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Nitric Oxide as an Initiator of Brain Lesions During the Development of Alzheimer Disease

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Abstract

Nitric oxide (NO) is an important regulatory molecule for the host defense that plays a fundamental role in the cardiovascular, immune, and nervous systems. NO is synthesized through the conversion of l-arginine to l-citrulline by the enzyme NO synthase (NOS), which is found in three isoforms classified as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Recent evidence supports the theory that this bioactive molecule has an influential role in the disruption of normal brain and vascular homeostasis, a condition known to elucidate chronic hypoperfusion which ultimately causes the development of brain lesions and the pathology that typify Alzheimer disease (AD). In addition, vascular NO activity appears to be a major contributor to this pathology before any overexpression of NOS isoforms is observed in the neuron, glia, and microglia of the brain tree, where the overexpression the NOS isoforms causes the formation of a large amount of NO. We hypothesize that since an imbalance between the NOS isoforms and endothelin-1 (ET-1), a human gene that encodes for blood vessel constriction, can cause antioxidant system insufficiency; by using pharmacological intervention with NO donors and/or NO suppressors, the brain lesions and the downstream progression of brain pathology and dementia in AD should be delayed or minimized.

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References

  • Akar CA, Feinstein DL (2009) Modulation of inducible nitric oxide synthase expression by sumoylation. J Neuroinflammation 6:12. doi:10.1186/1742-2094-6-12

    Google Scholar 

  • Aliev G (2002) Is non-genetic Alzheimer’s disease a vascular disorder with neurodegenerative consequences? J Alzheimers Dis 4:513–516

    PubMed  Google Scholar 

  • Aliev G, Burnstock G (1998) Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis. Histol Histopathol 13:797–817

    PubMed  CAS  Google Scholar 

  • Aliev G, Cirillo R, Salvatico E, Paro M, Prosdocimi M (1993) Changes in vessel ultrastructure during ischemia and reperfusion of rabbit hindlimb: implications for therapeutic intervention. Microvasc Res 46:65–76

    PubMed  CAS  Google Scholar 

  • Aliev G, Ralevic V, Burnstock G (1996) Depression of endothelial nitric oxide synthase but increased expression of endothelin-1 immunoreactivity in rat thoracic aortic endothelium associated with long-term, but not short-term, sympathectomy. Circ Res 79:317–323

    PubMed  CAS  Google Scholar 

  • Aliev G, Shi J, Perry G, Friedland RP, LaManna JC (2000) Decreased constitutive nitric oxide synthase, but increased inducible nitric oxide synthase and endothelin-1 immunoreactivity in aortic endothelial cells of donryu rats on a cholesterol-enriched diet. Anat Rec 260:16–25

    PubMed  CAS  Google Scholar 

  • Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL, Vinters HV, Head E, Perry G, La Manna JC, Friedland RP, Cotman CW (2002a) Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann NY Acad Sci 977:45–64

    PubMed  CAS  Google Scholar 

  • Aliev G, Smith MA, Seyidova D, Neal ML, Shi J, Loizidou M, Turmaine M, Friedland RP, Taylor I, Burnstock G, Perry G, La Manna JC (2002b) Increased expression of NOS and ET-1 immunoreactivity in human colorectal metastatic liver tumours is associated with selective depression of constitutive NOS immunoreactivity in vessel endothelium. J Submicrosc Cytol Pathol 34:37–50

    PubMed  CAS  Google Scholar 

  • Aliev G, Obrenovich ME, Smith MA, Perry G (2003a) Hypoperfusion, mitochondria failure, oxidative stress, and Alzheimer disease. J Biomed Biotechnol 2003:162–163

    PubMed  Google Scholar 

  • Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G (2003b) Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease. Neurotox Res 5:491–504

    PubMed  Google Scholar 

  • Aliev G, Shenk JC, Fischbach K, Perry G (2008) Stem cell niches as clinical targets for anti-ischemic therapy. Nat Clin Pract Cardiovasc Med 5:590–591

    PubMed  CAS  Google Scholar 

  • Aliev G, Liu J, Shenk JC, Fischbach K, Pacheco GJ, Chen SG, Obrenovich ME, Ward WF, Richardson AG, Smith MA, Gasimov E, Perry G, Ames BN (2009) Neuronal mitochondrial amelioration by feeding acetyl-l-carnitine and lipoic acid to aged rats. J Cell Mol Med 13:320–333

    PubMed  CAS  Google Scholar 

  • Aliyev A, Seyidova D, Rzayev N, Obrenovich ME, Lamb BT, Chen SG, Smith MA, Perry G, de la Torre JC, Aliev G (2004) Is nitric oxide a key target in the pathogenesis of brain lesions during the development of Alzheimer’s disease? Neurol Res 26:547–553

    PubMed  CAS  Google Scholar 

  • Aliyev A, Chen SG, Seyidova D, Smith MA, Perry G, de la Torre J, Aliev G (2005) Mitochondria DNA deletions in atherosclerotic hypoperfused brain microvessels as a primary target for the development of Alzheimer’s disease. J Neurol Sci 229–230:285–292

    PubMed  Google Scholar 

  • Almeida A, Bolanos JP, Medina JM (1999) Nitric oxide mediates glutamate-induced mitochondrial depolarization in rat cortical neurons. Brain Res 816:580–586

    PubMed  CAS  Google Scholar 

  • Alves E, Binienda Z, Carvalho F, Alves CJ, Fernandes E, de Lourdes Bastos M, Tavares MA, Summavielle T (2008) Acetyl-l-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain. Neuroscience 158(2):514–523

    PubMed  Google Scholar 

  • Andresen J, Shafi NI, Bryan RM Jr (2006) Endothelial influences on cerebrovascular tone. J Appl Physiol 100:318–327

    PubMed  CAS  Google Scholar 

  • Bates TE, Loesch A, Burnstock G, Clark JB (1996) Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation? Biochem Biophys Res Commun 218:40–44

    PubMed  CAS  Google Scholar 

  • Bayraktutan U, Ulker S (2003) Effects of angiotensin II on nitric oxide generation in proliferating and quiescent rat coronary microvascular endothelial cells. Hypertens Res 26:749–757

    PubMed  CAS  Google Scholar 

  • Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366

    PubMed  CAS  Google Scholar 

  • Beckman JS (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15:53–59

    PubMed  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    PubMed  CAS  Google Scholar 

  • Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364:584

    PubMed  CAS  Google Scholar 

  • Bellien J, Thuillez C, Joannides R (2008) Contribution of endothelium-derived hyperpolarizing factors to the regulation of vascular tone in humans. Fundam Clin Pharmacol 22:363–377

    PubMed  CAS  Google Scholar 

  • Bera S, Ray M (2009) The transcriptional cascade associated with creatine kinase down-regulation and mitochondrial biogenesis in mice sarcoma. Cell Mol Biol Lett. doi:10.2478/s11658-009-0014-4

  • Bogumil R, Knipp M, Fundel SM, Vasak M (1998) Characterization of dimethylargininase from bovine brain: evidence for a zinc binding site. Biochemistry 37:4791–4798

    PubMed  CAS  Google Scholar 

  • Bras-Silva C, Leite-Moreira AF (2008) Myocardial effects of endothelin-1. Rev Port Cardiol 27:925–951

    PubMed  Google Scholar 

  • Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195

    PubMed  CAS  Google Scholar 

  • Buisson A, Plotkine M, Boulu RG (1992) The neuroprotective effect of a nitric oxide inhibitor in a rat model of focal cerebral ischaemia. Br J Pharmacol 106:766–767

    PubMed  CAS  Google Scholar 

  • Buisson A, Margaill I, Callebert J, Plotkine M, Boulu RG (1993) Mechanisms involved in the neuroprotective activity of a nitric oxide synthase inhibitor during focal cerebral ischemia. J Neurochem 61:690–696

    PubMed  CAS  Google Scholar 

  • Cao S, Yao J, McCabe TJ, Yao Q, Katusic ZS, Sessa WC, Shah V (2001) Direct interaction between endothelial nitric-oxide synthase and dynamin-2. Implications for nitric-oxide synthase function. J Biol Chem 276:14249–14256

    PubMed  CAS  Google Scholar 

  • Cao S, Yao J, Shah V (2003) The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function. J Biol Chem 278:5894–5901

    PubMed  CAS  Google Scholar 

  • Cazevieille C, Muller A, Meynier F, Bonne C (1993) Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury. Free Radic Biol Med 14:389–395

    PubMed  CAS  Google Scholar 

  • Crow JP, Ye YZ, Strong M, Kirk M, Barnes S, Beckman JS (1997) Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L. J Neurochem 69:1945–1953

    PubMed  CAS  Google Scholar 

  • Dawson DA (1994) Nitric oxide and focal cerebral ischemia: multiplicity of actions and diverse outcome. Cerebrovasc Brain Metab Rev 6:299–324

    PubMed  CAS  Google Scholar 

  • Dawson VL, Dawson TM (1996) Nitric oxide in neuronal degeneration. Proc Soc Exp Biol Med 211:33–40

    PubMed  CAS  Google Scholar 

  • Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88:6368–6371

    PubMed  CAS  Google Scholar 

  • Dawson VL, Brahmbhatt HP, Mong JA, Dawson TM (1994) Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33:1425–1430

    PubMed  CAS  Google Scholar 

  • de la Torre JC (2002a) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162

    PubMed  Google Scholar 

  • de la Torre JC (2002b) Alzheimer’s disease: how does it start? J Alzheimers Dis 4:497–512

    PubMed  Google Scholar 

  • de la Torre JC (2004) Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 3:184–190

    PubMed  Google Scholar 

  • de la Torre JC, Aliev G (2005) Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab 25:663–672

    PubMed  Google Scholar 

  • de la Torre JC, Stefano GB (2000) Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev 34:119–136

    PubMed  Google Scholar 

  • Di Benedetto R, Denti MA, Salvati S, Attorri L, Di Biase A (2008) PMP70 knock-down generates oxidative stress and pro-inflammatory cytokine production in C6 glial cells. Neurochem Int 54(1):37–42

    PubMed  Google Scholar 

  • Fabian RH, Perez-Polo JR, Kent TA (2008) Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia. Am J Physiol Heart Circ Physiol 295:H1809–H1814

    PubMed  CAS  Google Scholar 

  • Faraci FM (1991) Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 261:H1038–H1042

    PubMed  CAS  Google Scholar 

  • Faraci FM, Heistad DD (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53–97

    PubMed  CAS  Google Scholar 

  • Frade JG, Barbosa RM, Laranjinha J (2008) Stimulation of NMDA and AMPA glutamate receptors elicits distinct concentration dynamics of nitric oxide in rat hippocampal slices. Hippocampus. doi:10.1002/hipo.20536

  • Gallagher PE, Ferrario CM, Tallant EA (2008) MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. Am J Physiol Cell Physiol 295:C1169–C1174

    PubMed  CAS  Google Scholar 

  • Garthwaite J, Beaumont PS (1989) Excitatory amino acid receptors in the parallel fibre pathway in rat cerebellar slices. Neurosci Lett 107:151–156

    PubMed  CAS  Google Scholar 

  • Gates PE, Strain WD, Shore AC (2008) Human endothelial function and microvascular ageing. Exp Physiol 94(3):311–316

    PubMed  Google Scholar 

  • Gorgone G, Ursini F, Altamura C, Bressi F, Tombini M, Curcio G, Chiovenda P, Squitti R, Silvestrini M, Ientile R, Pisani F, Rossini PM, Vernieri F (2009) Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: a correlation study in patients with cognitive impairment. Atherosclerosis. doi:10.1016/j.atherosclerosis.2009.02.028

  • Hamada Y, Hayakawa T, Hattori H, Mikawa H (1994) Inhibitor of nitric oxide synthesis reduces hypoxic-ischemic brain damage in the neonatal rat. Pediatr Res 35:10–14

    PubMed  CAS  Google Scholar 

  • Hamel E, Nicolakakis N, Aboulkassim T, Ongali B, Tong XK (2008) Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer’s disease. Exp Physiol 93:116–120

    PubMed  CAS  Google Scholar 

  • Hara H, Huang PL, Panahian N, Fishman MC, Moskowitz MA (1996) Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. J Cereb Blood Flow Metab 16:605–611

    PubMed  CAS  Google Scholar 

  • Harrison DG, Cai H (2003) Endothelial control of vasomotion and nitric oxide production. Cardiol Clin 21:289–302

    PubMed  Google Scholar 

  • Hernanz R, Briones AM, Martin A, Beltran AE, Tejerina T, Salaices M, Alonso MJ (2008) Ouabain treatment increases nitric oxide bioavailability and decreases superoxide anion production in cerebral vessels. J Hypertens 26:1944–1954

    PubMed  CAS  Google Scholar 

  • Hosoi T, Sasaki M, Baba S, Ozawa K (2008) Effect of pranoprofen on endoplasmic reticulum stress in the primary cultured glial cells. Neurochem Int 54(1):1–6

    PubMed  Google Scholar 

  • Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883–1885

    PubMed  CAS  Google Scholar 

  • Iadecola C (1992) Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci USA 89:3913–3916

    PubMed  CAS  Google Scholar 

  • Iadecola C, Zhang F, Xu X (1995a) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol 268:R286–R292

    PubMed  CAS  Google Scholar 

  • Iadecola C, Li J, Ebner TJ, Xu X (1995b) Nitric oxide contributes to functional hyperemia in cerebellar cortex. Am J Physiol 268:R1153–R1162

    PubMed  CAS  Google Scholar 

  • Iadecola C, Zhang F, Xu S, Casey R, Ross ME (1995c) Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:378–384

    PubMed  CAS  Google Scholar 

  • Iadecola C, Zhang F, Casey R, Clark HB, Ross ME (1996) Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27:1373–1380

    PubMed  CAS  Google Scholar 

  • Kara P, Friedlander MJ (1998) Dynamic modulation of cerebral cortex synaptic function by nitric oxide. Prog Brain Res 118:183–198

    PubMed  CAS  Google Scholar 

  • Kaur C, Ling EA (2008) Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem 15:3068–3080

    PubMed  CAS  Google Scholar 

  • Kennedy JA, Hua X, Mishra K, Murphy GA, Rosenkranz AC, Horowitz JD (2009) Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. Eur J Pharmacol 602:28–35

    PubMed  CAS  Google Scholar 

  • Kimoto M, Tsuji H, Ogawa T, Sasaoka K (1993) Detection of NG, NG-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch Biochem Biophys 300:657–662

    PubMed  CAS  Google Scholar 

  • Kimoto M, Whitley GS, Tsuji H, Ogawa T (1995) Detection of NG, NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody. J Biochem (Tokyo) 117:237–238

    CAS  Google Scholar 

  • Kimura C, Oike M, Ohnaka K, Nose Y, Ito Y (2004) Constitutive nitric oxide production in bovine aortic and brain microvascular endothelial cells: a comparative study. J Physiol 554:721–730

    PubMed  CAS  Google Scholar 

  • Kone BC (2000) Protein-protein interactions controlling nitric oxide synthases. Acta Physiol Scand 168:27–31

    PubMed  CAS  Google Scholar 

  • Kumar VB, Viji RI, Kiran MS, Sudhakaran PR (2008) Negative modulation of eNOS by laminin involving post-translational phosphorylation. J Cell Physiol 219(1):123–131

    Google Scholar 

  • Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J (1993a) NMDA-dependent superoxide production and neurotoxicity. Nature 364:535–537

    PubMed  CAS  Google Scholar 

  • Lafon-Cazal M, Culcasi M, Gaven F, Pietri S, Bockaert J (1993b) Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology 32:1259–1266

    PubMed  CAS  Google Scholar 

  • Liclican EL, McGiff JC, Falck JR, Carroll MA (2008) Failure to upregulate the adenosine2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats. Am J Physiol Renal Physiol 295:F1696–F1704

    PubMed  CAS  Google Scholar 

  • Lin Y, Wang LN, Xi YH, Li HZ, Xiao FG, Zhao YJ, Tian Y, Yang BF, Xu CQ (2008) L-arginine inhibits isoproterenol-induced cardiac hypertrophy through nitric oxide and polyamine pathways. Basic Clin Pharmacol Toxicol 103:124–130

    PubMed  CAS  Google Scholar 

  • Liu J, Sessa WC (1994) Identification of covalently bound amino-terminal myristic acid in endothelial nitric oxide synthase. J Biol Chem 269:11691–11694

    PubMed  CAS  Google Scholar 

  • MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P (1996) Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540

    PubMed  CAS  Google Scholar 

  • Marletta MA (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78:927–930

    PubMed  CAS  Google Scholar 

  • Michel T, Feron O (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100:2146–2152

    PubMed  CAS  Google Scholar 

  • Morris SM Jr, Billiar TR (1994) New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266:E829–E839

    PubMed  CAS  Google Scholar 

  • Nakashima MN, Yamashita K, Kataoka Y, Yamashita YS, Niwa M (1995) Time course of nitric oxide synthase activity in neuronal, glial, and endothelial cells of rat striatum following focal cerebral ischemia. Cell Mol Neurobiol 15:341–349

    PubMed  CAS  Google Scholar 

  • Obrenovich ME, Smith MA, Siedlak SL, Chen SG, de la Torre JC, Perry G, Aliev G (2006) Overexpression of GRK2 in Alzheimer disease and in a chronic hypoperfusion rat model is an early marker of brain mitochondrial lesions. Neurotox Res 10:43–56

    Article  PubMed  CAS  Google Scholar 

  • Okada D, Yap CC, Kojima H, Kikuchi K, Nagano T (2004) Distinct glutamate receptors govern differential levels of nitric oxide production in a layer-specific manner in the rat cerebellar cortex. Neuroscience 125:461–472

    PubMed  CAS  Google Scholar 

  • Park CS, Pardhasaradhi K, Gianotti C, Villegas E, Krishna G (1994) Human retina expresses both constitutive and inducible isoforms of nitric oxide synthase mRNA. Biochem Biophys Res Commun 205:85–91

    PubMed  CAS  Google Scholar 

  • Park Y, Capobianco S, Gao X, Falck JR, Dellsperger KC, Zhang C (2008) Role of EDHF in type 2 diabetes-induced endothelial dysfunction. Am J Physiol Heart Circ Physiol 295:H1982–H1988

    PubMed  CAS  Google Scholar 

  • Patel JD, Krupka T, Anderson JM (2007) iNOS-mediated generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils. J Biomed Mater Res 80:381–390

    Google Scholar 

  • Peebles KC, Richards AM, Celi L, McGrattan K, Murrell CJ, Ainslie PN (2008) Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases. J Appl Physiol 105:1060–1068

    PubMed  Google Scholar 

  • Radenovic L, Selakovic V (2005) Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection. Brain Res Bull 67:133–141

    PubMed  CAS  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250

    PubMed  CAS  Google Scholar 

  • Ravichandran LV, Johns RA, Rengasamy A (1995) Direct and reversible inhibition of endothelial nitric oxide synthase by nitric oxide. Am J Physiol 268:H2216–H2223

    PubMed  CAS  Google Scholar 

  • Reddy PH (2006) Mitochondrial oxidative damage in aging and Alzheimer’s disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol 2006:31372

    PubMed  Google Scholar 

  • Reddy PH (2007) Mitochondrial dysfunction in aging and Alzheimer’s disease: strategies to protect neurons. Antioxid Redox Signal 9:1647–1658

    PubMed  CAS  Google Scholar 

  • Rengasamy A, Johns RA (1993) Inhibition of nitric oxide synthase by a superoxide generating system. J Pharmacol Exp Ther 267:1024–1027

    PubMed  CAS  Google Scholar 

  • Robinson LJ, Weremowicz S, Morton CC, Michel T (1994) Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. Genomics 19:350–357

    PubMed  CAS  Google Scholar��

  • Samdani AF, Dawson TM, Dawson VL (1997) Nitric oxide synthase in models of focal ischemia. Stroke 28:1283–1288

    PubMed  CAS  Google Scholar 

  • Sessa WC (1994) The nitric oxide synthase family of proteins. J Vasc Res 31:131–143

    PubMed  CAS  Google Scholar 

  • Seyidova D, Aliyev A, Rzayev N, Obrenovich M, Lamb BT, Smith MA, de la Torre JC, Perry G, Aliev G (2004) The role of nitric oxide in the pathogenesis of brain lesions during the development of Alzheimer’s disease. In Vivo 18:325–333

    PubMed  CAS  Google Scholar 

  • Shin T, Weinstock D, Castro MD, Acland H, Walter M, Kim HY, Purchase HG (2000) Immunohistochemical study of constitutive neuronal and inducible nitric oxide synthase in the central nervous system of goat with natural listeriosis. J Vet Sci 1:77–80

    PubMed  CAS  Google Scholar 

  • Smith MA, Sayre LM, Perry G (1996) Is Alzheimer’s a disease of oxidative stress? Alzheimers Dis Rev 1:63–67

    CAS  Google Scholar 

  • Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657

    PubMed  CAS  Google Scholar 

  • Smith MA, Vasak M, Knipp M, Castellani RJ, Perry G (1998) Dimethylargininase, a nitric oxide regulatory protein, in Alzheimer disease. Free Radic Biol Med 25:898–902

    PubMed  CAS  Google Scholar 

  • Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78:931–936

    PubMed  CAS  Google Scholar 

  • Stuehr DJ (1997) Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol 37:339–359

    PubMed  CAS  Google Scholar 

  • Styczynska M, Strosznajder JB, Religa D, Chodakowska-Zebrowska M, Pfeffer A, Gabryelewicz T, Czapski GA, Kobrys M, Karciauskas G, Barcikowska M (2008) Association between genetic and environmental factors and the risk of Alzheimer’s disease. Folia Neuropathol 46:249–254

    PubMed  CAS  Google Scholar 

  • Szeto HH (2008) Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann NY Acad Sci 1147:112–121

    Article  PubMed  CAS  Google Scholar 

  • Takaki A, Morikawa K, Murayama Y, Yamagishi H, Hosoya M, Ohashi J, Shimokawa H (2008) Roles of endothelial oxidases in endothelium-derived hyperpolarizing factor responses in mice. J Cardiovasc Pharmacol 52:510–517

    PubMed  CAS  Google Scholar 

  • Thorns V, Hansen L, Masliah E (1998) nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer’s disease. Exp Neurol 150:14–20

    PubMed  CAS  Google Scholar 

  • Viji RI, Sameer Kumar VB, Kiran MS, Sudhakaran PR (2008) Modulation of endothelial nitric oxide synthase by fibronectin. Mol Cell Biochem 323(1–2):91–100

    PubMed  Google Scholar 

  • Walsh T, Donnelly T, Lyons D (2008) Impaired endothelial nitric oxide bioavailability: a common link between aging, hypertension, and atherogenesis? J Am Geriatr Soc 57(1):140–145

    PubMed  Google Scholar 

  • Wang Q, Pelligrino DA, Baughman VL, Koenig HM, Albrecht RF (1995) The role of neuronal nitric oxide synthase in regulation of cerebral blood flow in normocapnia and hypercapnia in rats. J Cereb Blood Flow Metab 15:774–778

    PubMed  CAS  Google Scholar 

  • Wang JY, Wen LL, Huang YN, Chen YT, Ku MC (2006) Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr Pharm Des 12:3521–3533

    PubMed  CAS  Google Scholar 

  • Wang SM, Tsai HP, Huang JJ, Huang HC, Lin JL, Liu PH (2009) Inhibition of nitric oxide synthase promotes facial axonal regeneration following neurorrhaphy. Exp Neurol. doi:10.1016/j.expneurol.2009.01.006

  • Weiner MF, de la Plata CM, Fields BA, Womack KB, Rosenberg RN, Gong YH, Qu BX, Diaz-Arrastia R, Hynan LS (2009) Brain MRI, apoliprotein E genotype, and plasma homocysteine in American Indian Alzheimer disease patients and Indian controls. Curr Alzheimer Res 6:52–58

    PubMed  CAS  Google Scholar 

  • Wever RM, Luscher TF, Cosentino F, Rabelink TJ (1998) Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97:108–112

    PubMed  CAS  Google Scholar 

  • Wood CE, Giroux D (2006) Expression of nitric oxide synthase isoforms in the ovine fetal brain: alteration by hormonal and hemodynamic stimuli. J Soc Gynecol Investig 13:329–337

    PubMed  CAS  Google Scholar 

  • Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL (1996) Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA 93:6770–6774

    PubMed  CAS  Google Scholar 

  • Xu ZQ, Hokfelt T (1997) Expression of galanin and nitric oxide synthase in subpopulations of serotonin neurons of the rat dorsal raphe nucleus. J Chem Neuroanat 13:169–187

    PubMed  CAS  Google Scholar 

  • Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki T (1988) A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl 6:S188–S191

    PubMed  CAS  Google Scholar 

  • Yin T, Ma X, Zhao L, Cheng K, Wang H (2008) Angiotensin II promotes NO production, inhibits apoptosis and enhances adhesion potential of bone marrow-derived endothelial progenitor cells. Cell Res 18:792–799

    PubMed  CAS  Google Scholar 

  • Yin C, Salloum FN, Kukreja RC (2009) A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ Res 104:572–575

    PubMed  CAS  Google Scholar 

  • Zhang Y, Lu J, Shi J, Lin X, Dong J, Zhang S, Liu Y, Tong Q (2008) Central administration of angiotensin-(1–7) stimulates nitric oxide release and upregulates the endothelial nitric oxide synthase expression following focal cerebral ischemia/reperfusion in rats. Neuropeptides 42:593–600

    PubMed  CAS  Google Scholar 

  • Zoccolella S, Dell’aquila C, Abruzzese G, Antonini A, Bonuccelli U, Canesi M, Cristina S, Marchese R, Pacchetti C, Zagaglia R, Logroscino G, Defazio G, Lamberti P, Livrea P (2009) Hyperhomocysteinemia in levodopa-treated patients with Parkinson’s disease dementia. Mov Disord. PMID: 19353704

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Acknowledgments

Supported by grants from the Alzheimer Association and Philip Morris USA Research Management Groups.

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Authors and Affiliations

  1. Department of Biology and Electron Microscopy Research Center, University of Texas at San Antonio, San Antonio, TX, 78249, USA

    Gjumrakch Aliev, Hector H. Palacios & Kathryn Fischbach

  2. Department of Nutrition and Biochemistry, Faculty of Sciences, Javeriana University, Bogota D.C, Colombia

    Gjumrakch Aliev & Ludis Morales

  3. Stress Relief and Memory Training Center, Brooklyn, New York, USA

    Gjumrakch Aliev & Valentin Bragin

  4. Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Amanda E. Lipsitt

  5. Department of Neuroscience, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Bruce T. Lamb

  6. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Mark E. Obrenovich

  7. Department of Cytology, Histology and Embryology, Azerbaijan Medical University, Baku, Azerbaijan

    Eldar Gasimov

Authors
  1. Gjumrakch Aliev
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  2. Hector H. Palacios
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  3. Amanda E. Lipsitt
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  4. Kathryn Fischbach
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  5. Bruce T. Lamb
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  6. Mark E. Obrenovich
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  7. Ludis Morales
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  8. Eldar Gasimov
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  9. Valentin Bragin
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Correspondence to Gjumrakch Aliev.

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Aliev, G., Palacios, H.H., Lipsitt, A.E. et al. Nitric Oxide as an Initiator of Brain Lesions During the Development of Alzheimer Disease. Neurotox Res 16, 293–305 (2009). https://doi.org/10.1007/s12640-009-9066-5

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  • DOI: https://doi.org/10.1007/s12640-009-9066-5

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