Advertisement

Striatal Protection in nNOS Knock-Out Mice After Quinolinic Acid-Induced Oxidative Damage

  • C. Gerónimo-Olvera
  • L. Tristán-López
  • J. C. Martínez-Lazcano
  • L. García-Lara
  • A. Sánchez-Mendoza
  • A. Morales-Martínez
  • M. A. Hernández-Melesio
  • L. Arregui
  • C. Ríos
  • F. Pérez-Severiano
Original Paper
  • 5 Downloads

Abstract

Under pathological conditions, nitric oxide can become a mediator of oxidative cellular damage, generating an unbalance between oxidant and antioxidant systems. The participation of neuronal nitric oxide synthase (nNOS) in the neurodegeneration mechanism has been reported; the activation of N-methyl-d-aspartate (NMDA) receptors by agonist quinolinic acid (QUIN) triggers an increase in nNOS function and promotes oxidative stress. The aim of the present work was to elucidate the participation of nNOS in QUIN-induced oxidative stress in knock-out mice (nNOS−/−). To do so, we microinjected saline solution or QUIN in the striatum of wild-type (nNOS +/+), heterozygote (nNOS+/−), and knock-out (nNOS−/−) mice, and measured circling behavior, GABA content levels, oxidative stress, and NOS expression and activity. We found that the absence of nNOS provides a protection against striatal oxidative damage induced by QUIN, resulting in decreased circling behavior, oxidative stress, and a partial protection reflected in GABA depletion. We have shown that nNOS-derived NO is involved in neurological damage induced by oxidative stress in a QUIN-excitotoxic model.

Keywords

Excitotoxicity Quinolinic acid Nitric oxide synthase Oxidative stress Neuronal nitric oxide synthase knock-out mice 

Abbreviations

CB

Circling behavior

DCF

Dichlorofluorescein

DCFH-DA

2’,7’-Dichlorodihydrofluorescein diacetate

ECL

Enhanced chemiluminescence

HD

Huntington’s disease

HPLC

High-performance liquid chromatography

LP

Lipid peroxidation

NEO

Neomycin

NO

Nitric oxide

nNOS

Neuronal nitric oxide synthase

OD

Optical density

QUIN

Quinolinic acid

ROS

Reactive oxygen species

SEM

Standard error of the mean

SS

Saline solution

Notes

Funding

This work was supported by Conacyt Grant CB-2014 #241911 to F.P-S and was partially supported by Grant FOSISS-2015-2-261721 to L.T-L.

References

  1. 1.
    Calabrese V, Mancuso C, Calvani M et al (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775.  https://doi.org/10.1038/nrn2214 CrossRefGoogle Scholar
  2. 2.
    Vieira H, Kroemer G (2004) Mitochondria as targets of apoptosis regulation by nitric oxide. IUBMB Life 55:613–616.  https://doi.org/10.1080/15216540310001639652 CrossRefGoogle Scholar
  3. 3.
    Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47:122–129.  https://doi.org/10.1016/J.CECA.2010.01.003 CrossRefGoogle Scholar
  4. 4.
    Pérez-Severiano F, Escalante B, Ríos C (1998) Nitric oxide synthase inhibition prevents acute quinolinate-induced striatal neurotoxicity. Neurochem Res 23:1297–1302CrossRefGoogle Scholar
  5. 5.
    Perez-Severiano F, Escalante B, Vergara P et al (2002) Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington’s disease mutation. Brain Res 951:36–42.  https://doi.org/10.1016/S0006-8993(02)03102-5 CrossRefGoogle Scholar
  6. 6.
    Canzoniero LMT, Granzotto A, Turetsky DM et al (2013) nNOS(+) striatal neurons, a subpopulation spared in Huntington’s disease, possess functional NMDA receptors but fail to generate mitochondrial ROS in response to an excitotoxic challenge. Front Physiol 4:112.  https://doi.org/10.3389/fphys.2013.00112 CrossRefGoogle Scholar
  7. 7.
    Pérez-Severiano F, Montes S, Gerónimo-Olvera C, Segovia J (2013) Study of oxidative damage and antioxidant systems in two Huntington’s disease rodent models. Humana Press, Totowa, pp 177–200Google Scholar
  8. 8.
    Huang PL, Dawson TM, Bredt DS et al (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75(7):1273–1286CrossRefGoogle Scholar
  9. 9.
    Martínez-Lazcano JC, Pérez-Severiano F, Escalante B et al (2007) Selective protection against oxidative damage in brain of mice with a targeted disruption of the neuronal nitric oxide synthase gene. J Neurosci Res 85:1391–1402.  https://doi.org/10.1002/jnr.21261 CrossRefGoogle Scholar
  10. 10.
    Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Elsevier, BostonGoogle Scholar
  11. 11.
    Petersén A, Chase K, Puschban Z et al (2002) Maintenance of susceptibility to neurodegeneration following intrastriatal injections of quinolinic acid in a new transgenic mouse model of Huntington’s disease. Exp Neurol 175:297–300.  https://doi.org/10.1006/exnr.2002.7885 CrossRefGoogle Scholar
  12. 12.
    García-Lara L, Pérez-Severiano F, González-Esquivel D et al (2015) Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress. J Neurosci Res 93:1423–1433.  https://doi.org/10.1002/jnr.23595 CrossRefGoogle Scholar
  13. 13.
    Pérez-Neri I, Castro E, Montes S et al (2007) Arginine, citrulline and nitrate concentrations in the cerebrospinal fluid from patients with acute hydrocephalus. J Chromatogr B 851:250–256.  https://doi.org/10.1016/j.jchromb.2006.10.047 CrossRefGoogle Scholar
  14. 14.
    Triggs WJ, Willmore LJ (1984) In vivo lipid peroxidation in rat brain following intracortical Fe2+ injection. J Neurochem 42:976–980.  https://doi.org/10.1111/j.1471-4159.1984.tb12699.x CrossRefGoogle Scholar
  15. 15.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  16. 16.
    Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685CrossRefGoogle Scholar
  17. 17.
    García-Tovar CG, Luna J, Mena R et al (2002) Dystrophin isoform Dp7l is present in lamellipodia and focal complexes in human astrocytoma cells U-373 MG. Acta Histochem 104:245–254CrossRefGoogle Scholar
  18. 18.
    Ungerstedt U (1971) Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. Acta Physiol Scand 82:49–68.  https://doi.org/10.1111/j.1365-201X.1971.tb10999.x CrossRefGoogle Scholar
  19. 19.
    Girouard H, Wang G, Gallo EF et al (2009) NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci 29:2545–2552.  https://doi.org/10.1523/JNEUROSCI.0133-09.2009 CrossRefGoogle Scholar
  20. 20.
    Cheng A, Wang S, Cai J et al (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol 258(2):319–333CrossRefGoogle Scholar
  21. 21.
    Fritzen S, Schmitt A, Köth K et al (2007) Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independently of BDNF. Mol Cell Neurosci 35(2):261–271.  https://doi.org/10.1016/j.mcn.2007.02.021 CrossRefGoogle Scholar
  22. 22.
    Kolarow R, Kuhlmann CRW, Munsch T et al (2014) BDNF-induced nitric oxide signals in cultured rat hippocampal neurons: time course, mechanism of generation, and effect on neurotrophin secretion. Front Cell Neurosci 8:323.  https://doi.org/10.3389/fncel.2014.00323 CrossRefGoogle Scholar
  23. 23.
    Dawson VL, Kizushi VM, Huang PL et al (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 76:2479–2487CrossRefGoogle Scholar
  24. 24.
    Ayata C, Ayata G, Hara H et al (1997) Mechanisms of reduced striatal NMDA excitotoxicity in type I nitric oxide synthase knock-out mice. J Neurosci 17:6908–6917CrossRefGoogle Scholar
  25. 25.
    Steinert JR, Chernova T, Forsythe ID (2010) Nitric oxide signaling in brain function, dysfunction, and dementia. Neurosci 16:435–452.  https://doi.org/10.1177/1073858410366481 CrossRefGoogle Scholar
  26. 26.
    Orrenius S, Zhivotovsky B, Nicotera P (2003) Calcium: regulation of cell death: the calcium–apoptosis link. Nat Rev Mol Cell Biol 4:552–565.  https://doi.org/10.1038/nrm1150 CrossRefGoogle Scholar
  27. 27.
    Qin Z, Wang Y, Chasea TN (2000) A caspase-3-like protease is involved in NF-kappaB activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum. Mol Brain Res 80:111–122CrossRefGoogle Scholar
  28. 28.
    Deckel AW, Tang V, Nuttal D et al (2002) Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice. Brain Res 939:76–86.  https://doi.org/10.1016/S0006-8993(02)02550-7 CrossRefGoogle Scholar
  29. 29.
    Heng MY, Detloff PJ, Wang PL et al (2009) In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J Neurosci 29:3200–3205.  https://doi.org/10.1523/JNEUROSCI.5599-08.2009 CrossRefGoogle Scholar
  30. 30.
    Li XJ, Sharp AH, Li SH, Dawson TM, Snyder SH, Ross CA (1996) Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 93(10):4839–4844CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • C. Gerónimo-Olvera
    • 1
  • L. Tristán-López
    • 1
  • J. C. Martínez-Lazcano
    • 2
  • L. García-Lara
    • 1
  • A. Sánchez-Mendoza
    • 3
  • A. Morales-Martínez
    • 1
  • M. A. Hernández-Melesio
    • 1
  • L. Arregui
    • 4
  • C. Ríos
    • 1
  • F. Pérez-Severiano
    • 1
  1. 1.Departamento de NeuroquímicaInstituto Nacional de Neurología y Neurocirugía Manuel Velasco SuárezCiudad de MéxicoMexico
  2. 2.Departamento de NeurofisiologíaInstituto Nacional de Neurología y Neurocirugía Manuel Velasco SuárezCiudad de MéxicoMéxico
  3. 3.Departamento de FarmacologíaInstituto Nacional de Cardiología Ignacio ChávezCiudad de MéxicoMexico
  4. 4.Departamento de Ciencias Naturales, División de Ciencias Naturales e IngenieríaUniversidad Autónoma Metropolitana-Unidad CuajimalpaCiudad de MéxicoMexico

Personalised recommendations