Skip to main content

Advertisement

SpringerLink
Log in

The Peculiar Facets of Nitric Oxide as a Cellular Messenger: From Disease-Associated Signaling to the Regulation of Brain Bioenergetics and Neurovascular Coupling

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In this review, we address the regulatory and toxic role of ·NO along several pathways, from the gut to the brain. Initially, we address the role on ·NO in the regulation of mitochondrial respiration with emphasis on the possible contribution to Parkinson’s disease via mechanisms that involve its interaction with a major dopamine metabolite, DOPAC. In parallel with initial discoveries of the inhibition of mitochondrial respiration by ·NO, it became clear the potential for toxic ·NO-mediated mechanisms involving the production of more reactive species and the post-translational modification of mitochondrial proteins. Accordingly, we have proposed a novel mechanism potentially leading to dopaminergic cell death, providing evidence that NO synergistically interact with DOPAC in promoting cell death via mechanisms that involve GSH depletion. The modulatory role of NO will be then briefly discussed as a master regulator on brain energy metabolism. The energy metabolism in the brain is central to the understanding of brain function and disease. The core role of ·NO in the regulation of brain metabolism and vascular responses is further substantiated by discussing its role as a mediator of neurovascular coupling, the increase in local microvessels blood flow in response to spatially restricted increase of neuronal activity. The many facets of NO as intracellular and intercellular messenger, conveying information associated with its spatial and temporal concentration dynamics, involve not only the discussion of its reactions and potential targets on a defined biological environment but also the regulation of its synthesis by the family of nitric oxide synthases. More recently, a novel pathway, out of control of NOS, has been the subject of a great deal of controversy, the nitrate:nitrite:NO pathway, adding new perspectives to ·NO biology. Thus, finally, this novel pathway will be addressed in connection with nitrate consumption in the diet and the beneficial effects of protein nitration by reactive nitrogen species.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

ALDH:

Aldehyde dehydrogenase

CBF:

Cerebral blood flow

CcO:

Cytochrome c oxidase

CSF:

Cerebrospinal fluid

DOPAC:

3,4-Dihydroxyphenylacetic acid

GSH:

Reduced glutathione

iNOS:

Inducible nitric oxide synthase

mGluR:

Metabotropic glutamate receptors

mtNOS:

Mitochondrial nitric oxide synthase

MAO:

Monoamine oxidase

nNOS:

Neuronal nitric oxide synthase

NVC:

Neurovascular coupling

OCR:

Oxygen consumption rates

PD:

Parkinson’s disease

PFK2.3:

Phosphofructokinase 2.3

sGC:

Soluble guanylate cyclase

SMCs:

Smooth muscle cells

SOD:

Superoxide dismutase

References

  1. Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hardingham N, Dachtler J, Fox K (2013) The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front Cell Neurosci 7:190

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic Biol Med 108:668–682

    Article  CAS  PubMed  Google Scholar 

  4. Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, Heales SJ (1997) Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 68:2227–2240

    Article  CAS  PubMed  Google Scholar 

  5. Heales SJ, Bolanos JP, Stewart VC, Brookes PS, Land JM, Clark JB (1999) Nitric oxide, mitochondria and neurological disease. Biochem Biophys Acta 1410:215–228

    CAS  PubMed  Google Scholar 

  6. Moncada S, Bolanos JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97:1676–1689

    Article  CAS  PubMed  Google Scholar 

  7. Spiers JG, Chen HC, Bourgognon JM, Steinert JR (2019) Dysregulation of stress systems and nitric oxide signaling underlies neuronal dysfunction in Alzheimer's disease. Free Radic Biol Med 134:468–483

    Article  CAS  PubMed  Google Scholar 

  8. Almeida A, Bolanos JP (2001) A transient inhibition of mitochondrial ATP synthesis by nitric oxide synthase activation triggered apoptosis in primary cortical neurons. J Neurochem 77:676–690

    Article  CAS  PubMed  Google Scholar 

  9. Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409

    Article  CAS  PubMed  Google Scholar 

  10. Dehmer T, Lindenau J, Haid S, Dichgans J, Schulz JB (2000) Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 74:2213–2216

    Article  CAS  PubMed  Google Scholar 

  11. Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med 2:1017–1021

    Article  CAS  PubMed  Google Scholar 

  12. Klivenyi P, Andreassen OA, Ferrante RJ, Lancelot E, Reif D, Beal MF (2000) Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity. NeuroReport 11:1265–1268

    Article  CAS  PubMed  Google Scholar 

  13. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989

    Article  CAS  PubMed  Google Scholar 

  14. Good PF, Hsu A, Werner P, Perl DP, Olanow CW (1998) Protein nitration in Parkinson's disease. J Neuropathol Exp Neurol 57:338–342

    Article  CAS  PubMed  Google Scholar 

  15. Ben-Shachar D, Zuk R, Glinka Y (1995) Dopamine neurotoxicity: inhibition of mitochondrial respiration. J Neurochem 64:718–723

    Article  CAS  PubMed  Google Scholar 

  16. LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. The Journal of neuroscience 19:1484–1491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Antunes F, Han D, Rettori D, Cadenas E (2002) Mitochondrial damage by nitric oxide is potentiated by dopamine in PC12 cells. Biochem Biophys Acta 1556:233–238

    CAS  PubMed  Google Scholar 

  18. Antunes F, Nunes C, Laranjinha J, Cadenas E (2005) Redox interactions of nitric oxide with dopamine and its derivatives. Toxicology 208:207–212

    Article  CAS  PubMed  Google Scholar 

  19. Ghafourifar P, Richter C (1997) Nitric oxide synthase activity in mitochondria. FEBS Lett 418:291–296

    Article  CAS  PubMed  Google Scholar 

  20. Giulivi C (2003) Characterization and function of mitochondrial nitric-oxide synthase. Free Radical Biol Med 34:397–408

    Article  CAS  Google Scholar 

  21. Tank AW, Weiner H, Thurman JA (1981) Enzymology and subcellular localization of aldehyde oxidation in rat liver. Oxidation of 3,4-dihydroxyphenylacetaldehyde derived from dopamine to 3,4-dihydroxyphenylacetic acid. Biochem Pharmacol 30:3265–3275

    Article  CAS  PubMed  Google Scholar 

  22. Laranjinha J, Cadenas E (2002) Oxidation of DOPAC by nitric oxide: effect of superoxide dismutase. J Neurochem 81:892–900

    Article  CAS  PubMed  Google Scholar 

  23. Nunes C, Almeida L, Laranjinha J (2005) Synergistic inhibition of respiration in brain mitochondria by nitric oxide and dihydroxyphenylacetic acid (DOPAC). Implications for Parkinson’s disease. Neurochem Int 47:173–182

    Article  CAS  PubMed  Google Scholar 

  24. Almeida A, Almeida J, Bolanos JP, Moncada S (2001) Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci USA 98:15294–15299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342:619–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nunes C, Almeida L, Laranjinha J (2008) 3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning. Neurotoxicology 29:998–1007

    Article  CAS  PubMed  Google Scholar 

  27. Nunes C, Barbosa RM, Almeida L, Laranjinha J (2011) Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis. Mol Cell Neurosci 48:94–103

    Article  CAS  PubMed  Google Scholar 

  28. Callizot N, Combes M, Henriques A, Poindron P (2019) Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins. PLoS ONE 14:e0215277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Graeber MB, Grasbon-Frodl E, Abell-Aleff P, Kosel S (1999) Nigral neurons are likely to die of a mechanism other than classical apoptosis in Parkinson's disease. Parkinson Relat Disord 5:187–192

    Article  CAS  Google Scholar 

  30. Han BS, Hong HS, Choi WS, Markelonis GJ, Oh TH, Oh YJ (2003) Caspase-dependent and -independent cell death pathways in primary cultures of mesencephalic dopaminergic neurons after neurotoxin treatment. J Neurosci 23:5069–5078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Janetzky B, Hauck S, Youdim MB, Riederer P, Jellinger K, Pantucek F, Zochling R, Boissl KW, Reichmann H (1994) Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson's disease. Neurosci Lett 169:126–128

    Article  CAS  PubMed  Google Scholar 

  32. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 54:823–827

    Article  CAS  PubMed  Google Scholar 

  33. Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci Lett 142:128–130

    Article  CAS  PubMed  Google Scholar 

  34. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36:348–355

    Article  CAS  PubMed  Google Scholar 

  35. Hsu M, Srinivas B, Kumar J, Subramanian R, Andersen J (2005) Glutathione depletion resulting in selective mitochondrial complex I inhibition in dopaminergic cells is via an NO-mediated pathway not involving peroxynitrite: implications for Parkinson's disease. J Neurochem 92:1091–1103

    Article  CAS  PubMed  Google Scholar 

  36. Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman HJ, Andersen JK (2000) Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. J Biol Chem 275:26096–26101

    Article  CAS  PubMed  Google Scholar 

  37. Barker JE, Bolanos JP, Land JM, Clark JB, Heales SJ (1996) Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration. Dev Neurosci 18:391–396

    Article  CAS  PubMed  Google Scholar 

  38. Bolanos JP, Heales SJ, Land JM, Clark JB (1995) Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture. J Neurochem 64:1965–1972

    Article  CAS  PubMed  Google Scholar 

  39. Bolanos JP, Heales SJ, Peuchen S, Barker JE, Land JM, Clark JB (1996) Nitric oxide-mediated mitochondrial damage: a potential neuroprotective role for glutathione. Free Radical Biol Med 21:995–1001

    Article  CAS  Google Scholar 

  40. Heales SJ, Bolanos JP, Clark JB (1996) Glutathione depletion is accompanied by increased neuronal nitric oxide synthase activity. Neurochem Res 21:35–39

    Article  CAS  PubMed  Google Scholar 

  41. Celli A, Que FG, Gores GJ, LaRusso NF (1998) Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes. Am J Physiol 275:G749–757

    CAS  PubMed  Google Scholar 

  42. Cadenas E, Poderoso JJ, Antunes F, Boveris A (2000) Analysis of the pathways of nitric oxide utilization in mitochondria. Free Radical Res 33:747–756

    Article  CAS  Google Scholar 

  43. Mignot E, Laude D, Elghozi JL (1984) Kinetics of drug-induced changes in dopamine and serotonin metabolite concentrations in the CSF of the rat. J Neurochem 42:819–825

    Article  CAS  PubMed  Google Scholar 

  44. Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson's disease. Adv Neurol 45:19–34

    CAS  PubMed  Google Scholar 

  45. Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F (2015) Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 9:322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Barros LF, Bolanos JP, Bonvento G, Bouzier-Sore AK, Brown A, Hirrlinger J, Kasparov S, Kirchhoff F, Murphy AN, Pellerin L, Robinson MB, Weber B (2018) Current technical approaches to brain energy metabolism. Glia 66:1138–1159

    Article  PubMed  Google Scholar 

  47. Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. Journal of neural transmission 121:799–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Attwell D, Gibb A (2005) Neuroenergetics and the kinetic design of excitatory synapses. Nat Rev Neurosci 6:841–849

    Article  CAS  PubMed  Google Scholar 

  49. Dias C, Lourenco CF, Barbosa RM, Laranjinha J, Ledo A (2018) Analysis of respiratory capacity in brain tissue preparations: high-resolution respirometry for intact hippocampal slices. Anal Biochem 551:43–50

    Article  CAS  PubMed  Google Scholar 

  50. Dias C, Lourenco CF, Ferreiro E, Barbosa RM, Laranjinha J, Ledo A (2016) Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation. Neurobiol Aging 46:84–95

    Article  CAS  PubMed  Google Scholar 

  51. Ledo A, Barbosa RM, Gerhardt GA, Cadenas E, Laranjinha J (2005) Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor. Proc Natl Acad Sci USA 102:17483–17488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Steinert JR, Kopp-Scheinpflug C, Baker C, Challiss RA, Mistry R, Haustein MD, Griffin SJ, Tong H, Graham BP, Forsythe ID (2008) Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse. Neuron 60:642–656

    Article  CAS  PubMed  Google Scholar 

  53. Santos RM, Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2012) Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. Int J Cell Biol 2012:391914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Santos RM, Lourenco CF, Pomerleau F, Huettl P, Gerhardt GA, Laranjinha J, Barbosa RM (2011) Brain nitric oxide inactivation is governed by the vasculature. Antioxid Redox Signal 14:1011–1021

    Article  CAS  PubMed  Google Scholar 

  55. Laranjinha J, Ledo A (2007) Coordination of physiologic and toxic pathways in hippocampus by nitric oxide and mitochondria. Front Biosci 12:1094–1106

    Article  CAS  PubMed  Google Scholar 

  56. Brown GC, Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 356:295–298

    Article  CAS  PubMed  Google Scholar 

  57. Martinez-Ruiz A, Cadenas S, Lamas S (2011) Nitric oxide signaling: classical, less classical, and nonclassical mechanisms. Free Radic Biol Med 51:17–29

    Article  CAS  PubMed  Google Scholar 

  58. Antunes F, Boveris A, Cadenas E (2004) On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide. Proc Natl Acad Sci USA 101:16774–16779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schweizer M, Richter C (1994) Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension. Biochem Biophys Res Commun 204:169–175

    Article  CAS  PubMed  Google Scholar 

  60. Bolanos JP, Peuchen S, Heales SJ, Land JM, Clark JB (1994) Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J Neurochem 63:910–916

    Article  CAS  PubMed  Google Scholar 

  61. San Martin A, Arce-Molina R, Galaz A, Perez-Guerra G, Barros LF (2017) Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism. J Biol Chem 292:9432–9438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stewart VC, Heales SJ (2003) Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol Med 34:287–303

    Article  CAS  PubMed  Google Scholar 

  63. Ledo A, Barbosa R, Cadenas E, Laranjinha J (2010) Dynamic and interacting profiles of *NO and O2 in rat hippocampal slices. Free Radic Biol Med 48:1044–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cooper CE, Giulivi C (2007) Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiology. Am J Physiol Cell Physiol 292:C1993–2003

    Article  CAS  PubMed  Google Scholar 

  65. Beltran B, Orsi A, Clementi E, Moncada S (2000) Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 129:953–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Clementi E, Brown GC, Feelisch M, Moncada S (1998) Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci USA 95:7631–7636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Loschen G, Azzi A, Richter C, Flohe L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72

    Article  CAS  PubMed  Google Scholar 

  69. Naqui A, Chance B, Cadenas E (1986) Reactive oxygen intermediates in biochemistry. Annu Rev Biochem 55:137–166

    Article  CAS  PubMed  Google Scholar 

  70. Radi R (2013) Peroxynitrite, a stealthy biological oxidant. J Biol Chem 288:26464–26472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Elfering SL, Sarkela TM, Giulivi C (2002) Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem 277:38079–38086

    Article  CAS  PubMed  Google Scholar 

  72. Ghafourifar P, Sen CK (2007) Mitochondrial nitric oxide synthase. Front Biosci 12:1072–1078

    Article  CAS  PubMed  Google Scholar 

  73. Radi R, Rodriguez M, Castro L, Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308:89–95

    Article  CAS  PubMed  Google Scholar 

  74. Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Encinas JM, Serrano J, Bentura ML, Munoz P, Martinez-Murillo R, Rodrigo J (2004) Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Neurobiol Dis 15:287–305

    Article  CAS  PubMed  Google Scholar 

  75. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C (1999) Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. Neurosci Lett 269:52–54

    Article  CAS  PubMed  Google Scholar 

  77. Ledo A, Lourenco CF, Caetano M, Barbosa RM, Laranjinha J (2015) Age-associated changes of nitric oxide concentration dynamics in the central nervous system of Fisher 344 rats. Cell Mol Neurobiol 35:33–44

    Article  CAS  PubMed  Google Scholar 

  78. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738

    Article  CAS  PubMed  Google Scholar 

  79. Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19:235–249

    Article  CAS  PubMed  Google Scholar 

  80. Almeida A, Moncada S, Bolanos JP (2004) Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 6:45–51

    Article  CAS  PubMed  Google Scholar 

  81. Okar DA, Manzano A, Navarro-Sabate A, Riera L, Bartrons R, Lange AJ (2001) PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Trends Biochem Sci 26:30–35

    Article  CAS  PubMed  Google Scholar 

  82. Pilkis SJ, Claus TH, Kurland IJ, Lange AJ (1995) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme. Annu Rev Biochem 64:799–835

    Article  CAS  PubMed  Google Scholar 

  83. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11:747–752

    Article  CAS  PubMed  Google Scholar 

  84. Rodriguez-Rodriguez P, Almeida A, Bolanos JP (2013) Brain energy metabolism in glutamate-receptor activation and excitotoxicity: role for APC/C-Cdh1 in the balance glycolysis/pentose phosphate pathway. Neurochem Int 62:750–756

    Article  CAS  PubMed  Google Scholar 

  85. Cali C, Tauffenberger A, Magistretti P (2019) The strategic location of glycogen and lactate: from body energy reserve to brain plasticity. Front Cell Neurosci 13:82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mason S (2017) Lactate shuttles in neuroenergetics-homeostasis. Allostasis and Beyond Frontiers in neuroscience 11:43

    PubMed  Google Scholar 

  87. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cerebral Blood Flow Metab 32:1152–1166

    Article  CAS  Google Scholar 

  88. Bolanos JP, Delgado-Esteban M, Herrero-Mendez A, Fernandez-Fernandez S, Almeida A (2008) Regulation of glycolysis and pentose-phosphate pathway by nitric oxide: impact on neuronal survival. Biochem Biophys Acta 1777:789–793

    CAS  PubMed  Google Scholar 

  89. Cidad P, Almeida A, Bolanos JP (2004) Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5′-AMP-activated protein kinase. Biochem J 384:629–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fu W, Shi D, Westaway D, Jhamandas JH (2015) Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. J Biol Chem 290:12504–12513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Harris JJ, Jolivet R, Attwell D (2012) Synaptic energy use and supply. Neuron 75:762–777

    Article  CAS  PubMed  Google Scholar 

  92. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hosford PS, Gourine AV (2019) What is the key mediator of the neurovascular coupling response? Neurosci Biobehav Rev 96:174–181

    Article  PubMed  PubMed Central  Google Scholar 

  94. Lourenço CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic Biol Med 108:668–682

    Article  PubMed  CAS  Google Scholar 

  95. Brown LA, Key BJ, Lovick TA (2000) Fluorescent imaging of nitric oxide production in neuronal varicosities associated with intraparenchymal arterioles in rat hippocampal slices. Neurosci Lett 294:9–12

    Article  CAS  PubMed  Google Scholar 

  96. Lourenço CF, Santos RM, Barbosa RM, Cadenas E, Radi R, Laranjinha J (2014) Neurovascular coupling in hippocampus is mediated via diffusion by neuronal-derived nitric oxide. Free Radic Biol Med 73:421–429

    Article  PubMed  CAS  Google Scholar 

  97. Mapelli L, Gagliano G, Soda T, Laforenza U, Moccia F, D'Angelo EU (2017) Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System. J Neurosci 37:1340–1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rancillac A, Rossier J, Guille M, Tong XK, Geoffroy H, Amatore C, Arbault S, Hamel E, Cauli B (2006) Glutamatergic Control of Microvascular Tone by Distinct GABA Neurons in the Cerebellum. J Neurosci 26:6997–7006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular uncoupling in the triple transgenic model of Alzheimer's disease: Impaired cerebral blood flow response to neuronal-derived nitric oxide signaling. Exp Neurol 291:36–43

    Article  CAS  PubMed  Google Scholar 

  100. Lourenco CF, Ledo A, Caetano M, Barbosa RM, Laranjinha J (2018) Age-Dependent Impairment of Neurovascular and Neurometabolic Coupling in the Hippocampus. Front Physiol 9:913

    Article  PubMed  PubMed Central  Google Scholar 

  101. Lourenco CF, Santos RM, Barbosa RM, Cadenas E, Radi R, Laranjinha J (2014) Neurovascular coupling in hippocampus is mediated via diffusion by neuronal-derived nitric oxide. Free Radic Biol Med 73:421–429

    Article  CAS  PubMed  Google Scholar 

  102. Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267

    Article  CAS  PubMed  Google Scholar 

  103. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50

    Article  CAS  PubMed  Google Scholar 

  104. Fujimoto Y, Uno E, Sakuma S (2004) Effects of reactive oxygen and nitrogen species on cyclooxygenase-1 and -2 activities. Prostaglandins Leukot Essent Fatty Acids 71:335–340

    Article  CAS  PubMed  Google Scholar 

  105. Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199

    Article  CAS  PubMed  Google Scholar 

  106. Buxton RB (2010) Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism. Front Neuroenerg 2:8

    Google Scholar 

  107. Boedtkjer E (2018) Acid-base regulation and sensing: Accelerators and brakes in metabolic regulation of cerebrovascular tone. J Cerebral Blood Flow Metab 38:588–602

    Article  CAS  Google Scholar 

  108. Nippert AR, Biesecker KR, Newman EA (2018) Mechanisms Mediating Functional Hyperemia in the Brain. Neuroscientist 24:73–83

    Article  CAS  PubMed  Google Scholar 

  109. Gordon GR, Choi HB, Rungta RL, Ellis-Davies GC, MacVicar BA (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456:745–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gordon GR, Howarth C, MacVicar BA (2016) bidirectional control of blood flow by astrocytes: a role for tissue oxygen and other metabolic factors. Adv Exp Med Biol 903:209–219

    Article  CAS  PubMed  Google Scholar 

  111. Boillat Y, Xin L, van der Zwaag W, Gruetter R (2019) Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla. J Cerebral Blood Flow Metab. 40(3):488–500

    Article  Google Scholar 

  112. Zhou S, Giannetto M, DeCourcey J, Kang H, Kang N, Li Y, Zheng S, Zhao H, Simmons WR, Wei HS, Bodine DM, Low PS, Nedergaard M, Wan J (2019) Oxygen tension-mediated erythrocyte membrane interactions regulate cerebral capillary hyperemia. Sci Adv 5:eaaw4466

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Pelligrino DA, Vetri F, Xu HL (2011) Purinergic mechanisms in gliovascular coupling. Semin Cell Dev Biol 22:229–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015) Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 309:H1837–1845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hibbs JB Jr, Taintor RR, Vavrin Z, Rachlin EM (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157:87–94

    Article  CAS  PubMed  Google Scholar 

  117. Garthwaite J, Garthwaite G, Palmer RM, Moncada S (1989) NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol 172:413–416

    Article  CAS  PubMed  Google Scholar 

  118. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    CAS  PubMed  Google Scholar 

  119. Lundberg JO, Weitzberg E, Lundberg JM, Alving K (1994) Intragastric nitric oxide production in humans: measurements in expelled air. Gut 35:1543–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Benjamin N, O'Driscoll F, Dougall H, Duncan C, Smith L, Golden M, McKenzie H (1994) Stomach NO synthesis. Nature 368:502

    Article  CAS  PubMed  Google Scholar 

  121. Lundberg JO, Weitzberg E, Gladwin MT (2008) The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discovery 7:156–167

    Article  CAS  PubMed  Google Scholar 

  122. Kahn T, Bosch J, Levitt MF, Goldstein MH (1975) Effect of sodium nitrate loading on electrolyte transport by the renal tubule. Am J Physiol 229:746–753

    Article  CAS  PubMed  Google Scholar 

  123. Fritsch P, de Saint BG, Klein D (1985) Excretion of nitrates and nitrites in saliva and bile in the dog. Food Chem Toxicol 23:655–659

    Article  CAS  PubMed  Google Scholar 

  124. Qin L, Liu X, Sun Q, Fan Z, Xia D, Ding G, Ong HL, Adams D, Gahl WA, Zheng C, Qi S, Jin L, Zhang C, Gu L, He J, Deng D, Ambudkar IS, Wang S (2012) Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane. Proc Natl Acad Sci USA 109:13434–13439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Li H, Duncan C, Townend J, Killham K, Smith LM, Johnston P, Dykhuizen R, Kelly D, Golden M, Benjamin N, Leifert C (1997) Nitrate-reducing bacteria on rat tongues. Appl Environ Microbiol 63:924–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Carlstrom M, Lundberg JO, Weitzberg E (2018) Mechanisms underlying blood pressure reduction by dietary inorganic nitrate. Acta Physiol 224:e13080

    Article  CAS  Google Scholar 

  127. Lundberg JO, Carlstrom M, Weitzberg E (2018) Metabolic effects of dietary nitrate in health and disease. Cell Metab 28:9–22

    Article  CAS  PubMed  Google Scholar 

  128. Bjorne HH, Petersson J, Phillipson M, Weitzberg E, Holm L, Lundberg JO (2004) Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Investig 113:106–114

    Article  PubMed Central  Google Scholar 

  129. Petersson J, Phillipson M, Jansson EA, Patzak A, Lundberg JO, Holm L (2007) Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am J Physiol Gastrointest Liver Physiol 292:G718–724

    Article  CAS  PubMed  Google Scholar 

  130. Jadert C, Petersson J, Massena S, Ahl D, Grapensparr L, Holm L, Lundberg JO, Phillipson M (2012) Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury. Free Radic Biol Med 52:683–692

    Article  PubMed  CAS  Google Scholar 

  131. Woessner MN, McIlvenna LC, Ortiz de Zevallos J, Neil CJ, Allen JD (2018) Dietary nitrate supplementation in cardiovascular health: an ergogenic aid or exercise therapeutic? Am J Physiol Heart Circ Physiol 314:H195–H212

    Article  PubMed  CAS  Google Scholar 

  132. Presley TD, Morgan AR, Bechtold E, Clodfelter W, Dove RW, Jennings JM, Kraft RA, King SB, Laurienti PJ, Rejeski WJ, Burdette JH, Kim-Shapiro DB, Miller GD (2011) Acute effect of a high nitrate diet on brain perfusion in older adults. Nitric Oxide Biol Chem 24:34–42

    Article  CAS  Google Scholar 

  133. Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR (2011) Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 10:429–437

    Article  CAS  PubMed  Google Scholar 

  134. Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, Gladwin MT (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 204:2089–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Carlstrom M, Larsen FJ, Nystrom T, Hezel M, Borniquel S, Weitzberg E, Lundberg JO (2010) Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA 107:17716–17720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B (2007) Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol 191:59–66

    Article  CAS  Google Scholar 

  137. Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E (2011) Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab 13:149–159

    Article  CAS  PubMed  Google Scholar 

  138. Rocha BS, Gago B, Barbosa RM, Lundberg JO, Radi R, Laranjinha J (2012) Intragastric nitration by dietary nitrite: implications for modulation of protein and lipid signaling. Free Radic Biol Med 52:693–698

    Article  CAS  PubMed  Google Scholar 

  139. Gago B, Lundberg JO, Barbosa RM, Laranjinha J (2007) Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic Biol Med 43:1233–1242

    Article  CAS  PubMed  Google Scholar 

  140. Peri L, Pietraforte D, Scorza G, Napolitano A, Fogliano V, Minetti M (2005) Apples increase nitric oxide production by human saliva at the acidic pH of the stomach: a new biological function for polyphenols with a catechol group? Free Radic Biol Med 39:668–681

    Article  CAS  PubMed  Google Scholar 

  141. Rocha BS, Gago B, Barbosa RM, Laranjinha J (2009) Dietary polyphenols generate nitric oxide from nitrite in the stomach and induce smooth muscle relaxation. Toxicology 265:41–48

    Article  CAS  PubMed  Google Scholar 

  142. Rocha BS, Gago B, Barbosa RM, Laranjinha J (2010) Diffusion of nitric oxide through the gastric wall upon reduction of nitrite by red wine: physiological impact. Nitric Oxide Biol Chem 22:235–241

    Article  CAS  Google Scholar 

  143. Wink DAM, Mitchell JB, Grisham MB, Fukuto J, Feelisch M (2000) The chemical biology of nitric oxide: balancing nitric oxide with oxidative and nitrosative stress. In: Mayer B (ed) Handbook of experimental pharmacology. Springer, New York, pp 7–29

  144. Rocha BS, Gago B, Pereira C, Barbosa RM, Bartesaghi S, Lundberg JO, Radi R, Laranjinha J (2011) Dietary nitrite in nitric oxide biology: a redox interplay with implications for pathophysiology and therapeutics. Curr Drug Targets 12:1351–1363

    Article  CAS  PubMed  Google Scholar 

  145. Lundberg JO, Weitzberg E (2013) Biology of nitrogen oxides in the gastrointestinal tract. Gut 62:616–629

    Article  CAS  PubMed  Google Scholar 

  146. Gago B, Nystrom T, Cavaleiro C, Rocha BS, Barbosa RM, Laranjinha J, Lundberg JO (2008) The potent vasodilator ethyl nitrite is formed upon reaction of nitrite and ethanol under gastric conditions. Free Radic Biol Med 45:404–412

    Article  CAS  PubMed  Google Scholar 

  147. Rocha BS, Gago B, Barbosa RM, Cavaleiro C, Laranjinha J (2015) Ethyl nitrite is produced in the human stomach from dietary nitrate and ethanol, releasing nitric oxide at physiological pH: potential impact on gastric motility. Free Radic Biol Med 82:160–166

    Article  CAS  PubMed  Google Scholar 

  148. Pereira C, Barbosa RM, Laranjinha J (2015) Dietary nitrite induces nitrosation of the gastric mucosa: the protective action of the mucus and the modulatory effect of red wine. J Nutr Biochem 26:476–483

    Article  CAS  PubMed  Google Scholar 

  149. Rocha BS, Gago B, Barbosa RM, Lundberg JO, Mann GE, Radi R, Laranjinha J (2013) Pepsin is nitrated in the rat stomach, acquiring antiulcerogenic activity: a novel interaction between dietary nitrate and gut proteins. Free Radic Biol Med 58:26–34

    Article  CAS  PubMed  Google Scholar 

  150. Rocha BS, Correia MG, Fernandes RC, Goncalves JS, Laranjinha J (2016) Dietary nitrite induces occludin nitration in the stomach. Free Radic Res 50:1257–1264

    Article  CAS  PubMed  Google Scholar 

  151. Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discovery 6:662–680

    Article  CAS  PubMed  Google Scholar 

  152. Bolanos JP, Garcia-Nogales P, Almeida A (2004) Provoking neuroprotection by peroxynitrite. Curr Pharm Des 10:867–877

    Article  CAS  PubMed  Google Scholar 

  153. Bolanos JP, Moro MA, Lizasoain I, Almeida A (2009) Mitochondria and reactive oxygen and nitrogen species in neurological disorders and stroke: therapeutic implications. Adv Drug Deliv Rev 61:1299–1315

    Article  CAS  PubMed  Google Scholar 

  154. Vega-Agapito V, Almeida A, Heales SJ, Medina JM, Bolanos JP (1999) Peroxynitrite anion stimulates arginine release from cultured rat astrocytes. J Neurochem 73:1446–1452

    Article  CAS  PubMed  Google Scholar 

  155. Rocha BS, Lundberg JO, Radi R, Laranjinha J (2016) Role of nitrite, urate and pepsin in the gastroprotective effects of saliva. Redox Biol 8:407–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ferrer-Sueta G, Campolo N, Trujillo M, Bartesaghi S, Carballal S, Romero N, Alvarez B, Radi R (2018) Biochemistry of peroxynitrite and protein tyrosine nitration. Chem Rev 118:1338–1408

    Article  CAS  PubMed  Google Scholar 

  157. Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lundberg JO, Govoni M (2004) Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 37:395–400

    Article  CAS  PubMed  Google Scholar 

  159. Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AMG (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775

    Article  CAS  PubMed  Google Scholar 

  160. Calabrese V, Cornelius C, Rizzarelli E, Owen JB, Dinkova-Kostova AT, Butterfield DA (2009) Nitric oxide in cell survival: a janus molecule. Antioxid Redox Signal 11:2717–2739

    Article  CAS  PubMed  Google Scholar 

  161. Calabrese V, Cornelius C, Dinkova-Kostova A, Calabrese EJ, Mattson MP (2010) Cellular stress responses, the hormesis paradigm and vitagens: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 13:1763–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Martínez-Reyes I, Chandel NS (2020) Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11:102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:17–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was financed by the European Regional Development Fund (FEDER) funds through the Operational Program for Competitiveness and Internationalization—COMPETE and national funds by FCT—Foundation for Science and Technology under the project POCI-01-0145-FEDER-029099 and through the Centro 2020 Regional Operational Program, under the project CENTRO-01-0145-FEDER-000012-HealthyAging2020.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal

    João Laranjinha, Carla Nunes, Bárbara Rocha & Rui M. Barbosa

  2. Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal

    João Laranjinha, Carla Nunes, Ana Ledo, Cátia Lourenço, Bárbara Rocha & Rui M. Barbosa

Authors
  1. João Laranjinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carla Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Ledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cátia Lourenço
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bárbara Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui M. Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João Laranjinha.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This is a special issue honoring Professor Juan Bolaños. Being in the field of nitric oxide biology, it is inevitable to come across and be motivated by Juan Bolaños’ work, so many and important were his contributions to the field. In this short review, using an autobiographic style, we intend to address many facets of ·NO biology, from the gut to the brain, as a master modulator of diverse signaling pathways, ranging from disease-associated NO signaling (e.g., Parkinons’s and Alzheimer’s diseases) to the regulation of brain bioenergetics and metabolic and neurovascular coupling. Finally, the impact of the nitrate:nitrite:NO pathway is discussed in connection with gut microbial involvement in NO generation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laranjinha, J., Nunes, C., Ledo, A. et al. The Peculiar Facets of Nitric Oxide as a Cellular Messenger: From Disease-Associated Signaling to the Regulation of Brain Bioenergetics and Neurovascular Coupling. Neurochem Res 46, 64–76 (2021). https://doi.org/10.1007/s11064-020-03015-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03015-0

Keywords

Search

Navigation