Neurotoxicity Research

, Volume 16, Issue 3, pp 293–305 | Cite as

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

  • Gjumrakch AlievEmail author
  • Hector H. Palacios
  • Amanda E. Lipsitt
  • Kathryn Fischbach
  • Bruce T. Lamb
  • Mark E. Obrenovich
  • Ludis Morales
  • Eldar Gasimov
  • Valentin Bragin


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.


Alzheimer disease Nitric oxide Mitochondria Nitric oxide synthase Metabolism Oxidative stress 



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


  1. 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
  2. Aliev G (2002) Is non-genetic Alzheimer’s disease a vascular disorder with neurodegenerative consequences? J Alzheimers Dis 4:513–516PubMedGoogle Scholar
  3. Aliev G, Burnstock G (1998) Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis. Histol Histopathol 13:797–817PubMedGoogle Scholar
  4. 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 46:65–76PubMedGoogle Scholar
  5. 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 79:317–323PubMedGoogle Scholar
  6. 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 260:16–25PubMedGoogle Scholar
  7. 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 977:45–64PubMedGoogle Scholar
  8. 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 34:37–50PubMedGoogle Scholar
  9. Aliev G, Obrenovich ME, Smith MA, Perry G (2003a) Hypoperfusion, mitochondria failure, oxidative stress, and Alzheimer disease. J Biomed Biotechnol 2003:162–163PubMedGoogle Scholar
  10. 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 5:491–504PubMedGoogle Scholar
  11. Aliev G, Shenk JC, Fischbach K, Perry G (2008) Stem cell niches as clinical targets for anti-ischemic therapy. Nat Clin Pract Cardiovasc Med 5:590–591PubMedGoogle Scholar
  12. 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 13:320–333PubMedGoogle Scholar
  13. 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 26:547–553PubMedGoogle Scholar
  14. 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 229–230:285–292PubMedGoogle Scholar
  15. Almeida A, Bolanos JP, Medina JM (1999) Nitric oxide mediates glutamate-induced mitochondrial depolarization in rat cortical neurons. Brain Res 816:580–586PubMedGoogle Scholar
  16. 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):514–523PubMedGoogle Scholar
  17. Andresen J, Shafi NI, Bryan RM Jr (2006) Endothelial influences on cerebrovascular tone. J Appl Physiol 100:318–327PubMedGoogle Scholar
  18. Bates TE, Loesch A, Burnstock G, Clark JB (1996) Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation? Biochem Biophys Res Commun 218:40–44PubMedGoogle Scholar
  19. Bayraktutan U, Ulker S (2003) Effects of angiotensin II on nitric oxide generation in proliferating and quiescent rat coronary microvascular endothelial cells. Hypertens Res 26:749–757PubMedGoogle Scholar
  20. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366PubMedGoogle Scholar
  21. Beckman JS (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15:53–59PubMedGoogle Scholar
  22. 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 87:1620–1624PubMedGoogle Scholar
  23. Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364:584PubMedGoogle Scholar
  24. Bellien J, Thuillez C, Joannides R (2008) Contribution of endothelium-derived hyperpolarizing factors to the regulation of vascular tone in humans. Fundam Clin Pharmacol 22:363–377PubMedGoogle Scholar
  25. 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
  26. Bogumil R, Knipp M, Fundel SM, Vasak M (1998) Characterization of dimethylargininase from bovine brain: evidence for a zinc binding site. Biochemistry 37:4791–4798PubMedGoogle Scholar
  27. Bras-Silva C, Leite-Moreira AF (2008) Myocardial effects of endothelin-1. Rev Port Cardiol 27:925–951PubMedGoogle Scholar
  28. Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195PubMedGoogle Scholar
  29. 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 106:766–767PubMedGoogle Scholar
  30. 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 61:690–696PubMedGoogle Scholar
  31. 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 276:14249–14256PubMedGoogle Scholar
  32. 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 278:5894–5901PubMedGoogle Scholar
  33. Cazevieille C, Muller A, Meynier F, Bonne C (1993) Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury. Free Radic Biol Med 14:389–395PubMedGoogle Scholar
  34. 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 69:1945–1953PubMedGoogle Scholar
  35. Dawson DA (1994) Nitric oxide and focal cerebral ischemia: multiplicity of actions and diverse outcome. Cerebrovasc Brain Metab Rev 6:299–324PubMedGoogle Scholar
  36. Dawson VL, Dawson TM (1996) Nitric oxide in neuronal degeneration. Proc Soc Exp Biol Med 211:33–40PubMedGoogle Scholar
  37. 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 88:6368–6371PubMedGoogle Scholar
  38. 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 33:1425–1430PubMedGoogle Scholar
  39. de la Torre JC (2002a) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162PubMedGoogle Scholar
  40. de la Torre JC (2002b) Alzheimer’s disease: how does it start? J Alzheimers Dis 4:497–512PubMedGoogle Scholar
  41. de la Torre JC (2004) Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 3:184–190PubMedGoogle Scholar
  42. 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 25:663–672PubMedGoogle Scholar
  43. 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 34:119–136PubMedGoogle Scholar
  44. 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):37–42PubMedGoogle Scholar
  45. 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–H1814PubMedGoogle Scholar
  46. Faraci FM (1991) Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation. Am J Physiol 261:H1038–H1042PubMedGoogle Scholar
  47. Faraci FM, Heistad DD (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53–97PubMedGoogle Scholar
  48. 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
  49. 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–C1174PubMedGoogle Scholar
  50. Garthwaite J, Beaumont PS (1989) Excitatory amino acid receptors in the parallel fibre pathway in rat cerebellar slices. Neurosci Lett 107:151–156PubMedGoogle Scholar
  51. Gates PE, Strain WD, Shore AC (2008) Human endothelial function and microvascular ageing. Exp Physiol 94(3):311–316PubMedGoogle Scholar
  52. 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
  53. 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 35:10–14PubMedGoogle Scholar
  54. 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 93:116–120PubMedGoogle Scholar
  55. 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 16:605–611PubMedGoogle Scholar
  56. Harrison DG, Cai H (2003) Endothelial control of vasomotion and nitric oxide production. Cardiol Clin 21:289–302PubMedGoogle Scholar
  57. 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 26:1944–1954PubMedGoogle Scholar
  58. 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):1–6PubMedGoogle Scholar
  59. 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 265:1883–1885PubMedGoogle Scholar
  60. Iadecola C (1992) Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci USA 89:3913–3916PubMedGoogle Scholar
  61. Iadecola C, Zhang F, Xu X (1995a) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol 268:R286–R292PubMedGoogle Scholar
  62. Iadecola C, Li J, Ebner TJ, Xu X (1995b) Nitric oxide contributes to functional hyperemia in cerebellar cortex. Am J Physiol 268:R1153–R1162PubMedGoogle Scholar
  63. 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 15:378–384PubMedGoogle Scholar
  64. 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 27:1373–1380PubMedGoogle Scholar
  65. Kara P, Friedlander MJ (1998) Dynamic modulation of cerebral cortex synaptic function by nitric oxide. Prog Brain Res 118:183–198PubMedGoogle Scholar
  66. Kaur C, Ling EA (2008) Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem 15:3068–3080PubMedGoogle Scholar
  67. 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 602:28–35PubMedGoogle Scholar
  68. 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 300:657–662PubMedGoogle Scholar
  69. 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) 117:237–238Google Scholar
  70. 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 554:721–730PubMedGoogle Scholar
  71. Kone BC (2000) Protein-protein interactions controlling nitric oxide synthases. Acta Physiol Scand 168:27–31PubMedGoogle Scholar
  72. Kumar VB, Viji RI, Kiran MS, Sudhakaran PR (2008) Negative modulation of eNOS by laminin involving post-translational phosphorylation. J Cell Physiol 219(1):123–131Google Scholar
  73. Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J (1993a) NMDA-dependent superoxide production and neurotoxicity. Nature 364:535–537PubMedGoogle Scholar
  74. 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 32:1259–1266PubMedGoogle Scholar
  75. 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–F1704PubMedGoogle Scholar
  76. 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 103:124–130PubMedGoogle Scholar
  77. Liu J, Sessa WC (1994) Identification of covalently bound amino-terminal myristic acid in endothelial nitric oxide synthase. J Biol Chem 269:11691–11694PubMedGoogle Scholar
  78. 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 119:1533–1540PubMedGoogle Scholar
  79. Marletta MA (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78:927–930PubMedGoogle Scholar
  80. Michel T, Feron O (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100:2146–2152PubMedGoogle Scholar
  81. Morris SM Jr, Billiar TR (1994) New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266:E829–E839PubMedGoogle Scholar
  82. 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 15:341–349PubMedGoogle Scholar
  83. 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 10:43–56PubMedCrossRefGoogle Scholar
  84. 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 125:461–472PubMedGoogle Scholar
  85. 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 205:85–91PubMedGoogle Scholar
  86. 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–H1988PubMedGoogle Scholar
  87. Patel JD, Krupka T, Anderson JM (2007) iNOS-mediated generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils. J Biomed Mater Res 80:381–390Google Scholar
  88. 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 105:1060–1068PubMedGoogle Scholar
  89. 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 67:133–141PubMedGoogle Scholar
  90. Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250PubMedGoogle Scholar
  91. Ravichandran LV, Johns RA, Rengasamy A (1995) Direct and reversible inhibition of endothelial nitric oxide synthase by nitric oxide. Am J Physiol 268:H2216–H2223PubMedGoogle Scholar
  92. Reddy PH (2006) Mitochondrial oxidative damage in aging and Alzheimer’s disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol 2006:31372PubMedGoogle Scholar
  93. Reddy PH (2007) Mitochondrial dysfunction in aging and Alzheimer’s disease: strategies to protect neurons. Antioxid Redox Signal 9:1647–1658PubMedGoogle Scholar
  94. Rengasamy A, Johns RA (1993) Inhibition of nitric oxide synthase by a superoxide generating system. J Pharmacol Exp Ther 267:1024–1027PubMedGoogle Scholar
  95. Robinson LJ, Weremowicz S, Morton CC, Michel T (1994) Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. Genomics 19:350–357PubMedGoogle Scholar
  96. Samdani AF, Dawson TM, Dawson VL (1997) Nitric oxide synthase in models of focal ischemia. Stroke 28:1283–1288PubMedGoogle Scholar
  97. Sessa WC (1994) The nitric oxide synthase family of proteins. J Vasc Res 31:131–143PubMedGoogle Scholar
  98. 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 18:325–333PubMedGoogle Scholar
  99. 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 1:77–80PubMedGoogle Scholar
  100. Smith MA, Sayre LM, Perry G (1996) Is Alzheimer’s a disease of oxidative stress? Alzheimers Dis Rev 1:63–67Google Scholar
  101. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657PubMedGoogle Scholar
  102. Smith MA, Vasak M, Knipp M, Castellani RJ, Perry G (1998) Dimethylargininase, a nitric oxide regulatory protein, in Alzheimer disease. Free Radic Biol Med 25:898–902PubMedGoogle Scholar
  103. Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78:931–936PubMedGoogle Scholar
  104. Stuehr DJ (1997) Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol 37:339–359PubMedGoogle Scholar
  105. 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 46:249–254PubMedGoogle Scholar
  106. Szeto HH (2008) Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann NY Acad Sci 1147:112–121PubMedCrossRefGoogle Scholar
  107. 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 52:510–517PubMedGoogle Scholar
  108. 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 150:14–20PubMedGoogle Scholar
  109. Viji RI, Sameer Kumar VB, Kiran MS, Sudhakaran PR (2008) Modulation of endothelial nitric oxide synthase by fibronectin. Mol Cell Biochem 323(1–2):91–100PubMedGoogle Scholar
  110. 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):140–145PubMedGoogle Scholar
  111. 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 15:774–778PubMedGoogle Scholar
  112. 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 12:3521–3533PubMedGoogle Scholar
  113. 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
  114. 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 6:52–58PubMedGoogle Scholar
  115. Wever RM, Luscher TF, Cosentino F, Rabelink TJ (1998) Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97:108–112PubMedGoogle Scholar
  116. 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 13:329–337PubMedGoogle Scholar
  117. 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 93:6770–6774PubMedGoogle Scholar
  118. 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 13:169–187PubMedGoogle Scholar
  119. 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–S191PubMedGoogle Scholar
  120. 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 18:792–799PubMedGoogle Scholar
  121. 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 104:572–575PubMedGoogle Scholar
  122. 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 42:593–600PubMedGoogle Scholar
  123. 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: 19353704Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Gjumrakch Aliev
    • 1
    • 2
    • 3
    Email author
  • Hector H. Palacios
    • 1
  • Amanda E. Lipsitt
    • 4
  • Kathryn Fischbach
    • 1
  • Bruce T. Lamb
    • 5
  • Mark E. Obrenovich
    • 6
  • Ludis Morales
    • 2
  • Eldar Gasimov
    • 7
  • Valentin Bragin
    • 3
  1. 1.Department of Biology and Electron Microscopy Research CenterUniversity of Texas at San AntonioSan AntonioUSA
  2. 2.Department of Nutrition and Biochemistry, Faculty of SciencesJaveriana UniversityBogota D.CColombia
  3. 3.Stress Relief and Memory Training CenterBrooklyn, New YorkUSA
  4. 4.Department of Medicine, Division of Infectious DiseasesUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  5. 5.Department of NeuroscienceThe Lerner Research InstituteClevelandUSA
  6. 6.Department of PathologyCase Western Reserve UniversityClevelandUSA
  7. 7.Department of Cytology, Histology and EmbryologyAzerbaijan Medical UniversityBakuAzerbaijan

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