Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

The role of neuronal nitric oxide and its pathways in the protection and recovery from neurotoxin-induced de novo hypokinetic motor behaviors in the embryonic zebrafish (Danio rerio)

Department of Biology, Center for Molecular, Cellular, and Biological Chemistry, Virginia Military Institute, Lexington, VA 24450, USA

Special Issues: Special Issue on Neuronal Nitric Oxide

Neuronal nitric oxide (nNO) has been shown to affect motor function in the brain. Specifically, nNO acts in part through regulation of dopamine (DA) release, transporter function, and the elicitation of neuroprotection/neurodegeneration of neurons in conditions such as Parkinson’s disease (PD). Recently, the zebrafish has been proposed to be a new model for the study of PD since neurotoxin damage to their nigrostriatal-like neurons exhibit PD-like motor dysfunctions similar to those of mammalian models and human patients. Results from this study demonstrate that treatment of 5 days post fertilization (dpf) fish with a nNO synthase inhibitor as a co-treatment with 6-OHDA facilitates long-term survival and accelerates the recovery from 6-OHDA-induced hypokinesia-like symptoms. These findings are unique in that under conditions of neurotoxin-induced stress, the inhibition of the NO-related S-nitrosylation indirect pathway dramatically facilitates recovery from 6-OHDA treatment but inhibition of the NO-sGC-cGMP direct pathway is essential for survival in 5 dpf treated fish. In conclusion, these results indicate that nNOS and the inhibition of the NO-linked S-nitrosylation pathway plays an important role in antagonizing the protection and recovery of fish from neurotoxin treatment. These data begin to help in the understanding of the role of NO as a neuroprotectant in dopaminergic pathways, particularly those that influence motor dysfunctions.
  Article Metrics

Keywords neuronal nitric oxide synthase (nNOS); nNOS inhibitor; DTT; ODQ; motor dysfunction; dopamine; 6-hydroxydopamine neuronal toxicity; zebrafish

Citation: Amber Woodard, Brandon Barbery, Reid Wilkinson, Jonathan Strozyk, Mathew Milner, Patrick Doucette, Jarred Doran, Kendra Appleby, Henry Atwill, Wade E. Bell, James E. Turner. The role of neuronal nitric oxide and its pathways in the protection and recovery from neurotoxin-induced de novo hypokinetic motor behaviors in the embryonic zebrafish (Danio rerio). AIMS Neuroscience, 2019, 6(1): 25-42. doi: 10.3934/Neuroscience.2019.1.25


  • 1. Stephenson-Jones M, Ericsson J, Robertson B, et al. (2012) Evolution of the basal ganglia: dual-output pathways conserved throughout vertebrate phylogeny. J Comp Neurol 520: 2957–2973.    
  • 2. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson's disease. J Neurochem 139: 318–324.    
  • 3. Naghavi M, Wang H, Lozano R, et al. (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385: 117–171.    
  • 4. Bradley S, Tossell K, Lockley R, et al. (2010) Nitric oxide synthase regulates morphogenesis of zebrafish spinal cord motor neurons. J Neurosci 30: 16818–16831.    
  • 5. Hammond J, Balligand JL (2011) Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: from contractility to remodeling. J Mol Cell Cardiol 52: 330–340.
  • 6. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33: 829–837.    
  • 7. Gupta S, Goswami P, Biswas J, et al. (2015) 6-hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: involvement of nitric oxide and mitochondria. Mutat Res Genet Toxicol Environ Mutagen 778: 22–36.    
  • 8. Aquilano K, Baldelli S, Rotilio G, et al. (2008) Fole of nitric oxide synthases in Parkinson's disease: A review on the antioxidant and anti-inflammatory activity of polyphenols. Neurochem Res 33: 2416–2426.    
  • 9. Karaçay B, Bonthius DJ (2015) The neuronal nitric oxide synthase (nNOS) gene and neuroprotection against alcohol toxicity. Cell Mol Neurobiol 35: 449–461.    
  • 10. Kurauchi Y, Hisatsune A, Isohama Y, et al. (2013) Nitric oxide/soluble guanylyl cyclase signaling mediates depolarization-induced protection of rat mesencephalic dopaminergic neurons from MPP+ cytotoxicity. Neuroscience 231: 206–215.    
  • 11. Gao Y (2010) The multiple actions of NO. Pflugers Arch 459: 829–839.    
  • 12. Tota B, Amelio D, Pelligrino D, et al. (2005) NO modulation of myocardial performance in fish hearts. Comp Biochem Physiol 142: 164–177.
  • 13. Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81: 533–559.    
  • 14. Lorenc-Koci E, Czarnecka A (2013) Role of nitric oxide in the regulation of motor function. An overview of behavioral, biochemical and histological studies in animal models. Pharmaco Rep 65: 1043–1055.
  • 15. Cersosimo MG, Benarroch EE (2015) Estrogen actions in the nervous system: complexity and clinical implications. Neurology 85: 263–273.    
  • 16. Smith KM, Dahodwala N (2014) Sex differences in Parkinson's disease and other movement disorders. Exp Neurol 259: 44–56.    
  • 17. Delaruelle Z, Honore PJ, Santens P (2016) Adult-onset Sydenham's chorea or drug-induced movement disorder? A case report. Acta Neurol Belg 116: 399–400.    
  • 18. Chambliss KL, Shaul PW (2002) Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. Steroids 67: 413–419.    
  • 19. Flinn L, Bretaud S, Lo C, et al. (2008) Zebrafish as a new animal model for movement disorders. J Neurochem 106: 1991–1997.    
  • 20. Rink E, Wullimann MF (2001) The teleostean (zebrafish) dopaminergic system ascending to the subpallium (striatum) is located in the basal diencephalon (posterior tuberculum). Brain Res 889: 316–330.    
  • 21. McKinley ET, Baranowski TC, Blavo DO, et al. (2005) Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons. Brain Res Mol Brain Res 141: 128–137.    
  • 22. Parng C, Roy NM, Ton C, et al. (2007) Neurotoxicity assessment using zebrafish. J Pharmacol Toxicol Methods 55: 103–112.    
  • 23. Nelson B, Henriet RP, Holt AW, et al. (2008) The role of estrogen on the developmental appearance of sensory-motor behaviors in the zebrafish (Danio rerio): The characterization of the "listless" mode. Brain Res 1222: 118–128.    
  • 24. Houser A, McNair C, Piccinini R, et al. (2011) Effects of estrogen on the neuromuscular system in the embryonic zebrafish (Danio rerio). Brain Res 1381: 106–116.    
  • 25. Allgood OE Jr, Hamad A, Fox J, et al. (2013) Estrogen prevents cardiac and vascular failure in the 'listless' zebrafish (Danio rerio) developmental model. Gen Comp Endocrinol 189: 33–42.    
  • 26. Murcia V, Johnson L, Baldasare M, et al. (2016) Estrogen, nitric oxide and dopamine interactions in the zebrafish "listless" model of locomotor dysfunction. Toxics 4: 24.    
  • 27. Conor S, Wilkinson R, Woodard A, et al. (2018) The roles of estrogen, nitric oxide, and dopamine in the generation of hyperkinetic motor behaviors in embryonic zebrafish (Danio rerio). Recent Advances in Zebrafish Researches. Yusuf Bozkurt, IntechOpen, DOI: 10.5772/intechopen.73869. Available from: https://www.intechopen.com/books/recent-advances-in-zebrafish-researches/the-roles-of-estrogen-nitric-oxide-and-dopamine-in-the-generation-of-hyperkinetic-motor-behaviors-in
  • 28. Jay M, Bradley S, McDearmid JR (2014) Effects of nitric oxide on neuromuscular properties of developing zebrafish embryos. PLoS One 9: e86930.    
  • 29. Padovan-Neto FE, Echeverry MB, Chiavegatto S, et al. (2011) Nitric oxide synthase inhibitor improves de novo and long-term l-DOPA-induced dyskinesia in hemiparkinsonian rats. Front Syst Neurosci 5: 40.
  • 30. Feng CW, Wen ZH, Huang SY, et al. (2014) Effects of 6-hydroxydopamine exposure on motor activity and biochemical expression in zebrafish (Danio rerio) larvae. Zebrafish 11: 227–239.    
  • 31. Marret S, Bonnier C, Raymackers JM, et al. (1999) Glycine antagonist and NO synthase inhibitor protect the developing mouse brain against neonatal excitotoxic lesions. Pediatr Res 45: 337–342.    
  • 32. Hicks CA, Ward MA, Swettenham JB, et al. (1999) Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia. Eur J Pharmacol 381: 113–119.    
  • 33. Lorenc-Koci E, Czarnecka A (2013) Role of nitric oxide in the regulation of motor function. An overview of behavioral, biochemical and histological studies in animal models. Pharmacol Rep 65: 1043–1055.
  • 34. Anichtchik OV, Kaslin J, Peitsaro N, et al. (2004) Neurochemical and behavioural changes in zebrafish Danio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 88: 443–453.
  • 35. Koriyama Y, Furukawa A (2018) S-nitrosylation regulates cell survival and death in the central nervous system. Neurochem Res 43: 41–49.    
  • 36. Estevez AG, Spear N, Manuel SM, et al. (1998) Role of endogenous nitric oxide and peroxynitrite formation in the survival and death of motor neurons in culture. Prog Brain Res 118: 269–280.    


This article has been cited by

  • 1. Valentina Bashkatova, Athineos Philippu, Role of nitric oxide in psychostimulant-induced neurotoxicity, AIMS Neuroscience, 2019, 6, 3, 191, 10.3934/Neuroscience.2019.3.191

Reader Comments

your name: *   your email: *  

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved