Alzheimer’s Disease: A Contextual Link with Nitric Oxide Synthase | Bentham Science
Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Alzheimer’s Disease: A Contextual Link with Nitric Oxide Synthase

Author(s): Harikesh Dubey, Kavita Gulati and Arunabha Ray*

Volume 20, Issue 7, 2020

Page: [505 - 515] Pages: 11

DOI: 10.2174/1566524019666191129103117

Price: $65

Open Access Journals Promotions 2
Abstract

Nitric oxide (NO) is a gasotransmitter with pleiotropic effects which has made a great impact on biology and medicine. A multidimensional neuromodulatory role of NO has been shown in the brain with specific reference to neurodegenerative disorders like Alzheimer’s disease (AD) and cognitive dysfunction. It has been found that NO/cGMP signalling pathway has an important role in learning and memory. Initially, it was considered that indirectly NO exerted neurotoxicity in AD via glutamatergic excitotoxicity. However, considering the early development of cognitive functions involved in the learning memory process including long term potentiation and synaptic plasticity, NO has a crucial role. Increasing evidence uncovered the above facts that isoforms of NOS viz endothelial NO synthase (eNOS), neuronal NO synthase (nNOS) and inducible NO synthase (iNOS) having a variable expression in AD are mainly responsible for learning and memory activities. In this review, we focus on the role of NOS isoforms in AD parallel to NO. Further, this review provides convergent evidence that NO could provide a therapeutic avenue in AD via modulation of the relevant NOS expression.

Keywords: Alzheimer's disease, nitric oxide, cGMP, excitotoxicity, NOS, gasotransmitter.

Next »
[1]
Khazan M, Hdayati M. The role of nitric oxide in health and diseases. Scimetr 2015; 3(1)e20987
[2]
Gulati K, Joshi JC, Ray A. Recent advances in stress research: Focus on nitric oxide. Eur J Pharmacol 2015; 765: 406-14.
[http://dx.doi.org/10.1016/j.ejphar.2015.08.055] [PMID: 26341014]
[3]
Bruhwyler J, Chleide E, Liégeois JF, Carreer F. Nitric oxide: a new messenger in the brain. Neurosci Biobehav Rev 1993; 17(4): 373-84.
[http://dx.doi.org/10.1016/S0149-7634(05)80114-9] [PMID: 7906024]
[4]
Esplugues JV. NO as a signalling molecule in the nervous system. Br J Pharmacol 2002; 135(5): 1079-95.
[http://dx.doi.org/10.1038/sj.bjp.0704569] [PMID: 11877313]
[5]
Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 2015; 9: 322.
[http://dx.doi.org/10.3389/fncel.2015.00322] [PMID: 26347610]
[6]
Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 1999; 31(6): 577-96.
[http://dx.doi.org/10.1080/10715769900301161] [PMID: 10630682]
[7]
Zhang J, Snyder SH. Nitric oxide in the nervous system. Annu Rev Pharmacol Toxicol 1995; 35(1): 213-33.
[http://dx.doi.org/10.1146/annurev.pa.35.040195.001241] [PMID: 7598492]
[8]
Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007; 8(10): 766-75.
[http://dx.doi.org/10.1038/nrn2214] [PMID: 17882254]
[9]
Krumenacker JS, Hanafy KA, Murad F. Regulation of nitric oxide and soluble guanylyl cyclase. Brain Res Bull 2004; 62(6): 505-15.
[http://dx.doi.org/10.1016/S0361-9230(03)00102-3] [PMID: 15036565]
[10]
Guix FX, Uribesalgo I, Coma M, Muñoz FJ. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005; 76(2): 126-52.
[http://dx.doi.org/10.1016/j.pneurobio.2005.06.001] [PMID: 16115721]
[11]
Joca SR, Guimarães FS, Del-Bel E. Inhibition of nitric oxide synthase increases synaptophysin mRNA expression in the hippocampal formation of rats. Neurosci Lett 2007; 421(1): 72-6.
[http://dx.doi.org/10.1016/j.neulet.2007.05.026] [PMID: 17548163]
[12]
Joca SRL, Sartim AG, Roncalho AL, Diniz CFA, Wegener G. Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res 2019; 377(1): 45-58.
[http://dx.doi.org/10.1007/s00441-018-02987-4] [PMID: 30649612]
[13]
Nakane M. Soluble guanylyl cyclase: physiological role as an NO receptor and the potential molecular target for therapeutic application. Clin Chem Lab Med 2003; 41(7): 865-70.
[http://dx.doi.org/10.1515/CCLM.2003.131] [PMID: 12940510]
[14]
He J, Wang T, Wang P, Han P, Yin Q, Chen C. A novel mechanism underlying the susceptibility of neuronal cells to nitric oxide: the occurrence and regulation of protein S-nitrosylation is the checkpoint. J Neurochem 2007; 102(6): 1863-74.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04651.x] [PMID: 17767703]
[15]
Tutka P, Klonowski P, Dzieciuch J, Kleinrok Z, Czuczwar SJ. NG-nitro-L-arginine differentially affects glutamate- or kainate-induced seizures. Neuroreport 1996; 7(10): 1605-8.
[http://dx.doi.org/10.1097/00001756-199607080-00015] [PMID: 8904765]
[16]
Urbańska EM, Drelewska E, Borowicz KK, Błaszczak P, Kleinrok Z, Czuczwar SJ. NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice. J Neural Transm (Vienna) 1996; 103(10): 1145-52.
[http://dx.doi.org/10.1007/BF01271199] [PMID: 9013401]
[17]
Gulati K, Ray A, Pal G, Vijayan VK. Possible role of free radicals in theophylline-induced seizures in mice. Pharmacol Biochem Behav 2005; 82(1): 241-5.
[http://dx.doi.org/10.1016/j.pbb.2005.06.019] [PMID: 16185759]
[18]
Ray A, Gulati K, Anand S, Vijayan VK. Pharmacological studies on mechanisms of aminophylline-induced seizures in rats. Indian J Exp Biol 2005; 43(10): 849-53.
[PMID: 16235715]
[19]
Gulati K, Ray A. Differential neuromodulatory role of NO in anxiety and seizures: an experimental study. Nitric Oxide 2014; 43: 55-61.
[http://dx.doi.org/10.1016/j.niox.2014.08.008] [PMID: 25152447]
[20]
Chanrion B, Mannoury la Cour C, Bertaso F, et al. Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci USA 2007; 104(19): 8119-24.
[http://dx.doi.org/10.1073/pnas.0610964104] [PMID: 17452640]
[21]
Anand R, Gulati K, Ray A. Pharmacological evidence for the role of nitric oxide in the modulation of stress-induced anxiety by morphine in rats. Eur J Pharmacol 2012; 676(1-3): 71-4.
[http://dx.doi.org/10.1016/j.ejphar.2011.11.032] [PMID: 22142992]
[22]
Chakraborti A, Gulati K, Ray A. Involvement of nitric oxide in the protective effects of dehydroepiandrosterone sulphate on stress induced neurobehavioral suppression and brain oxidative injury in rats. Eur J Pharmacol 2011; 652(1-3): 55-9.
[http://dx.doi.org/10.1016/j.ejphar.2010.11.002] [PMID: 21114993]
[23]
Chakraborti A, Gulati K, Ray A. Possible role of nitric oxide (NO) in the regulation of gender related differences in stress induced anxiogenesis in rats. Nitric Oxide 2014; 43: 74-80.
[http://dx.doi.org/10.1016/j.niox.2014.08.005] [PMID: 25175896]
[24]
Joshi JC, Ray A, Gulati K. Effects of morphine on stress induced anxiety in rats: role of nitric oxide and Hsp70. Physiol Behav 2015; 139: 393-6.
[http://dx.doi.org/10.1016/j.physbeh.2014.11.056] [PMID: 25460538]
[25]
Bulatov E, Khaiboullina S. Ubiquitin-Proteasome System: Promising Therapeutic Targets in Autoimmune and Neurodegenerative Diseases. Bionanoscience 2016; 6(4): 341-4.
[http://dx.doi.org/10.1007/s12668-016-0233-x]
[26]
Salari S, Bagher M. A review of animal models of Alzheimer’s disease: a brief insight into pharmacologic and genetic models. Physiol Pharmacol 2016; 20: 5-11.
[27]
Kumar A, Aggarwal A, Singh A. Pattipati Sreenivaslu Naidu. Animal models in drug discovery of Alzheimer’s disease: A mini review. ECPT 2016; 2(1): 60-79.
[28]
Neha Sodhi RK, Jaggi AS, et al. Animal models of dementia and cognitive dysfunction. Life Sci 2014; 109(2): 73-86.
[29]
Carolindah MN, Rosli R, Adam A, et al. An overview of in vitro research models for Alzheimer’s disease (AD). Regenerative Res 2013; 2(2): 8-13.
[30]
Law A, Gauthier S, Quirion R. Say NO to Alzheimer’s disease: the putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Res Brain Res Rev 2001; 35(1): 73-96.
[http://dx.doi.org/10.1016/S0165-0173(00)00051-5] [PMID: 11245887]
[31]
Dubey H, Gulati K, Ray A. Effects of Nitric Oxide (NO) Modulators on cognitive function and brain oxidative stress in experimental model of Alzheimer’s disease in rats. J Pharmacol Rep 2017; 2: 126.
[32]
Dubey H, Gulati K, Ray A. Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer’s disease in rats. Neurotoxicology 2018; 66: 58-65.
[http://dx.doi.org/10.1016/j.neuro.2018.03.001] [PMID: 29522778]
[33]
Thatcher GR, Bennett BM, Reynolds JN. Nitric oxide mimetic molecules as therapeutic agents in Alzheimer’s disease. Curr Alzheimer Res 2005; 2(2): 171-82.
[http://dx.doi.org/10.2174/1567205053585945] [PMID: 15974915]
[34]
Hu Y, Zhu DY. Hippocampus and nitric oxide. Vitam Horm 2014; 96: 127-60.
[http://dx.doi.org/10.1016/B978-0-12-800254-4.00006-4] [PMID: 25189386]
[35]
Dubey H, Gulati K, Ray A. Recent studies on cellular and molecular mechanisms in Alzheimer’s disease: focus on epigenetic factors and histone deacetylase. Rev Neurosci 2018; 29(3): 241-60. a
[http://dx.doi.org/10.1515/revneuro-2017-0049] [PMID: 29397389]
[36]
Nott A, Watson PM, Robinson JD, Crepaldi L, Riccio A. S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 2008; 455(7211): 411-5.
[http://dx.doi.org/10.1038/nature07238] [PMID: 18754010]
[37]
Yamada K, Noda Y, Hasegawa T, et al. The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice. J Pharmacol Exp Ther 1996; 276(2): 460-6.
[PMID: 8632310]
[38]
Lee JM, Zipfel GJ, Choi DW. The changing landscape of ischaemic brain injury mechanisms. Nature 1999; 399(6738)(Suppl.): A7-A14.
[http://dx.doi.org/10.1038/399a007] [PMID: 10392575]
[39]
Malinski T. Nitric oxide and nitroxidative stress in Alzheimer’s disease. J Alzheimers Dis 2007; 11(2): 207-18.
[http://dx.doi.org/10.3233/JAD-2007-11208] [PMID: 17522445]
[40]
Asiimwe N, Yeo SG, Kim MS, et al. Nitric Oxide: Exploring the contextual link with Alzheimer’s disease. Oxid Med Cell Longev 2016; 1-10.
[41]
Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron 1991; 6(4): 487-98.
[http://dx.doi.org/10.1016/0896-6273(91)90052-2] [PMID: 1673054]
[42]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256(5054): 184-5.
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
[43]
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular drainage of amyloid-β peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 2008; 18(2): 253-66.
[http://dx.doi.org/10.1111/j.1750-3639.2008.00133.x] [PMID: 18363936]
[44]
Jung SM, Jandu S, Steppan J, et al. Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice. Am J Physiol Heart Circ Physiol 2013; 305(6): H803-10.
[http://dx.doi.org/10.1152/ajpheart.00103.2013] [PMID: 23873798]
[45]
Sagare AP, Bell RD, Zlokovic BV. Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2(10): 1-18.
[http://dx.doi.org/10.1101/cshperspect.a011452] [PMID: 23028132]
[46]
Jeynes B, Provias J. Significant negative correlations between capillary expressed eNOS and Alzheimer lesion burden. Neurosci Lett 2009; 463(3): 244-8.
[http://dx.doi.org/10.1016/j.neulet.2009.07.091] [PMID: 19660523]
[47]
Austin SA, Katusic ZS. Partial loss of endothelial nitric oxide leads to increased cerebrovascular beta amyloid. J Cereb Blood Flow Metab 2019.X18822474
[http://dx.doi.org/10.1177/0271678X18822474] [PMID: 30614363]
[48]
Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 1984; 225(4667): 1168-70.
[http://dx.doi.org/10.1126/science.6474172] [PMID: 6474172]
[49]
Haul S, Gödecke A, Schrader J, Haas HL, Luhmann HJ. Impairment of neocortical long-term potentiation in mice deficient of endothelial nitric oxide synthase. J Neurophysiol 1999; 81(2): 494-7.
[http://dx.doi.org/10.1152/jn.1999.81.2.494] [PMID: 10036253]
[50]
Doreulee N, Sergeeva OA, Yanovsky Y, et al. Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice. Brain Res 2003; 964(1): 159-63.
[http://dx.doi.org/10.1016/S0006-8993(02)04121-5] [PMID: 12573525]
[51]
Hopper RA, Garthwaite J. Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J Neurosci 2006; 26(45): 11513-21.
[http://dx.doi.org/10.1523/JNEUROSCI.2259-06.2006] [PMID: 17093072]
[52]
Faraco G, Iadecola C. Hypertension: a harbinger of stroke and dementia. Hypertension 2013; 62(5): 810-7.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01063] [PMID: 23980072]
[53]
Austin SA, Santhanam AV, Hinton DJ, Choi DS, Katusic ZS. Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J Neurochem 2013; 127(5): 691-700. a
[http://dx.doi.org/10.1111/jnc.12334] [PMID: 23745722]
[54]
Austin SA, Santhanam AV, Katusic ZS. Endothelial nitric oxide modulates expression and processing of amyloid precursor protein. Circ Res 2010; 107(12): 1498-502.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.233080] [PMID: 21127294]
[55]
Austin SA, d’Uscio LV, Katusic ZS. Supplementation of nitric oxide attenuates AβPP and BACE1 protein in cerebral microcirculation of eNOS-deficient mice. J Alzheimers Dis 2013; 33(1): 29-33. b
[http://dx.doi.org/10.3233/JAD-2012-121351] [PMID: 22886025]
[56]
Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 2014; 35(14): 888-94.
[http://dx.doi.org/10.1093/eurheartj/eht544] [PMID: 24357508]
[57]
Chen J, Zacharek A, Zhang C, et al. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 2005; 25(9): 2366-75.
[http://dx.doi.org/10.1523/JNEUROSCI.5071-04.2005] [PMID: 15745963]
[58]
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288(5789): 373-6.
[http://dx.doi.org/10.1038/288373a0] [PMID: 6253831]
[59]
Dimmeler S, Zeiher AM. Nitric oxide and apoptosis: another paradigm for the double-edged role of nitric oxide. Nitric Oxide 1997; 1(4): 275-81.
[http://dx.doi.org/10.1006/niox.1997.0133] [PMID: 9441899]
[60]
Vodovotz Y, Lucia MS, Flanders KC, et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med 1996; 184(4): 1425-33.
[http://dx.doi.org/10.1084/jem.184.4.1425] [PMID: 8879214]
[61]
Nathan C, Calingasan N, Nezezon J, et al. Protection from Alzheimer’s-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J Exp Med 2005; 202(9): 1163-9.
[http://dx.doi.org/10.1084/jem.20051529] [PMID: 16260491]
[62]
Kummer MP, Hermes M, Delekarte A, et al. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 2011; 71(5): 833-44.
[http://dx.doi.org/10.1016/j.neuron.2011.07.001] [PMID: 21903077]
[63]
Jiang Q, Lee CYD, Mandrekar S, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron 2008; 58(5): 681-93.
[http://dx.doi.org/10.1016/j.neuron.2008.04.010] [PMID: 18549781]
[64]
Zoubovsky SP, Pogorelov VM, Taniguchi Y, et al. Working memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function. Biochem Biophys Res Commun 2011; 408(4): 707-12.
[http://dx.doi.org/10.1016/j.bbrc.2011.04.097] [PMID: 21539806]
[65]
Yildiz Akar F, Ulak G, Tanyeri P, Erden F, Utkan T, Gacar N. 7-Nitroindazole, a neuronal nitric oxide synthase inhibitor, impairs passive-avoidance and elevated plus-maze memory performance in rats. Pharmacol Biochem Behav 2007; 87(4): 434-43.
[http://dx.doi.org/10.1016/j.pbb.2007.05.019] [PMID: 17602730]
[66]
Fuentealba P, Begum R, Capogna M, et al. Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 2008; 57(6): 917-29.
[http://dx.doi.org/10.1016/j.neuron.2008.01.034] [PMID: 18367092]
[67]
Gotti S, Sica M, Viglietti-Panzica C, Panzica G. Distribution of nitric oxide synthase immunoreactivity in the mouse brain. Microsc Res Tech 2005; 68(1): 13-35.
[http://dx.doi.org/10.1002/jemt.20219] [PMID: 16208717]
[68]
O’Dell TJ, Hawkins RD, Kandel ER, Arancio O. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA 1991; 88(24): 11285-9.
[http://dx.doi.org/10.1073/pnas.88.24.11285] [PMID: 1684863]
[69]
Selvakumar B, Huganir RL, Snyder SH. S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors. Proc Natl Acad Sci USA 2009; 106(38): 16440-5.
[http://dx.doi.org/10.1073/pnas.0908949106] [PMID: 19805317]
[70]
Selvakumar B, Jenkins MA, Hussain NK, Huganir RL, Traynelis SF, Snyder SH. S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis. Proc Natl Acad Sci USA 2013; 110(3): 1077-82.
[http://dx.doi.org/10.1073/pnas.1221295110] [PMID: 23277581]
[71]
Walton JC, Selvakumar B, Weil ZM, Snyder SH, Nelson RJ. Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice. Behav Brain Res 2013; 256: 320-7.
[http://dx.doi.org/10.1016/j.bbr.2013.08.003] [PMID: 23948215]
[72]
Jessberger S, Aigner S, Clemenson GD Jr, et al. Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol 2008; 6(11)e272
[http://dx.doi.org/10.1371/journal.pbio.0060272] [PMID: 18998770]
[73]
Jessberger S, Gage FH, Eisch AJ, Lagace DC. Making a neuron: Cdk5 in embryonic and adult neurogenesis. Trends Neurosci 2009; 32(11): 575-82.
[http://dx.doi.org/10.1016/j.tins.2009.07.002] [PMID: 19782409]
[74]
Cruz JC, Tsai LH. A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 2004; 14(3): 390-4.
[http://dx.doi.org/10.1016/j.conb.2004.05.002] [PMID: 15194121]
[75]
Kwon KJ, Park JH, Jo I, et al. Disruption of neuronal nitric oxide synthase dimerization contributes to the development of Alzheimer’s disease: Involvement of cyclin-dependent kinase 5-mediated phosphorylation of neuronal nitric oxide synthase at Ser(293). Neurochem Int 2016; 99: 52-61.
[http://dx.doi.org/10.1016/j.neuint.2016.06.005] [PMID: 27296112]
[76]
Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function Eur Heart J 2012; 33(7) 829-837, 837a-837d.
[http://dx.doi.org/10.1093/eurheartj/ehr304] [PMID: 21890489]
[77]
Dagdeviren M. Role of Nitric Oxide synthase in normal brain function and pathophysiology of neural diseases Nitric oxide synthase. IntechOpen 2017.
[http://dx.doi.org/10.5772/67267]
[78]
Balez R, Ooi L. Getting to NO Alzheimer’s disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxid Med Cell Longev 2016; 20163806157
[http://dx.doi.org/10.1155/2016/3806157] [PMID: 26697132]
[79]
Bundy R, Minihane AM. Mediterranean diet, exercise and dementia risk in UK adults (MedEx-UK) Identification No NCT03673722 2018. Retrieved from https://clinicaltrials.gov/ct2/show/study/NCT03673722?term=nitric+oxide+in+Alzheimer%27s+disease&draw=2&rank=7#contacts
[80]
Shannon OM, Stephan BCM, Minihane AM, Mathers JC, Siervo M. Nitric oxide boosting effects of the mediterranean diet: a potential mechanism of action. J Gerontol A Biol Sci Med Sci 2018; 73(7): 902-4.
[http://dx.doi.org/10.1093/gerona/gly087] [PMID: 29684102]
[81]
Boyd JA, Doubal F. LACunar intervention (LACI-2) trial-2: assessment of safety and efficacy of cilostazol and isosorbide mononitrate to prevent recurrent lacunar stroke and progression of cerebral small vessel disease Identification No NCT03451591 2017. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03451591?term=nitric+oxide+in+Alzheimer%27s+disease&draw=2&rank=5
[82]
Park SY. Effects of mitochondrial-targeted antioxidant on mild cognitive impairment (MCI) patients. Identification No NCT03514875 2018. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03514875?term=nitric+oxide+in+Alzheimer%27s+disease&draw=2&rank=1#contacts

Rights & Permissions Print Cite
Article Metrics
53
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy