The ROCK inhibitor Fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in rat hippocampus

Gonzalo García-Rojo, Cristóbal Fresno, Natalia Vilches, Gabriela Díaz-Véliz, Sergio Mora, Felipe Aguayo, Aníbal Pacheco, Nicolás Parra-Fiedler, Claudio S. Parra, Paulina S. Rojas, Macarena Tejos, Esteban Aliaga, Jenny L. Fiedler

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudiltreated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.

Original languageEnglish
Pages (from-to)336-345
Number of pages10
JournalInternational Journal of Neuropsychopharmacology
Volume20
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017
Externally publishedYes

Keywords

  • Antidepressant
  • Behavior
  • Dendritic spines
  • ROCK inhibitor Fasudil
  • Stress

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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