier E, Roman FS, et al. Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease. Front Aging Neurosci 5: 96. (2013)
[] [PMID: 24399967]
de Jong IEM, Mørk A. Antagonism of the 5-HT6 receptor - Preclinical rationale for the treatment of Alzheimer’s disease. Neuropharmacology 125: 50-63. (2017)
[] [PMID: 28711518]
Wicke K, Haupt A, Bespalov A. Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 24(12): 1515-28. (2015)
[] [PMID: 26548316]
Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol 13(8): 1021-33. (2010)
[] [PMID: 20569520]
Gravius A, Laszy J, Pietraszek M, Sághy K, Nagel J, Chambon C, et al. Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity. Behav Pharmacol 22(2): 122-35. (2011)
[] [PMID: 21301322]
Hatcher PD, Brown VJ, Tait DS, Bate S, Overend P, Hagan JJ, et al. 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology (Berl) 181(2): 253-9. (2005)
[] [PMID: 15846482]
Kendall I, Slotten HA, Codony X, Burgueño J, Pauwels PJ, Vela JM, et al. E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacology (Berl) 213(2-3): 413-30. (2011)
[] [PMID: 20405281]
King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KCF. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47(2): 195-204. (2004)
[] [PMID: 15223298]
Meneses A. Effects of the 5-HT(6) receptor antagonist Ro 04-6790 on learning consolidation. Behav Brain Res 118(1): 107-10. (2001)
[] [PMID: 11163639]
Perez-García G, Meneses A. Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task. Pharmacol Biochem Behav 81(3): 673-82. (2005)
[] [PMID: 15964617]
Rogers DC, Hagan JJ. 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology (Berl) 158(2): 114-9. (2001)
[] [PMID: 11702084]
Thur KE, Nelson AJD, Cassaday HJ. Ro 04-6790-induced cognitive enhancement: no effect in trace conditioning and novel object recognition procedures in adult male Wistar rats. Pharmacol Biochem Behav 127: 42-8. (2014)
[] [PMID: 25450117]
Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N, et al. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29(1): 93-100. (2004)
[] [PMID: 14571256]
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 38(8): 1083-152. (1999)
[] [PMID: 10462127]
Borroni B, Costanzi C, Padovani A. Genetic susceptibility to behavioural and psychological symptoms in Alzheimer disease. Curr Alzheimer Res 7(2): 158-64. (2010)
[] [PMID: 19715553]
Becker G, Streichenberger N, Billard T, Newman-Tancredi A, Zimmer L. A postmortem study to compare agonist and antagonist 5-HT1A receptor-binding sites in Alzheimer’s disease. CNS Neurosci Ther 20(10): 930-4. (2014)
[] [PMID: 25041947]
Preston AR, Eichenbaum H. Interplay of hippocampus and prefrontal cortex in memory. Curr Biol 23(17): R764-73. (2013)
[] [PMID: 24028960]
Madroñal N, Delgado-García JM, Fernández-Guizán A, Chatterjee J, Köhn M, Mattucci C, et al. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells. Nat Commun 7: 10923. (2016)
[] [PMID: 26988806]
Schechter LE, Smith DLS, Rosenzweig-Lipson S, Sukoff SJ, Dawson LA, Marquis K, et al. 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 314(3): 1274-89. (2005)
[] [PMID: 15951399]
Price DL, Bonhaus DW, McFarland K. Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease. Behav Pharmacol 23(4): 426-33. (2012)
[] [PMID: 22750845]
Baranger K, Giannoni P, Girard SD. Girot S1, Gaven F2, Stephan D, et al Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer’s disease. Neuropharmacology 126: 128-41. (2017)
[] [PMID: 28844596]
Freret T, Lelong-Boulouard V, Lecouflet P, Hamidouche K, Dauphin F, Boulouard M. Co-modulation of an allosteric modulator of nicotinic receptor-cholinesterase inhibitor (galantamine) and a 5-HT4 receptor agonist (RS-67333): effect on scopolamine-induced memory deficit in the mouse. Psychopharmacology (Berl) 234(15): 2365-74. (2017)
[] [PMID: 28631100]
Shacham S, Milgram B, Araujo J, Ragazzino M, Mohler E, Marantz Y, et al. PRX-03140: a novel 5-HT4 partial agonist with a dual cholinergic/disease-modifying mechanism for the treatment of Alzheimer disease. Alzheimers Dement 2(3): S62. (2006)
Minabe Y, Shirayama Y, Hashimoto K, Routledge C, Hagan JJ, Ashby CR Jr. Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse 52(1): 20-8. (2004)
[] [PMID: 14755629]
Amat-Foraster M, Leiser SC, Herrik KF, Richard N, Agerskov C, Bundgaard C, et al. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleepwake architecture. Neuropharmacology 113(Pt A): 45-59 (2017).
Herrik KF, Mørk A, Richard N, Bundgaard C, Bastlund JF, de Jong IEM. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology 107: 351-63. (2016)
[] [PMID: 27039041]
Patat A, Parks V, Raje S, Plotka A, Chassard D, Le Coz F. Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects. Br J Clin Pharmacol 67(3): 299-308. (2009)
[] [PMID: 19523013]
Pfizer. Study evaluating lecozotan sr in mild to moderate Alzheimer’s disease (AD) (2013). Available from.
Pfizer. Study evaluating the safety, tolerability, and efficacy of lecozotan SR in outpatients with Alzheimer’s disease (2013). Available from:
Raje S, Patat AA, Parks V, Schechter L, Plotka A, Paul J, et al. A positron emission tomography study to assess binding of lecozotan, a novel 5-hydroxytryptamine-1A silent antagonist, to brain 5-HT1A receptors in healthy young and elderly subjects, and in patients with Alzheimer’s disease. Clin Pharmacol Ther 83(1): 86-96. (2008)
[] [PMID: 17507923]
Epix pharmaceuticals. short term effects of PRX-03140 in patients with mild Alzheimer’s disease being treated with aricept (2008). Available from:
Megerian JT, Shacham S, Kalafer M, and Uprichard A. Results of a phase 2A study of a novel 5HT4 agonist for the treatment of Alzheimer’s disease (2008). Available from _073008.pdf
Epix Pharmaceuticals. A study of PRX-03140 in subjects with Alzheimer’s disease receiving a stable dose of donepezil (2009) Available from
Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, et al. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry 26(5): 536-44. (2011)
[] [PMID: 20872778]
Wilkinson D, Windfeld K, Colding-Jørgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 13(11): 1092-9. (2014)
[] [PMID: 25297016]
Atri A, Frölich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with alzheimer disease: three randomized clinical trials. JAMA 319(2): 130-42. (2018)
[] [PMID: 29318278]
Ballard C, Banister C, Khan Z, Cummings J. Demos GCoate B, et al Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 17(3): 213-22. (2018)
[] [PMID: 29452684]
Blier P, Piñeyro G, el Mansari M, Bergeron R, de Montigny C. Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Ann N Y Acad Sci 861: 204-16. (1998)
[] [PMID: 9928258]
Yamauchi M, Miyara T, Matsushima T, Imanishi T. Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors. Brain Res 1067(1): 164-9. (2006)
[] [PMID: 16360124]
Choe YM, Kim KW, Jhoo JH, Ryu SH, Seo EH, Sohn BK, et al. Multicenter, randomized, placebo-controlled, double-blind clinical trial of escitalopram on the progression-delaying effects in Alzheimer’s disease. Int J Geriatr Psychiatry 31(7): 731-9. (2016)
[] [PMID: 26553313]
Viscogliosi G, Chiriac IM, Ettorre E. Efficacy and safety of citalopram compared to atypical antipsychotics on agitation in nursing home residents with Alzheimer dementia. J Am Med Dir Assoc 18(9): 799-802. (2017)
[] [PMID: 28739492]
Johns Hopkins University. Venlafaxine for depression in Alzheimer’s disease (DIADs-3) (2018). Available from:.
Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, et al. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol 173(18): 2702-25. (2016)
[] [PMID: 27314810]
Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden L, Pablos MI, Tan DX. Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radio immunoassay evidence. J Cell Biochem 53(4): 373-82. (1993)
[] [PMID: 8300754]
Menendez-Pelaez A, Reiter RJ. Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 15(2): 59-69. (1993)
[] [PMID: 8283386]
Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C, et al. Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52(2): 217-27. (2012)
[] [PMID: 21884551]
Payne JK. The trajectory of biomarkers in symptom management for older adults with cancer. Semin Oncol Nurs 22(1): 31-5. (2006)
[] [PMID: 16458180]
Karasek M, Reiter RJ. Melatonin and aging. Neuroendocrinol Lett 23(Suppl. 1): 14-6. (2002)
[PMID: 12019345]
Sharma M, Palacios-Bois J, Schwartz G, Iskandar H, Thakur M, Quirion R, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 25(3): 305-19. (1989)
[] [PMID: 2914154]
Mahlberg R, Tilmann A, Salewski L, Kunz D. Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84. Psychoneuroendocrinology 31(5): 634-41. (2006)
[] [PMID: 16584848]
Reiter RJ, Tan DX, Galano A. Melatonin: exceeding expectations. Physiology (Bethesda) (2014); 29(5): 325-33.
[] [PMID: 25180262]
Clement N, Renault N, Guillaume JL, Cecon E, Journé AS, Laurent X, et al. Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50. Br J Pharmacol 175(16): 3281-97. (2018)
Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 175(16): 3263-80. (2018)
Owino S, Buonfiglio DDC, Tchio C, Tosini G. Melatonin signaling a key regulator of glucose homeostasis and energy metabolism. Front Endocrinol (Lausanne) 10: 488. (2019)
Wiesenberg I, Missbach M, Carlberg C. The potential role of the transcription factor RZR/ROR as a mediator of nuclear melatonin signaling. Restor Neurol Neurosci 12(2-3): 143-50. (1998)
Reiter RJ. Melatonin: lowering the high price of free radicals. News Physiol Sci 15: 246-50. (2000)
[] [PMID: 11390919]
Boafo A, Greenham S, Alenezi S, Robillard R, Pajer K, Tavakoli P, et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep 11: 1-10. (2019)
Ramos E, Egea J, de Los Ríos C, Marco-Contelles J, Romero A. Melatonin as a versatile molecule to design novel multitarget hybrids against neurodegeneration. Future Med Chem 9(8): 765-80. (2017)
[] [PMID: 28498717]
Hardeland R. Melatonin in aging and disease -multiple consequences of reduced secretion, options and limits of treatment. Aging Dis 3(2): 194-225. (2012)
[PMID: 22724080]
Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 54(10): 1299-321. (2002)
[] [PMID: 12396291]
Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD, et al. Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26(5): 497-502. (1995)
[] [PMID: 7492947]
Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36(1): 1-9. (2004)
[] [PMID: 14675124]
Andersen LP, Werner MU, Rosenkilde MM, Harpsøe NG, Fuglsang H, Rosenberg J, et al. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacol Toxicol 17: 8. (2016)
Gupta YK, Gupta M, Kohli K. Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol 47(4): 373-86. (2003)
[PMID: 15266948]
Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res 54(2): 127-38. (2013)
[] [PMID: 23137057]
Reiter RJ. The pineal gland and melatonin in relation to aging: a summary of the theories and of the data. Exp Gerontol 30(3-4): 199-212. (1995)
[] [PMID: 7556503]
Reiter RJ, Tan DX, Poeggeler B, Menendez-Pelaez A, Chen LD, Saarela S. Melatonin as a free radical scavenger: implications for aging and age-related diseases. Ann N Y Acad Sci 719: 1-12. (1994)
[] [PMID: 8010585]
Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35(2): 125-30. (2003)
[] [PMID: 12887656]
Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velázquez M, Martínez-Barboza G, Acosta-Martínez JP, et al. Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. J Pineal Res 35(2): 80-4. (2003)
[] [PMID: 12887649]
Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, et al. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70(5): 2212-5. (1998)
[] [PMID: 9572310]
Legros C, Chesneau D, Boutin JA, Barc C, Malpaux B. Melatonin from cerebrospinal fluid but not from blood reaches sheep cerebral tissues under physiological conditions. J Neuroendocrinol 26(3): 151-63. (2014)
[] [PMID: 24460899]
Reiter RJ, Tan DX, Kim SJ, Cruz MH. Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces. Brain Struct Funct 219(6): 1873-87. (2014)
[] [PMID: 24553808]
Wu YH, Feenstra MG, Zhou JN, Liu RY, Toranõ JS, Van Kan HJ, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 88(12): 5898-906. (2003)
[] [PMID: 14671188]
Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 38(3): 145-52. (2005)
[] [PMID: 15725334]
Wu YH, Swaab DF. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Med 8(6): 623-36. (2007)
Cardinali DP. Melatonin: clinical perspectives in neurodegeneration. Front Endocrinol (Lausanne) 10: 480. (2019)
Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, et al. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol 35(9-10): 1239-50. (2000)
[] [PMID: 11113605]
Ohashi Y, Okamoto N, Uchida K, Iyo M, Mori N, Morita Y. Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer’s type. Biol Psychiatry 45(12): 1646-52. (1999)
[] [PMID: 10376127]
Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 84(1): 323-7. (1999)
[PMID: 9920102]
Janssens J, Atmosoerodjo SD, Vermeiren Y, Absalom AR, den Daas I, De Deyn PP. Sampling issues of cerebrospinal fluid and plasma monoamines: Investigation of the circadian rhythm and rostrocaudal concentration gradient. Neurochem Int 128: 154-62. (2019)
Friedland RP, Luxenberg JS, Koss E. A quantitative study of intracranial calcification in dementia of the Alzheimer type. Int Psychogeriatr 2(1): 36-43. (1990)
[] [PMID: 2101296]
Wu YH, Fischer DF, Swaab DF. A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer’s disease patients. Brain Res 1167: 13-9. (2007)
[] [PMID: 17692293]
Cohen-Mansfield J, Garfinkel D, Lipson S. Melatonin for treatment of sundowning in elderly persons with dementia - a preliminary study. Arch Gerontol Geriatr (2000); 31(1): 65-76.
[] [PMID: 10989165]
Brusco LI, Márquez M, Cardinali DP. Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuroendocrinol Lett 21(1): 39-42. (2000)
[PMID: 11455329]
Brusco LI, Márquez M, Cardinali DP. Monozygotic twins with Alzheimer’s disease treated with melatonin: Case report. J Pineal Res 25(4): 260-3. (1998)
[] [PMID: 9885996]
Cardinali DP, Brusco LI, Pérez Lloret S, Furio AM. Melatonin in sleep disorders and jet-lag. Neuroendocrinol Lett 23(1): 9-13. (2002)
[PMID: 12019344]
Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer’s disease. Neuroendocrinol Lett 23(1): 20-3. (2002)
[PMID: 12019347]
Karasek M, Reiter RJ, Cardinali DP, Pawlikowski M. Future of melatonin as a therapeutic agent. Neuroendocrinol Lett 23(1): 118-21. (2002)
[PMID: 12019364]
Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 26(7): 893-901. (2003)
[] [PMID: 14655926]
Ling ZQ, Tian Q, Wang L, Fu ZQ, Wang XC, Wang Q, et al. Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. J Alzheimers Dis 16(2): 287-300. (2009)
[] [PMID: 19221418]
Avila J, Pérez M, Lucas JJ, Gómez-Ramos A, Santa María I, Moreno F, et al. Assembly in vitro of tau protein and its implications in Alzheimer’s disease. Curr Alzheimer Res 1(2): 97-101. (2004)
[] [PMID: 15975073]
Sahara N, DeTure M, Ren Y, Ebrahim AS, Kang D, Knight J, et al. Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain. J Alzheimers Dis 33(1): 249-63. (2013)
[] [PMID: 22941973]
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18(2): 291-5. (2012)
[] [PMID: 22286308]
Khatoon S, Grundke-Iqbal I, Iqbal K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer’s disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem 59(2): 750-3. (1992)
[] [PMID: 1629745]
Khatoon S, Grundke-Iqbal I, Iqbal K. Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett 351(1): 80-4. (1994)
[] [PMID: 8076698]
Deng YQ, Xu GG, Duan P, Zhang Q, Wang JZ. Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin 26(5): 519-26. (2005)
[] [PMID: 15842767]
Li XC, Wang ZF, Zhang JX, Wang Q, Wang JZ. Effect of melatonin on calyculin A-induced tau hyperphosphorylation. Eur J Pharmacol 510(1-2): 25-30. (2005)
[] [PMID: 15740721]
Li SP, Deng YQ, Wang XC, Wang YP, Wang JZ. Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. J Pineal Res 36(3): 186-91. (2004)
[] [PMID: 15009509]
Yang X, Yang Y, Fu Z, Li Y, Feng J, Luo J, Zhang Q, et al. Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol (Oxford) 25(8): 1118-25 (2011).
[] [PMID: 20542922]
Wang YP, Li XT, Liu SJ, Zhou XW, Wang XC, Wang JZ. Melatonin ameliorated okadaic-acid induced Alzheimer-like lesions. Acta Pharmacol Sin 25(3): 276-80. (2004)
[PMID: 15000877]
Liu SJ, Wang JZ. Alzheimer-like tau phosphorylation induced by wortmannin in vivo and its attenuation by melatonin. Acta Pharmacol Sin 23(2): 183-7. (2002)
[PMID: 11866882]
Wang DL, Ling ZQ, Cao FY, Zhu LQ, Wang JZ. Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain. J Pineal Res 37(1): 11-6. (2004)
[] [PMID: 15230863]
Wang XC, Zhang J, Yu X, Han L, Zhou ZT, Zhang Y, et al. Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat. Sheng Li Xue Bao (2005); 57(1): 7-12.
[PMID: 15719129]
Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett 476(1-2): 89-92. (2000)
[] [PMID: 10878257]
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm (Vienna) 112(6): 813-38. (2005)
[] [PMID: 15517432]
Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S. Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci 939: 200-15. (2001)
[] [PMID: 11462772]
Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48(4): 297-310. (2010)
[] [PMID: 20433638]
Romero A, Egea J, García AG, López MG. Synergistic neuroprotective effect of combined low concentrations of galantamine and melatonin against oxidative stress in SH-SY5Y neuroblastoma cells. J Pineal Res 49(2): 141-8. (2010)
[] [PMID: 20536682]
Hardeland R, Tan DX, Reiter RJ. Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res 47(2): 109-26. (2009)
[] [PMID: 19573038]
Jou MJ, Peng TI, Hsu LF, Jou SB, Reiter RJ, Yang CM, et al. Visualization of melatonin’s multiple mitochondrial levels of protection against mitochondrial Ca(2+)-mediated permeability transition and beyond in rat brain astrocytes. J Pineal Res 48(1): 20-38. (2010)
[] [PMID: 19925580]
Hong Y, Palaksha KJ, Park K, Park S, Kim HD, Reiter RJ, et al. Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury. J Pineal Res 49(3): 201-9. (2010)
[] [PMID: 20626592]
Das A, McDowell M, Pava MJ, Smith JA, Reiter RJ, Woodward JJ, et al. The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors. J Pineal Res 48(2): 157-69. (2010)
[] [PMID: 20082663]
Lahiri DK. Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types. J Pineal Res 26(3): 137-46. (1999)
[] [PMID: 10231726]
Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, et al. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85(5): 1101-8. (2003)
[] [PMID: 12753069]
Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH. Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 36(4): 224-31. (2004)
[] [PMID: 15066046]
Song W, Lahiri DK. Melatonin alters the metabolism of the beta-amyloid precursor protein in the neuroendocrine cell line PC12. J Mol Neurosci (1997); 9(2): 75-92.
[] [PMID: 9407389]
Zhang YC, Wang ZF, Wang Q, Wang YP, Wang JZ. Melatonin attenuates beta-amyloid-induced inhibition of neurofilament expression. Acta Pharmacol Sin 25(4): 447-51. (2004)
[] [PMID: 15066211]
Olivieri G, Hess C, Savaskan E. Ly C, Meier F, Baysang G, Brockhaus M, et al. Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 31(4): 320-5. (2001)
[] [PMID: 11703561]
Skribanek Z, Baláspiri L, Mák M. Interaction between synthetic amyloid-beta-peptide (1-40) and its aggregation inhibitors studied by electrospray ionization mass spectrometry. J Mass Spectrom 36(11): 1226-9. (2001)
[] [PMID: 11747119]
Feng Z, Chang Y, Cheng Y, Zhang BL, Qu ZW, Qin C, et al. Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer’s disease. J Pineal Res 37(2): 129-36. (2004)
[] [PMID: 15298672]
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326(5955): 1005-7. (2009)
[] [PMID: 19779148]
Chung SY, Han SH. Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition. J Pineal Res 34(2): 95-102. (2003)
[] [PMID: 12562500]
Carocci A, Catalano A, Sinicropi MS. Melatonergic drugs in development. Clin Pharmacol 6: 127-37. (2014)
[] [PMID: 25258560]
Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 48(2): 301-10. (2005)
[] [PMID: 15695169]
Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther 15(1): 32-51. (2009)
[] [PMID: 19228178]
Tabeeva GR, Sergeev AV, Gromova SA. Possibilities of preventive treatment of migraine with the MT1- and MT2 agonist and 5-HT2c receptor antagonist agomelatin (valdoxan). Zh Nevrol Psikhiatr Im S S Korsakova 111(9): 32-6. (2011)
[PMID: 22027667]
Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet 373(9662): 482-91. (2009)
[] [PMID: 19054552]
Hardeland R. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. Curr Opin Investig Drugs 10(7): 691-701. (2009)
[PMID: 19579175]
Hardeland R, Poeggeler B. Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system. Cent Nerv Syst Agents Med Chem 12(3): 189-216. (2012)
[] [PMID: 22640220]
Rivara S, Mor M, Bedini A, Spadoni G, Tarzia G. Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders. Curr Top Med Chem (2008); 8(11): 954-68.
[] [PMID: 18673165]
Landolt HP, Wehrle R. Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood? Eur J Neurosci 29(9): 1795-809. (2009)
[] [PMID: 19473234]
Chojnacki JE, Liu K, Yan X, Toldo S, Selden T, Estrada M, et al. Discovery of 5-(4-hydroxyphenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide as a neuroprotectant for Alzheimer’s disease by hybridization of curcumin and melatonin. ACS Chem Neurosci 5(8): 690-9. (2014)
[] [PMID: 24825313]
Gerenu G, Liu K, Chojnacki JE, Saathoff JM, Martínez-Martín P, Perry G, et al. Curcumin/melatonin hybrid 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide ameliorates AD-like pathology in the APP/PS1 mouse model. ACS Chem Neurosci 6(8): 1393-9. (2015)
[] [PMID: 25893520]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy