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Effects of N-acetylcysteine amide on anxiety and stress behavior in zebrafish

  • Carlos G. Reis
  • Ricieri Mocelin
  • Radharani Benvenutti
  • Matheus Marcon
  • Adrieli Sachett
  • Ana P. Herrmann
  • Elaine Elisabetsky
  • Angelo PiatoEmail author
Original Article
  • 47 Downloads

Abstract

Anxiety disorders are highly prevalent and a leading cause of disability worldwide. Their etiology is related to stress, an adaptive response of the organism to restore homeostasis, in which oxidative stress and glutamatergic hyperactivity are involved. N-Acetylcysteine (NAC) is a multitarget approved drug proved to be beneficial in the treatment of various mental disorders. Nevertheless, NAC has low membrane permeability and poor bioavailability and its limited delivery to the brain may explain inconsistencies in the literature. N-Acetylcysteine amide (AD4) is a synthetic derivative of NAC in which the carboxyl group was modified to an amide. The amidation of AD4 improved lipophilicity and blood-brain barrier permeability and enhanced its antioxidant properties. The purpose of this study was to investigate the effects of AD4 on behavioral and biochemical parameters in zebrafish anxiety models. Neither AD4 nor NAC induced effects on locomotion and anxiety-related parameters in the novel tank test. However, in the light/dark test, AD4 (0.001 mg/L) increased the time spent in the lit side in a concentration 100 times lower than NAC (0.1 mg/L). In the acute restraint stress protocol, NAC and AD4 (0.001 mg/L) showed anxiolytic properties without meaningful effects on oxidative status. The study suggests that AD4 has anxiolytic effects in zebrafish with higher potency than the parent compound. Additional studies are warranted to characterize the anxiolytic profile of AD4 and its potential in the management of anxiety disorders.

Keywords

N-Acetylcysteine amide Anxiety Acute restraint stress AD4 NACA 

Notes

Acknowledgments

We thank Prof. Daphne Atlas from Hebrew University of Jerusalem for providing AD4 and encouraging this study and Brandon Guinalli for helping with the figure designs.

Authors’ contributions

CR designed and performed the experiments, analyzed the data, prepared figures and tables, and authored and reviewed drafts of the paper. RM, RB, MM, and AS performed the experiments and reviewed drafts of the paper. AH, EE, and AP designed the experiments, analyzed the data, contributed reagents/materials/analysis tools, prepared figures and tables, and authored and reviewed drafts of the paper. All authors read and approved the manuscript.

Funding information

This work was supported by CNPq (302800/2017-4) and FAPERGS (#17/2551-0000974-6); CGR is recipient of a fellowship from CAPES and AP from CNPq.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratório de Psicofarmacologia e Comportamento (LAPCOM), Programa de Pós-graduação em Neurociências, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.Programa de Pós-graduação em Farmacologia e Terapêutica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  3. 3.Programa de Pós-graduação em Ciência Biológicas: Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil

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