title: Neuroprotective effects of intrastriatal injection of rapamycin in a mouse model of excitotoxicity induced by quinolinic acid.
abstract: 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.
  
  
  
  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 μM; 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.
  
  
  
  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)-1β, IL-6, and tumor necrosis factor (TNF)-α 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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.|Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, 79104, Freiburg, Germany.
authors.forename: Soraya Wilke
authors.initials: SW
authors.lastname: Saliba
authors.affiliation: Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Erica Leandro Marciano
authors.initials: EL
authors.lastname: Vieira
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Rebeca Priscila de Melo
authors.initials: RP
authors.lastname: Santos
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.affiliation: Department of Psychiatry, University of Freiburg Medical School, Hauptstr. 5, 79104, Freiburg, Germany. bernd.fiebich@uniklinik-freiburg.de.
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Luciene Bruno
authors.initials: LB
authors.lastname: Vieira
authors.affiliation: Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Antonio Lucio
authors.initials: AL
authors.lastname: Teixeira
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, 31270-901, Belo Horizonte, MG, Brazil. antoniooliveira@icb.ufmg.br.
authors.forename: Antonio Carlos Pinheiro
authors.initials: AC
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000188:drug therapy* / Q000209:etiology*; D004856:Postural Balance / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017378:Quinolinic Acid / Q000633:toxicity*; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D011189:Potassium Chloride; D017378:Quinolinic Acid; D020123:Sirolimus
keywords: Glutamate; Inflammation; Neurodegeneration; Neurotrophic factors; Quinolinic acid; Rapamycin; mTOR