PMID- 30091005
OWN - NLM
STAT- MEDLINE
DCOM- 20181231
LR  - 20181231
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Linking)
VI  - 235
IP  - 10
DP  - 2018 Oct
TI  - Nucleocytoplasmic export of HDAC5 and SIRT2 downregulation: two epigenetic 
      mechanisms by which antidepressants enhance synaptic plasticity markers.
PG  - 2831-2846
LID - 10.1007/s00213-018-4975-8 [doi]
AB  - RATIONALE: Antidepressant action has been linked to increased synaptic plasticity 
      in which epigenetic mechanisms such as histone posttranslational acetylation 
      could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are 
      oppositely regulated by stress and antidepressants in mice prefrontal cortex 
      (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model 
      reliable to study drug effects with clear advantages over animals. OBJECTIVES: We 
      aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant 
      regulation of neuroplasticity. METHODS: SH-SY5Y cultures were incubated with 
      imipramine, fluoxetine, and reboxetine (10 muM, 2 and 24 h) as well as the 
      selective HDAC5 (MC3822, 5 muM, 24 h) or SIRT2 (33i, 5 muM, 24 h) inhibitors. The 
      regulation of the brain-derived neurotrophic factor (BDNF), the vesicular 
      glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), 
      HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these 
      antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. 
      RESULTS: Antidepressants increased both in vitro and in vivo expression of BDNF, 
      VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the 
      phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. 
      Further, SIRT2 was downregulated by all antidepressants. Finally, specific 
      inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. CONCLUSIONS: 
      This study supports the validity of the SH-SY5Y model for studying epigenetic 
      changes linked to synaptic plasticity induced by antidepressants as well as the 
      effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of 
      HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic 
      plasticity markers leading to antidepressant action.
FAU - Munoz-Cobo, I
AU  - Munoz-Cobo I
AD  - Department of Pharmacology and Toxicology, University of Navarra, C/ Irunlarrea 
      1, 31010, Pamplona, Spain.
FAU - Erburu, M M
AU  - Erburu MM
AD  - Department of Pharmacology and Toxicology, University of Navarra, C/ Irunlarrea 
      1, 31010, Pamplona, Spain.
FAU - Zwergel, C
AU  - Zwergel C
AD  - Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, 
      Italy.
FAU - Cirilli, R
AU  - Cirilli R
AD  - Istituto Superiore di Sanita, Sapienza University of Rome, Rome, Italy.
FAU - Mai, A
AU  - Mai A
AD  - Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, 
      Italy.
FAU - Valente, S
AU  - Valente S
AD  - Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, 
      Italy.
FAU - Puerta, E
AU  - Puerta E
AD  - Department of Pharmacology and Toxicology, University of Navarra, C/ Irunlarrea 
      1, 31010, Pamplona, Spain.
FAU - Tordera, Rosa M
AU  - Tordera RM
AUID- ORCID: 0000-0002-3564-4135
AD  - Department of Pharmacology and Toxicology, University of Navarra, C/ Irunlarrea 
      1, 31010, Pamplona, Spain. rtordera@unav.es.
LA  - eng
GR  - SAF2011-27910/Secretaria de Estado de Investigacion, Desarrollo e Innovacion/
GR  - BES-2012-052190/Secretaria de Estado de Investigacion, Desarrollo e Innovacion/
PT  - Journal Article
DEP - 20180808
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Antidepressive Agents)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 947S0YZ36I (Reboxetine)
RN  - EC 3.5.1.- (Sirt2 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 2)
RN  - EC 3.5.1.98 (Hdac5 protein, mouse)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - OGG85SX4E4 (Imipramine)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Down-Regulation/*drug effects/physiology
MH  - Epigenesis, Genetic/*drug effects/physiology
MH  - Fluoxetine/pharmacology
MH  - Histone Deacetylase Inhibitors/pharmacology
MH  - Histone Deacetylases/*metabolism
MH  - Humans
MH  - Imipramine/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neuronal Plasticity/*drug effects/physiology
MH  - Prefrontal Cortex/drug effects/metabolism
MH  - Random Allocation
MH  - Reboxetine/pharmacology
MH  - Sirtuin 2/*metabolism
OTO - NOTNLM
OT  - Antidepressants
OT  - Histone deacetylase 5 (HDAC5)
OT  - Major depression
OT  - Prefrontal cortex (PFC)
OT  - SH-SY5Y
OT  - Sirtuin 2 (Sirt2)
EDAT- 2018/08/10 06:00
MHDA- 2019/01/01 06:00
CRDT- 2018/08/10 06:00
PHST- 2017/11/05 00:00 [received]
PHST- 2018/07/17 00:00 [accepted]
PHST- 2018/08/10 06:00 [pubmed]
PHST- 2019/01/01 06:00 [medline]
PHST- 2018/08/10 06:00 [entrez]
AID - 10.1007/s00213-018-4975-8 [pii]
AID - 10.1007/s00213-018-4975-8 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2018 Oct;235(10):2831-2846. doi: 
      10.1007/s00213-018-4975-8. Epub 2018 Aug 8.