Neurochemical Research

, 34:1907 | Cite as

The Potential Role of Nitric Oxide Synthase in Survival and Regeneration of Magnocellular Neurons of Hypothalamo-Neurohypophyseal System

  • Qiuju Yuan
  • David E. Scott
  • Kwow-Fai So
  • Zhixiu Lin
  • Wutian Wu
Original Paper


Previous investigations from this laboratory have demonstrated that hypophysectomy induces up-regulation of neuronal nitric oxide synthase (nNOS) in magnocellular neurons of the mammalian hypothalamo-neurohypophyseal system (HNS). Accompanied by this upregulation of nNOS, both neuronal regeneration and degeneration are also observed in this system following hypophysectomy. The specific aim of this study was to determine the potential role of nNOS upregulation in neuronal survival and regeneration after hypophysectomy in the adult Sprague–Dawley (SD) rat by using a competitive nitric oxide synthase blocker, N(G)-nitrol-l-arginine methyl ester (l-NAME). We found that l-NAME treatment effectively blocked the regeneration of magnocellular neurons of the rodent hypothalamus as observed in the lumen of the third cerebral ventricle following hypophysectomy. However, l-NAME had no effect on the survival of magnocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei after hypophysectomy. These results suggest that the induced increase of nNOS expression enhance the regenerative ability of magnocellular neurons of the HNS following hypophysectomy.


Neuronal plasticity Nitric oxide Axonal injury Endocrine hypothalamus 


  1. 1.
    Choi BM, Pae HO, Jang SI, Kim YM, Chung HT (2002) Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator. J Biochem Mol Biol 35:116–126PubMedGoogle Scholar
  2. 2.
    Kibbe MR, Li J, Nie S, Choi BM, Kovesdi I, Lizonova A, Billiar TR, Tzeng E (2002) Potentiation of nitric oxide-induced apoptosis in p53-/- vascular smooth muscle cells. Am J Physiol Cell Physiol 282:C625–C634PubMedGoogle Scholar
  3. 3.
    Kim KM, Kim PK, Kwon YG, Bai SK, Nam WD, Kim YM (2002) Regulation of apoptosis by nitrosative stress. J Biochem Mol Biol 35:127–133PubMedGoogle Scholar
  4. 4.
    Leonelli M, Torrao AS, Britto LR (2009) Unconventional neurotransmitters, neurodegeneration and neuroprotection. Braz J Med Biol Res 42:68–75. doi: 10.1590/S0100-879X2009000100011 PubMedCrossRefGoogle Scholar
  5. 5.
    Chang HM, Ling EA, Lue JH, Wen CY, Shieh JY (2000) Melatonin attenuates neuronal NADPH-d/NOS expression in the hypoglossal nucleus of adult rats following peripheral nerve injury. Brain Res 873:243–251. doi: 10.1016/S0006-8993(00)02489-6 PubMedCrossRefGoogle Scholar
  6. 6.
    Chang HM, Lue JH, Wen CY, Shieh JY (2001) Axotomy along with hypoxia enhances the neuronal NADPH-d/NOS expression in lower brain stem motor neurons of adult rats. Exp Neurol 171:116–126. doi: 10.1006/exnr.2001.7731 PubMedCrossRefGoogle Scholar
  7. 7.
    Chang HM, Huang YL, Lan CT, Wu UI, Hu ME, Youn SC (2008) Melatonin preserves superoxide dismutase activity in hypoglossal motoneurons of adult rats following peripheral nerve injury. J Pineal Res 44:172–180. doi: 10.1111/j.1600-079X.2007.00505.x PubMedCrossRefGoogle Scholar
  8. 8.
    Wei IH, Huang CC, Tseng CY, Chang HM, Tu HC, Tsai MH, Wen CY, Shieh JY (2008) Mild hypoxic preconditioning attenuates injury-induced NADPH-d/nNOS expression in brainstem motor neurons of adult rats. J Chem Neuroanat 35:123–132. doi: 10.1016/j.jchemneu.2007.08.008 PubMedCrossRefGoogle Scholar
  9. 9.
    Yu WH (2002) Spatial and temporal correlation of nitric oxide synthase expression with CuZn-superoxide dismutase reduction in motor neurons following axotomy. Ann N Y Acad Sci 962:111–121PubMedCrossRefGoogle Scholar
  10. 10.
    Bostanci MO, Bagirici F (2008) Nitric oxide synthesis inhibition attenuates iron-induced neurotoxicity: a stereological study. Neurotoxicology 29:130–135. doi: 10.1016/j.neuro.2007.10.003 PubMedCrossRefGoogle Scholar
  11. 11.
    Chen J, Qin J, Liu X, Han Y, Yang Z, Chang X, Ji X (2008) Nitric oxide-mediated neuronal apoptosis in rats with recurrent febrile seizures through endoplasmic reticulum stress pathway. Neurosci Lett 443:134–139. doi: 10.1016/j.neulet.2008.07.060 PubMedCrossRefGoogle Scholar
  12. 12.
    Kim HJ, Im W, Kim S, Kim SH, Sung JJ, Kim M, Lee KW (2007) Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons. Exp Mol Med 39:574–582PubMedGoogle Scholar
  13. 13.
    Di MV, Benigno A, Pierucci M, Giuliano DA, Crescimanno G, Esposito E, Di Giovanni G (2006) 7-Nitroindazole protects striatal dopaminergic neurons against MPP + -induced degeneration: an in vivo microdialysis study. Ann N Y Acad Sci 1089:462–471CrossRefGoogle Scholar
  14. 14.
    Wu W, Li L (1993) Inhibition of nitric oxide synthase reduces motoneuron death due to spinal root avulsion. Neurosci Lett 153:121–124. doi: 10.1016/0304-3940(93)90303-3 PubMedCrossRefGoogle Scholar
  15. 15.
    Gulturk S, Kozan R, Bostanci MO, Sefil F, Bagirici F (2008) Inhibition of neuronal nitric oxide synthase prevents iron-induced cerebellar Purkinje cell loss in the rat. Acta Neurobiol Exp (Wars) 68:26–31Google Scholar
  16. 16.
    Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775. doi: 10.1038/nrn2214 PubMedCrossRefGoogle Scholar
  17. 17.
    Zhou L, Wu W (2006) Antisense oligos to neuronal nitric oxide synthase aggravate motoneuron death induced by spinal root avulsion in adult rat. Exp Neurol 197:84–92. doi: 10.1016/j.expneurol.2005.08.019 PubMedCrossRefGoogle Scholar
  18. 18.
    Renteria RC, Constantine-Paton M (1999) Nitric oxide in the retinotectal system: a signal but not a retrograde messenger during map refinement and segregation. J Neurosci 19:7066–7076PubMedGoogle Scholar
  19. 19.
    Van Wagenen S, Rehder V (1999) Regulation of neuronal growth cone filopodia by nitric oxide. J Neurobiol 39:168–185. doi: 10.1002/(SICI)1097-4695(199905)39:2<168::AID-NEU2>3.0.CO;2-F PubMedCrossRefGoogle Scholar
  20. 20.
    Chu TH, Wu WT (2006) Nitric oxide synthase inhibitor attenuates number of regenerating spinal motoneurons in adult rats. NeuroReport 17:969–973. doi: 10.1097/01.wnr.0000221839.05008.85 PubMedCrossRefGoogle Scholar
  21. 21.
    Cristino L, Pica A, Della CF, Bentivoglio M (2000) Co-induction of nitric oxide synthase, bcl-2 and growth-associated protein-43 in spinal motoneurons during axon regeneration in the lizard tail. Neuroscience 101:451–458. doi: 10.1016/S0306-4522(00)00393-6 PubMedCrossRefGoogle Scholar
  22. 22.
    Gonzalez-Hernandez T, Rustioni A (1999) Expression of three forms of nitric oxide synthase in peripheral nerve regeneration. J Neurosci Res 55:198–207. doi: 10.1002/(SICI)1097-4547(19990115)55:2<198::AID-JNR7>3.0.CO;2-M PubMedCrossRefGoogle Scholar
  23. 23.
    Stern M, Bicker G (2008) Nitric oxide regulates axonal regeneration in an insect embryonic CNS. Dev Neurobiol 68:295–308. doi: 10.1002/dneu.20585 PubMedCrossRefGoogle Scholar
  24. 24.
    Gonzalez-Hernandez T, Rustioni A (1999) Nitric oxide synthase and growth-associated protein are coexpressed in primary sensory neurons after peripheral injury. J Comp Neurol 404:64–74. doi: 10.1002/(SICI)1096-9861(19990201)404:1<64::AID-CNE5>3.0.CO;2-M PubMedCrossRefGoogle Scholar
  25. 25.
    Keilhoff G, Fansa H, Wolf G (2002) Differences in peripheral nerve degeneration/regeneration between wild-type and neuronal nitric oxide synthase knockout mice. J Neurosci Res 68:432–441. doi: 10.1002/jnr.10229 PubMedCrossRefGoogle Scholar
  26. 26.
    Zochodne DW, Levy D (2005) Nitric oxide in damage, disease and repair of the peripheral nervous system. Cell Mol Biol (Noisy-le-grand) 51:255–267Google Scholar
  27. 27.
    Sunico CR, Portillo F, Gonzalez-Forero D, Kasparov S, Moreno-Lopez B (2008) Evidence for a detrimental role of nitric oxide synthesized by endothelial nitric oxide synthase after peripheral nerve injury. Neuroscience 157:40–51. doi: 10.1016/j.neuroscience.2008.09.001 PubMedCrossRefGoogle Scholar
  28. 28.
    Zochodne DW, Misra M, Cheng C, Sun H (1997) Inhibition of nitric oxide synthase enhances peripheral nerve regeneration in mice. Neurosci Lett 228:71–74. doi: 10.1016/S0304-3940(97)00359-5 PubMedCrossRefGoogle Scholar
  29. 29.
    Scott DE, Wu W, Slusser J, Depto A, Hansen S (1995) Neural regeneration and neuronal migration following injury. I. The endocrine hypothalamus and neurohypophyseal system. Exp Neurol 131:23–38. doi: 10.1016/0014-4886(95)90004-7 PubMedCrossRefGoogle Scholar
  30. 30.
    Yuan Q, Scott DE, So KF, Wu W (2006) The response of magnocellular neurons of the hypothalamo-neurohyphyseal system to hypophysectomy, nitric oxide synthase expression as well as survival and regeneration in developing vs. adult rats. Brain Res 1113:45–53. doi: 10.1016/j.brainres.2006.07.052 PubMedCrossRefGoogle Scholar
  31. 31.
    Kawamoto K, Kawashima S (1987) Regeneration of neurohypophyseal hormone-producing neurons in hypophysectomized immature rats. Brain Res 422:106–117. doi: 10.1016/0006-8993(87)90545-2 PubMedCrossRefGoogle Scholar
  32. 32.
    Wang Y, Zhao C, Wang Z, Wang C, Feng W, Huang L, Zhang J, Qi S (2008) Apoptosis of supraoptic AVP neurons is involved in the development of central diabetes insipidus after hypophysectomy in rats. BMC Neurosci 9:54. doi: 10.1186/1471-2202-9-54 PubMedCrossRefGoogle Scholar
  33. 33.
    Thorngren KG, Hansson LI, Menander-Sellman K, Stenstrom A (1973) Effect of hypophysectomy on longitudinal bone growth in the rat. Calcif Tissue Res 11:281–300. doi: 10.1007/BF02547228 PubMedCrossRefGoogle Scholar
  34. 34.
    Zimmerman EA, Nilaver G, Hou-Yu A, Silverman AJ (1984) Vasopressinergic and oxytocinergic pathways in the central nervous system. Fed Proc 43:91–96PubMedGoogle Scholar
  35. 35.
    Wu W, Han K, Li L, Schinco FP (1994) Implantation of PNS graft inhibits the induction of neuronal nitric oxide synthase and enhances the survival of spinal motoneurons following root avulsion. Exp Neurol 129:335–339. doi: 10.1006/exnr.1994.1176 PubMedCrossRefGoogle Scholar
  36. 36.
    Ceccatelli S, Eriksson M (1993) The effect of lactation on nitric oxide synthase gene expression. Brain Res 625:177–179. doi: 10.1016/0006-8993(93)90153-E PubMedCrossRefGoogle Scholar
  37. 37.
    Popeski N, Amir S, Woodside B (1999) Changes in NADPH-d staining in the paraventricular and supraoptic nuclei during pregnancy and lactation in rats: role of ovarian steroids and oxytocin. J Neuroendocrinol 11:53–61. doi: 10.1046/j.1365-2826.1999.00291.x PubMedCrossRefGoogle Scholar
  38. 38.
    Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632. doi: 10.1038/364626a0 PubMedCrossRefGoogle Scholar
  39. 39.
    Ding M, St Pierre BA, Parkinson JF, Medberry P, Wong JL, Rogers NE, Ignarro LJ, Merrill JE (1997) Inducible nitric-oxide synthase and nitric oxide production in human fetal astrocytes and microglia. A kinetic analysis. J Biol Chem 272:11327–11335. doi: 10.1074/jbc.272.44.28142 PubMedCrossRefGoogle Scholar
  40. 40.
    Pahan K, Sheikh FG, Liu X, Hilger S, McKinney M, Petro TM (2001) Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. J Biol Chem 276:7899–7905. doi: 10.1074/jbc.M008262200 PubMedCrossRefGoogle Scholar
  41. 41.
    Possel H, Noack H, Putzke J, Wolf G, Sies H (2000) Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. Glia 32:51–59. doi: 10.1002/1098-1136(200010)32:1<51::AID-GLIA50>3.0.CO;2-4 PubMedCrossRefGoogle Scholar
  42. 42.
    Bains JS, Ferguson AV (1997) Nitric oxide regulates NMDA-driven GABAergic inputs to type I neurones of the rat paraventricular nucleus. J Physiol 499(Pt 3):733–746PubMedGoogle Scholar
  43. 43.
    Yang QZ, Hatton GI (1999) Nitric oxide via cGMP-dependent mechanisms increases dye coupling and excitability of rat supraoptic nucleus neurons. J Neurosci 19:4270–4279PubMedGoogle Scholar
  44. 44.
    Scott DE (1999) Post-traumatic migration and emergence of a novel cell line upon the ependymal surface of the third cerebral ventricle in the adult mammalian brain. Anat Rec 256:233–241. doi: 10.1002/(SICI)1097-0185(19991101)256:3<233::AID-AR3>3.0.CO;2-H PubMedCrossRefGoogle Scholar
  45. 45.
    Wu WT, Scott DE, Gilman AM (1989) Correlative scanning-immunoelectromicroscopic analysis of neuropeptide localization and neuronal plasticity in the endocrine hypothalamus. Brain Res Bull 22:399–410. doi: 10.1016/0361-9230(89)90067-1 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Qiuju Yuan
    • 1
    • 4
  • David E. Scott
    • 5
  • Kwow-Fai So
    • 1
    • 2
  • Zhixiu Lin
    • 4
  • Wutian Wu
    • 1
    • 2
    • 3
  1. 1.Department of Anatomy, Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamChina
  2. 2.State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamChina
  3. 3.Research Center of Reproduction, Development and Growth, Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamChina
  4. 4.School of Chinese Medicine, Faculty of ScienceThe Chinese University of Hong KongShatin, N.TChina
  5. 5.The Department of Pathology & AnatomyThe Eastern Virginia Medical SchoolNorfolkUSA

Personalised recommendations