PMID- 28143498
OWN - NLM
STAT- MEDLINE
DCOM- 20171011
LR  - 20181113
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 14
IP  - 1
DP  - 2017 Jan 31
TI  - Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model 
      of excitotoxicity induced by quinolinic acid.
PG  - 25
LID - 10.1186/s12974-017-0793-x [doi]
LID - 25
AB  - BACKGROUND: The mammalian target of rapamycin (mTOR) is a kinase involved in a 
      variety of physiological and pathological functions. However, the exact role of 
      mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of 
      mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, 
      as well as inflammatory profile caused by an excitotoxic stimulus. METHODS: A 
      single and unilateral striatal injection of quinolinic acid (QA) was used to 
      induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 muM; 
      intrastriatal route) was administered 15 min before QA injection. Forty-eight 
      hours after QA administration, rotarod test was performed to evaluate motor 
      coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to 
      evaluate neuronal cell death, microglia morphology, and astrocytes density, 
      respectively, at this time point. Levels of cytokines and neurotrophic factors 
      were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal 
      synaptosomes were used to evaluate the release of glutamate. RESULTS: We first 
      demonstrated that rapamycin prevented the motor impairment induced by QA. 
      Moreover, mTOR inhibition also reduced the neurodegeneration and the production 
      of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha induced by 
      excitotoxic stimulus. The lowest dose of rapamycin also increased the production 
      of IL-10 and prevented the reduction of astrocyte density induced by QA. By using 
      an in vitro approach, we demonstrated that rapamycin differently alters the 
      release of glutamate from striatal synaptosomes induced by QA, reducing or 
      enhancing the release of this neurotransmitter at low or high concentrations, 
      respectively. CONCLUSION: Taken together, these data demonstrated a protective 
      effect of rapamycin against an excitotoxic stimulus. Therefore, this study 
      provides new evidence of the detrimental role of mTOR in neurodegeneration, which 
      might represent an important target for the treatment of neurodegenerative 
      diseases.
FAU - Saliba, Soraya Wilke
AU  - Saliba SW
AD  - Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio 
      Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.
AD  - Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, 
      79104, Freiburg, Germany.
FAU - Vieira, Erica Leandro Marciano
AU  - Vieira EL
AD  - Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo 
      Horizonte, MG, Brazil.
FAU - Santos, Rebeca Priscila de Melo
AU  - Santos RP
AD  - Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio 
      Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.
FAU - Candelario-Jalil, Eduardo
AU  - Candelario-Jalil E
AD  - Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA.
FAU - Fiebich, Bernd L
AU  - Fiebich BL
AD  - Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, 
      79104, Freiburg, Germany. bernd.fiebich@uniklinik-freiburg.de.
FAU - Vieira, Luciene Bruno
AU  - Vieira LB
AD  - Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio 
      Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.
FAU - Teixeira, Antonio Lucio
AU  - Teixeira AL
AD  - Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo 
      Horizonte, MG, Brazil.
FAU - de Oliveira, Antonio Carlos Pinheiro
AU  - de Oliveira AC
AD  - Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio 
      Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil. antoniooliveira@icb.ufmg.br.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170131
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Cytokines)
RN  - 0 (Neuroprotective Agents)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 660YQ98I10 (Potassium Chloride)
RN  - F6F0HK1URN (Quinolinic Acid)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Body Weight/drug effects
MH  - Corpus Striatum/*drug effects/physiology
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Glutamic Acid/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Movement Disorders/drug therapy/etiology
MH  - Nerve Degeneration/drug therapy/etiology
MH  - Neuroglia/drug effects/pathology
MH  - Neurons/drug effects/pathology
MH  - Neuroprotective Agents/pharmacology/therapeutic use
MH  - Neurotoxicity Syndromes/complications/*drug therapy/*etiology
MH  - Postural Balance/drug effects
MH  - Potassium Chloride/pharmacology
MH  - Quinolinic Acid/*toxicity
MH  - Sirolimus/*pharmacology/*therapeutic use
MH  - Synaptosomes/drug effects/metabolism/ultrastructure
PMC - PMC5282622
OTO - NOTNLM
OT  - Glutamate
OT  - Inflammation
OT  - Neurodegeneration
OT  - Neurotrophic factors
OT  - Quinolinic acid
OT  - Rapamycin
OT  - mTOR
EDAT- 2017/02/02 06:00
MHDA- 2017/10/12 06:00
PMCR- 2017/01/31
CRDT- 2017/02/02 06:00
PHST- 2016/05/18 00:00 [received]
PHST- 2017/01/06 00:00 [accepted]
PHST- 2017/02/02 06:00 [entrez]
PHST- 2017/02/02 06:00 [pubmed]
PHST- 2017/10/12 06:00 [medline]
PHST- 2017/01/31 00:00 [pmc-release]
AID - 10.1186/s12974-017-0793-x [pii]
AID - 793 [pii]
AID - 10.1186/s12974-017-0793-x [doi]
PST - epublish
SO  - J Neuroinflammation. 2017 Jan 31;14(1):25. doi: 10.1186/s12974-017-0793-x.