Skip to main content
SpringerLink
Log in

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

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

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.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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

References

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  4. Pérez-Severiano F, Escalante B, Ríos C (1998) Nitric oxide synthase inhibition prevents acute quinolinate-induced striatal neurotoxicity. Neurochem Res 23:1297–1302

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 177–200

    Google Scholar 

  8. Huang PL, Dawson TM, Bredt DS et al (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75(7):1273–1286

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  10. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Elsevier, Boston

    Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  15. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  16. Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685

    Article  CAS  PubMed  Google Scholar 

  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 104:245–254

    Article  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):319–333

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 76:2479–2487

    Article  Google Scholar 

  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 17:6908–6917

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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 80:111–122

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):4839–4844

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur #3877, Col. La Fama Del. Tlalpan, 14269, Ciudad de México, Mexico

    C. Gerónimo-Olvera, L. Tristán-López, L. García-Lara, A. Morales-Martínez, M. A. Hernández-Melesio, C. Ríos & F. Pérez-Severiano

  2. Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur #3877, Col. La Fama Del. Tlalpan, 14269, Ciudad de México, México

    J. C. Martínez-Lazcano

  3. Departamento de Farmacología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano #1, Col. Sección XVI, Del. Tlalpan, 14080, Ciudad de México, Mexico

    A. Sánchez-Mendoza

  4. Departamento de Ciencias Naturales, División de Ciencias Naturales e Ingeniería, Universidad Autónoma Metropolitana-Unidad Cuajimalpa, Avenida Vasco de Quiroga #4871, 05370, Ciudad de México, Mexico

    L. Arregui

Authors
  1. C. Gerónimo-Olvera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Tristán-López
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. C. Martínez-Lazcano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. García-Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Sánchez-Mendoza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Morales-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. A. Hernández-Melesio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Arregui
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Ríos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F. Pérez-Severiano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. Pérez-Severiano.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gerónimo-Olvera, C., Tristán-López, L., Martínez-Lazcano, J.C. et al. Striatal Protection in nNOS Knock-Out Mice After Quinolinic Acid-Induced Oxidative Damage. Neurochem Res 44, 421–427 (2019). https://doi.org/10.1007/s11064-018-2688-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2688-3

Keywords

Search

Navigation