[Frontiers in Bioscience, Landmark, 22, 824-834, January 1, 2017]

Nitric oxide-mediated pathways and its role in the degenerative diseases

Nan Zhang 1 , 2 , Yu Diao 1 , Rongrong Hua 1 , Jun Wang 3 , Song Han 1 , Junfa Li 1 , Yanling Yin 1

1Department of Neurobiology and Beijing Institute for Brain Disorders, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China, 2Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China, 3Department of Anatomy and Embryology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China


1. Abstract
2. Introduction
    2.1. The synthesis and functions of nitric oxide in physiological conditions
    2.2. Effects of NO on major disease-related biological processes
      2.2.1. Endoplasmic reticulum (ER) stress (ERS)
      2.2.3. Autophagy
3. The actions of nitric oxide in nervous system
4. The role of nitric oxide in neurodegenerative diseases
5. Acknowledgements
6. References


Nitric oxide (NO) is a relatively short-lived inorganic free radical, which can be produced by different types of cells in multi-cellular organisms. This diffusible messenger functions as either an effector or a second messenger in many intercellular communications or intracellular signaling pathways. NO becomes noxious if it is produced in excess. These effects are mainly mediated by the reactivity of NO with various reactive oxygen species, which can be countered by antioxidant enzymes. In addition, NO can directly modify biological molecules via S-nitrosylation and lead to altered signaling responses. Accumulating evidence suggests that NO has a double-edged role in a dose-dependent, cell-type specific, and biological milieu-dependent way. In the present review, we summarized the synthesis and signaling pathway of NO, and especially focused on its involvement in biological processes, such as endoplasmic reticulum stress, apoptosis and autophagy. Besides, we discussed the functions of NO in the nervous system and its potential role in neurodegenerative diseases. We proposed the target on NO may shed light on the treatment of the related diseases.


1. R. F. Furchgott and J. V. Zawadzki: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373-6 (1980)
DOI: 10.1038/288373a0

2. R. M. Palmer, A. G. Ferrige and S. Moncada: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524-6 (1987)
DOI: 10.1038/327524a0

3. D. Fukumura, S. Kashiwagi and R. K. Jain: The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6, 521-34 (2006)
DOI: 10.1038/nrc1910

4. D. S. Bredt: Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 31, 577-96 (1999)
DOI: 10.1080/10715769900301161

5. H. Vahora, M. A. Khan, U. Alalami and A. Hussain: The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention. J Cancer Prev 21, 1-12 (2016)
DOI: 10.15430/JCP.2016.21.1.1

6. S. H. Francis, J. L. Busch, J. D. Corbin and D: Sibley. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol. Rev 62, 525-63 (2010)
DOI: 10.1124/pr.110.002907

7. J. P. Stasch, P. Schmidt, C. Alonso-Alija, H. Apeler, K. Dembowsky, M. Haerter, M. Heil, T. Minuth, E. Perzborn, U. Pleiss, M. Schramm, W. Schroeder, H. Schroder, E. Stahl, W. Steinke and F. Wunder: NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol 136, 773-83(2002)
DOI: 10.1038/sj.bjp.0704778

8. J. P. Stasch, P. M. Schmidt, P. I. Nedvetsky, T. Y. Nedvetskaya, S. A. H, S. Meurer, M. Deile, A. Taye, A. Knorr, H. Lapp, H. Muller, Y. Turgay, C. Rothkegel, A. Tersteegen, B. Kemp-Harper, W. Muller-Esterl and H. H. Schmidt: Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J. Clin. Invest 116, 2552-61(2006)
DOI: 10.1172/JCI28371

9. J. W. Denninger and M. A. Marletta: Guanylate cyclase and the. NO/cGMP signaling pathway. Biochim Biophys Acta 1411, 334-50 (1999)
DOI: 10.1016/S0005-2728(99)00024-9

10. N. Chaudhari, P. Talwar, A. Parimisetty, D. C. Lefebvre and P. Ravanan. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front. Cell. Neurosci 8, 213 (2014)
DOI: 10.3389/fncel.2014.00213

11. T. Uehara, T. Nakamura, D. Yao, Z. Q. Shi, Z. Gu, Y. Ma, E. Masliah, Y. Nomura and S. A. Lipton: S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513-7 (2006)
DOI: 10.1038/nature04782

12. R. Nakato, Y. Ohkubo, A. Konishi, M. Shibata, Y. Kaneko, T. Iwawaki, T. Nakamura, S. A. Lipton and T. Uehara: Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress. Sci Rep 5, 14812 (2015)
DOI: 10.1038/srep14812

13. L. Xu, J. P. Eu, G. Meissner and J. S. Stamler: Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279, 234-7 (1998)
DOI: 10.1126/science.279.5348.234

14. A. Csordas, E. Pankotai, J. A. Snipes, A. Cselenyak, Z. Sarszegi, A. Cziraki, B. Gaszner, L. Papp, R. Benko, L. Kiss, E. Kovacs, M. Kollai, C. Szabo, D. W. Busija and Z. Lacza: Human heart mitochondria do not produce physiologically relevant quantities of nitric oxide. Life Sci 80, 633-7 (2007)
DOI: 10.1016/j.lfs.2006.10.009

15. W. Xu, L. Liu, I. G. Charles and S: Moncada. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat. Cell Biol 6, 1129-34 (2004)
DOI: 10.1038/ncb1188

16. L. Leon-Bollotte, S. Subramaniam, O. Cauvard, S. Plenchette-Colas, C. Paul, C. Godard, A. Martinez-Ruiz, P. Legembre, J. F. Jeannin and A. Bettaieb: S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology 140, 2009-18, 2018.e1-4 (2011)

17. M. W. Baek, K. J. Seong, Y. J. Jeong, G. M. Kim, H. J. Park, S. H. Kim, H. J. Chung, W. J. Kim and J. Y. Jung: Nitric oxide induces apoptosis in human gingival fibroblast through mitochondria-dependent pathway and JNK activation. Int. Endod. J 48, 287-97 (2015)
DOI: 10.1111/iej.12314

18. P. S. Brookes, E. P. Salinas, K. Darley-Usmar, J. P. Eiserich, B. A. Freeman, V. M. Darley-Usmar and P. G. Anderson: Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release. J. Biol. Chem 275, 20474-9 (2000)
DOI: 10.1074/jbc.M001077200

19. L. L. Pearce, A. J. Kanai, M. W. Epperly and J. Peterson: Nitrosative stress results in irreversible inhibition of purified mitochondrial complexes I and III without modification of cofactors. Nitric Oxide 13, 254-63 (2005)
DOI: 10.1016/j.niox.2005.07.010

20. L. K. Folkes and P. O’Neill: DNA damage induced by nitric oxide during ionizing radiation is enhanced at replication. Nitric Oxide 34, 47-55 (2013)
DOI: 10.1016/j.niox.2013.04.005

21. I. H. Chae, K. W. Park, H. S. Kim and B. H. Oh: Nitric oxide-induced apoptosis is mediated by Bax/Bcl-2 gene expression, transition of cytochrome c, and activation of caspase-3 in rat vascular smooth muscle cells. Clin. Chim. Acta 341, 83-91 (2004)
DOI: 10.1016/j.cccn.2003.11.009

22. G. Rathnasamy, V. Sivakumar, P. Rangarajan, W. S. Foulds, E. A. Ling and C. Kaur: NF-kappaB-mediated nitric oxide production and activation of caspase-3 cause retinal ganglion cell death in the hypoxic neonatal retina. Invest Ophthalmol Vis Sci 55, 5878-89 (2014)
DOI: 10.1167/iovs.13-13718

23. W. Wu, O. W. Wan and K. K. Chung: S-nitrosylation of XIAP at Cys 213 of BIR2 domain impairs XIAP’s anti-caspase 3 activity and anti-apoptotic function. Apoptosis 20, 491-9 (2015)
DOI: 10.1007/s10495-015-1087-3

24. P. T. Saligrama, K. A. Fortner, M. A. Secinaro, C. C. Collins, J. Q. Russell and R. C. Budd: IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3. Cell Death Differ 21, 904-14 (2014)
DOI: 10.1038/cdd.2014.10

25. E. T. Chouchani, C. Methner, S. M. Nadtochiy, A. Logan, V. R. Pell, S. Ding, A. M. James, H. M. Cocheme, J. Reinhold, K. S. Lilley, L. Partridge, I. M. Fearnley, A. J. Robinson, R. C. Hartley, R. A. Smith, T. Krieg, P. S. Brookes and M. P. Murphy: Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med 19, 753-9 (2013)
DOI: 10.1038/nm.3212

26. N. Azad, V. Vallyathan, L. Wang, V. Tantishaiyakul, C. Stehlik, S. S. Leonard and Y. Rojanasakul: S-nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation. A novel antiapoptotic mechanism that suppresses apoptosis. J. Biol. Chem 281, 34124-34 (2006)
DOI: 10.1074/jbc.M602551200

27. B. Levine and G.: Kroemer. Autophagy in the pathogenesis of disease. Cell 132, 27-42 (2008)
DOI: 10.1016/j.cell.2007.12.018

28. C. He and D. J. Klionsky: Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet 43, 67-93 (2009)
DOI: 10.1146/annurev-genet-102808-114910

29. H. Yuan, C. N. Perry, C. Huang, E. Iwai-Kanai, R. S. Carreira, C. C. Glembotski and R. A. Gottlieb: LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection. Am J Physiol Heart Circ Physiol 296, H470-9 (2009)
DOI: 10.1152/ajpheart.01051.2008

30. F. Han, Y. X. Chen, Y. M. Lu, J. Y. Huang, G. S. Zhang, R. R. Tao, Y. L. Ji, M. H. Liao, K. Fukunaga and Z. H. Qin: Regulation of the ischemia-induced autophagy-lysosome processes by nitrosative stress in endothelial cells. J. Pineal Res 51, 124-35 (2011)
DOI: 10.1111/j.1600-079X.2011.00869.x

31. S. Sarkar, V. I. Korolchuk, M. Renna, S. Imarisio, A. Fleming, A. Williams, M. Garcia-Arencibia, C. Rose, S. Luo, B. R. Underwood, G. Kroemer, C. J. O’Kane and D. C. Rubinsztein: Complex inhibitory effects of nitric oxide on autophagy. Mol. Cell 43, 19-32 (2011)
DOI: 10.1016/j.molcel.2011.04.029

32. C. Shen, J. Yan, O. F. Erkocak, X. F. Zheng and X. D. Chen: Nitric oxide inhibits autophagy via suppression of JNK in meniscal cells. Rheumatology (Oxford) 53, 1022-33 (2014)
DOI: 10.1093/rheumatology/ket471

33. L. P. Bharath, R. Mueller, Y. Li, T. Ruan, D. Kunz, R. Goodrich, T. Mills, L. Deeter, A. Sargsyan, B. P. Anandh, T. E. Graham and J. D. Symons: Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability. Can J Physiol Pharmacol 92, 605-12 (2014)
DOI: 10.1139/cjpp-2014-0017

34. J. L. Fetterman, M. Holbrook, N. Flint, B. Feng, R. Bretomicronn-Romero, E. A. Linder, B. D. Berk, M. A. Duess, M. G. Farb, N. Gokce, O. S. Shirihai, N. M. Hamburg and J. A. Vita: Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis 247, 207-17 (2016)
DOI: 10.1016/j.atherosclerosis.2016.01.043

35. J. Garthwaite: Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci 27, 2783-802 (2008)
DOI: 10.1111/j.1460-9568.2008.06285.x

36. C. X. Luo and D. Y. Zhu: Research progress on neurobiology of neuronal nitric oxide synthase. Neurosci. Bull 27, 23-35(2011)
DOI: 10.1007/s12264-011-1038-0

37. N. Toda and A. G. Herman; Gastrointestinal function regulation by nitrergic efferent nerves. Pharmacol Rev 57, 315-38 (2005)
DOI: 10.1124/pr.57.3.4

38. X. X. Yan, L. S. Jen and L. J. Garey: NADPH-diaphorase-positive neurons in primate cerebral cortex colocalize with GABA and calcium-binding proteins. Cereb. Cortex 6, 524-9(1996)
DOI: 10.1093/cercor/6.3.524

39. K. S. Christopherson, B. J. Hillier, W. A. Lim and D. S. Bredt: PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J. Biol. Chem 274, 27467-73 (1999)
DOI: 10.1074/jbc.274.39.27467

40. K. T. Ota, V. J. Pierre, J. E. Ploski, K. Queen and G. E. Schafe: The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase. Learn Mem 15, 792-805 (2008)
DOI: 10.1101/lm.1114808

41. M. Michel, C. L. Green and L. C. Lyons: PKA and PKC are required for long-term but not short-term in vivo operant memory in Aplysia. Learn Mem 18, 19-23 (2011)
DOI: 10.1101/lm.2026311

42. S. K. Sharma, C. M. Sherff, J. Shobe, M. W. Bagnall, M. A. Sutton and T. J. Carew: Differential role of mitogen-activated protein kinase in three distinct phases of memory for sensitization in Aplysia. J. Neurosci 23, 3899-907 (2003)

43. M. Michel, C. L. Green, A. Eskin and L. C. Lyons; PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia. Learn Mem 18, 108-17 (2011)
DOI: 10.1101/lm.2063611

44. T. Nakamura and S. A. Lipton: Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol. Sci 37, 73-84 (2016)
DOI: 10.1016/j.tips.2015.10.002

45. G. T. Liberatore, V. Jackson-Lewis, S. Vukosavic, A. S. Mandir, M. Vila, W. G. McAuliffe, V. L. Dawson, T. M. Dawson and S. Przedborski: Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med 5, 1403-9 (1999)
DOI: 10.1038/70978

46. T. Nakamura, O. A. Prikhodko, E. Pirie, S. Nagar, M. W. Akhtar, C. K. Oh, S. R. McKercher, R. Ambasudhan, S. Okamoto and S. A. Lipton: Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol. Dis 84, 99-108 (2015)
DOI: 10.1016/j.nbd.2015.03.017

47. S. Singh and M. Dikshit: Apoptotic neuronal death in Parkinson’s disease: involvement of nitric oxide. Brain Res Rev 54, 233-50 (2007)
DOI: 10.1016/j.brainresrev.2007.02.001

48. R. Nakato, Y. Ohkubo, A. Konishi, M. Shibata, Y. Kaneko, T. Iwawaki, T. Nakamura, S. A. Lipton and T. Uehara: Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress. Sci Rep 5, 14812 (2015)
DOI: 10.1038/srep14812

49. T. Uehara, T. Nakamura, D. Yao, Z. Q. Shi, Z. Gu, Y. Ma, E. Masliah, Y. Nomura and S. A. Lipton: S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513-7 (2006)
DOI: 10.1038/nature04782

50. K. Ozawa, A. T. Komatsubara, Y. Nishimura, T. Sawada, H. Kawafune, H. Tsumoto, Y. Tsuji, J. Zhao, Y. Kyotani, T. Tanaka, R: Takahashi and M. Yoshizumi. S-nitrosylation regulates mitochondrial quality control via activation of parkin. Sci Rep 3, 2202 (2013)
DOI: 10.1038/srep02202

51. A. C. Poole, R. E. Thomas, L. A. Andrews, H. M. McBride, A. J. Whitworth and L. J. Pallanck: The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105, 1638-43 (2008)
DOI: 10.1073/pnas.0709336105

52. S. J. Chinta, J. K. Mallajosyula, A. Rane and J. K. Andersen: Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci. Lett 486, 235-9 (2010)
DOI: 10.1016/j.neulet.2010.09.061

53. X. Chen, T. Guan, C. Li, H. Shang, L. Cui, X. M. Li and J. Kong: SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI). J Neuroinflammation 9, 237 (2012)
DOI: 10.1186/1742-2094-9-237

54. S. Okamoto, Z. Li, C. Ju, M. N. Scholzke, E. Mathews, J. Cui, G. S. Salvesen, E. Bossy-Wetzel and S. A. Lipton: Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc Natl Acad Sci U S A 99, 3974-9 (2002)
DOI: 10.1073/pnas.022036399

55. J. B. Mannick, C. Schonhoff, N. Papeta, P. Ghafourifar, M. Szibor, K. Fang and B. Gaston: S-Nitrosylation of mitochondrial caspases. J. Cell Biol 154, 1111-6 (2001)
DOI: 10.1083/jcb.200104008

56. O. Felicity, S. Louis, E. Gazit and A. de Mel. Is Nitric Oxide Assuming a Janus-Face in The Central Nervous System? Curr. Med. Chem (2016)

57. R. Balez and L. Ooi: Getting to NO Alzheimer’s Disease: Neuroprotection versus Neurotoxicity Mediated by Nitric Oxide. Oxid. Med. Cell. Longev 2016, 3806157 (2016)

58. J. R. Steinert, T. Chernova and I. D. Forsythe: Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16, 435-52 (2010)
DOI: 10.1177/1073858410366481

59. M. W. Akhtar, S. Sanz-Blasco, N. Dolatabadi, J. Parker, K. Chon, M. S. Lee, W. Soussou, S. R. McKercher, R. Ambasudhan, T. Nakamura and S. A. Lipton: Elevated glucose and oligomeric beta-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat. Commun 7, 10242 (2016)
DOI: 10.1038/ncomms10242

60. A. L. Gharibyan, V. Zamotin, K. Yanamandra, O. S. Moskaleva, B. A. Margulis, I. A. Kostanyan and L. A. Morozova-Roche: Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways. J. Mol. Biol 365, 1337-49 (2007)
DOI: 10.1016/j.jmb.2006.10.101

61. W. Lin, M. Ding, J. Xue and W. Leng: The role of TLR2/JNK/NF-kappaB pathway in amyloid beta peptide-induced inflammatory response in mouse NG108-15 neural cells. Int. Immunopharmacol 17, 880-4 (2013)
DOI: 10.1016/j.intimp.2013.09.016

62. M. Shariatpanahi, F. Khodagholi, G. Ashabi, K. A. Aghazadeh, L. Azimi, M. Abdollahi, M. H. Ghahremani, S. N. Ostad, F. Noorbakhsh and M. Sharifzadeh: Ameliorating of Memory Impairment and Apoptosis in Amyloid beta-Injected Rats Via Inhibition of Nitric Oxide Synthase: Possible Participation of Autophagy. Iran. J. Pharm. Res 14, 811-24 (2015)

63. F. Shaerzadeh, F. Motamedi, D. Minai-Tehrani and F. Khodagholi: Monitoring of neuronal loss in the hippocampus of Abeta-injected rat: autophagy, mitophagy, and mitochondrial biogenesis stand against apoptosis. Neuromolecular Med 16, 175-90 (2014)
DOI: 10.1007/s12017-013-8272-8

64. R. M. Santos, C. F. Lourenco, A. Ledo, R. M. Barbosa and J. Laranjinha: Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. Int J Cell Biol 2012, 391914 (2012)

65. S. Kohgami, T. Ogata, T. Morino, H. Yamamoto and P. Schubert: Pharmacological shift of the ambiguous nitric oxide action from neurotoxicity to cyclic GMP-mediated protection. Neurol. Res 32, 938-44 (2010)
DOI: 10.1179/016164110X12681290831243

66. R. R. Mize and F. Lo: Nitric oxide, impulse activity, and neurotrophins in visual system development(1). Brain Res 886, 15-32 (2000)
DOI: 10.1016/S0006-8993(00)02750-5

67. A. Contestabile and E. Ciani: Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation. Neurochem. Int 45, 903-14 (2004)
DOI: 10.1016/j.neuint.2004.03.021

68. C. Estrada and M. Murillo-Carretero: Nitric oxide and adult neurogenesis in health and disease. Neuroscientist 11, 294-307 (2005)
DOI: 10.1177/1073858404273850

69. D. A. Golombek, P. V. Agostino, S. A. Plano and G. A. Ferreyra: Signaling in the mammalian circadian clock: the NO/cGMP pathway. Neurochem. Int 45, 929-36 (2004)
DOI: 10.1016/j.neuint.2004.03.023

70. A. J. Susswein, A. Katzoff, N. Miller and I. Hurwitz: Nitric oxide and memory. Neuroscientist 10, 153-62 (2004)
DOI: 10.1177/1073858403261226

71. A. Katzoff, T. Ben-Gedalya, I. Hurwitz, N. Miller, Y. Z. Susswein and A. J. Susswein: Nitric oxide signals that aplysia have attempted to eat, a necessary component of memory formation after learning that food is inedible. J. Neurophysiol 96, 1247-57 (2006)
DOI: 10.1152/jn.00056.2006

72. C. Rivier: Role of gaseous neurotransmitters in the hypothalamic-pituitary-adrenal axis. Ann N Y Acad Sci 933, 254-64 (2001)
DOI: 10.1111/j.1749-6632.2001.tb05829.x

73. V. Calabrese, C. Mancuso, M. Calvani, E. Rizzarelli, D. A. Butterfield and A. M. Stella: Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat. Rev. Neurosci 8, 766-75 (2007)
DOI: 10.1038/nrn2214

74. M. J. Oset-Gasque, M. Parramon, S. Hortelano, L. Bosca and M. P. Gonzalez: Nitric oxide implication in the control of neurosecretion by chromaffin cells. J. Neurochem 63, 1693-700 (1994)
DOI: 10.1046/j.1471-4159.1994.63051693.x

75. N. Toda, K. Ayajiki and T. Okamura: Nitric oxide and penile erectile function. Pharmacol Ther 106, 233-66 (2005)
DOI: 10.1016/j.pharmthera.2004.11.011

76. N. Toda and T. Okamura: Mechanism underlying the response to vasodilator nerve stimulation in isolated dog and monkey cerebral arteries. Am J Physiol 259, H1511-7 (1990)

77. N. Toda and T. Okamura: Possible role of nitric oxide in transmitting information from vasodilator nerve to cerebroarterial muscle. Biochem Biophys Res Commun 170, 308-13 (1990)
DOI: 10.1016/0006-291X(90)91275-W

78. K. Hebeiss and H. Kilbinger: Cholinergic and GABAergic regulation of nitric oxide synthesis in the guinea pig ileum. Am J Physiol 276, G862-6 (1999)

79. Nathan S. Bryan, Ka Bian, Ferid Murad: Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci, Landmark 14, 1 - 18 (2009)
DOI: 10.2741/3228

Key Words: Nitric Oxide (NO), Autophagy, Apoptosis, Endoplasmic Reticulum Stress (ERS), Neurodegenerative Diseases, Review

Send correspondence to: Yanling Yin, Departmentof Neurobiology, Beijing Institute for Brain Disorders, Capital Medical University, #10 You An Men Wai Xi Tou Tiao, Beijing 100069, P.R.China, Tel: 8610-8391-1492, Fax: Fax: 8610-8391-1491, E-mail: yyling@ccmu.edu.cn