PMID- 26660117
OWN - NLM
STAT- MEDLINE
DCOM- 20171222
LR  - 20211204
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
VI  - 53
IP  - 10
DP  - 2016 Dec
TI  - Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by 
      Corticosterone via PI3K/Akt/mTOR Pathway.
PG  - 6818-6834
AB  - Ketamine has emerged as a novel strategy to treat refractory depression, 
      producing rapid remission, but elicits some side effects that limit its use. In 
      an attempt to investigate a safer compound that may afford an antidepressant 
      effect similar to ketamine, this study examined the effects of the ergogenic 
      compound creatine in a model of depression, and the involvement of 
      phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin 
      (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like 
      behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) 
      for 21 days. This treatment increased immobility time in the tail suspension test 
      (TST), an effect abolished by a single administration of creatine (10 mg/kg, 
      p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., 
      conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 
      0.1 mug/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 
      0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and 
      ketamine. None of the treatments affected locomotor activity of mice. The 
      immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 
      protein (PSD95) were increased by creatine and ketamine in corticosterone or 
      vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased 
      hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished 
      by creatine or ketamine. Altogether, the results indicate that creatine shares 
      with ketamine the ability to acutely reverse the corticosterone-induced 
      depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and 
      modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, 
      indicating the relevance of targeting these proteins for the management of 
      depressive disorders. Moreover, we suggest that creatine should be further 
      investigated as a possible fast-acting antidepressant.
FAU - Pazini, Francis L
AU  - Pazini FL
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Cunha, Mauricio P
AU  - Cunha MP
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Rosa, Julia M
AU  - Rosa JM
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Colla, Andre R S
AU  - Colla AR
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Lieberknecht, Vicente
AU  - Lieberknecht V
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Oliveira, Agatha
AU  - Oliveira A
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil.
FAU - Rodrigues, Ana Lucia S
AU  - Rodrigues AL
AD  - Department of Biochemistry, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Campus Universitario, Trindade, Florianopolis, Santa Catarina, 
      88040-900, Brazil. alsrodri@gmail.com.
LA  - eng
PT  - Journal Article
DEP - 20151211
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - MU72812GK0 (Creatine)
RN  - W980KJ009P (Corticosterone)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/pharmacology/therapeutic use
MH  - *Behavior, Animal
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Corticosterone/blood
MH  - Creatine/administration & dosage/pharmacology/*therapeutic use
MH  - Depression/blood/*drug therapy/pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Fluoxetine
MH  - Ketamine/administration & dosage/pharmacology/*therapeutic use
MH  - Mice
MH  - Models, Biological
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Akt
OT  - Corticosterone
OT  - Creatine
OT  - Ketamine
OT  - Tail suspension test
OT  - mTOR
EDAT- 2015/12/15 06:00
MHDA- 2017/12/23 06:00
CRDT- 2015/12/15 06:00
PHST- 2015/09/24 00:00 [received]
PHST- 2015/11/29 00:00 [accepted]
PHST- 2015/12/15 06:00 [pubmed]
PHST- 2017/12/23 06:00 [medline]
PHST- 2015/12/15 06:00 [entrez]
AID - 10.1007/s12035-015-9580-9 [pii]
AID - 10.1007/s12035-015-9580-9 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2016 Dec;53(10):6818-6834. doi: 10.1007/s12035-015-9580-9. Epub 
      2015 Dec 11.