title: The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus.
abstract: 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.
  
  
  
  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.
  
  
  
  Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated 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.
  
  
  
  Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: García-Rojo
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Fresno
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vilches
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Díaz-Véliz
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Aguayo
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Aníbal
authors.initials: A
authors.lastname: Pacheco
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Parra-Fiedler
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Claudio S
authors.initials: CS
authors.lastname: Parra
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Paulina S
authors.initials: PS
authors.lastname: Rojas
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Tejos
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Esteban
authors.initials: E
authors.lastname: Aliaga
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; CONICET, Universidad Católica de Córdoba, Córdoba, Argentina; Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago, Chile; Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Fiedler
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects* / Q000648:ultrastructure; D003863:Depression / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D046353:Immobility Response, Tonic / Q000187:drug effects; D054461:Lim Kinases / Q000378:metabolism; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054645:Protein Phosphatase 1 / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000648:ultrastructure*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical / Q000009:adverse effects; D013550:Swimming / Q000523:psychology
chemical_list: D051339:Actin Depolymerizing Factors; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054461:Lim Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; C049347:fasudil
keywords: ROCK inhibitor Fasudil; antidepressant; behavior; dendritic spines; stress