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mTOR Pathway Inhibition Prevents Neuroinflammation and Neuronal Death in a Mouse Model of Spinal Cord Injury
Author(s) -
Esposito Emanuela,
Cordaro Marika,
Paterniti Irene,
Impellizzeri Daniela,
Siracusa Rosalba,
Cuzzocrea Salvatore
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.706.2
Subject(s) - pi3k/akt/mtor pathway , autophagy , neuroinflammation , sirolimus , microglia , spinal cord injury , programmed cell death , medicine , pharmacology , spinal cord , signal transduction , microbiology and biotechnology , neuroscience , inflammation , chemistry , biology , immunology , apoptosis , biochemistry
Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses, hypoxia and inflammation including induction of autophagy and cell survival. Spinal cord injury (SCI) is a serious and debilitating health problem that usually causes lifelong disability and leads to neurological dysfunction. While the mTOR signaling cascade has been linked to several neurological disorders, manipulation of the mTOR signaling cascade as a pre‐clinical therapeutic strategy in SCI has not been investigated. We hypothesized that mTOR pathway inhibition would diminish neuroinflammation and prevent neuronal death in a mouse model of SCI. Spinal cord compression injury was performed in adult male mice. SCI was induced in mice by the application of an aneurysm clip at T6‐T7 level. mTOR pathway inhibition was achieved with rapamycin (a mTOR inhibitor; 1mg/kg), or temsirolimus (rapamycin analogues; 0.6mg/kg), or KU0063794 (a dual mTORC1and mTORC2 inhibitor; 8mg/kg) following spinal cord trauma (1 and 6 hours after SCI), and then for 3 subsequent days. Phospho‐activation of the mTOR effectors p70S6kinase and ribosomal S6 protein and expression of infammatory parameters in perilesional area were assayed at 24 hrs, 48 and 72 hrs. Neuronal cell death was evaluated, autophagy was measured using Beclin‐1 and LC3II expression. Iba‐1 labeled, activated microglia were quantified. Neuronal death, and numerous Iba‐1 labeled, activated microglia were evident at 24 and 48h following SCI. Rapamycin or KU0063794 treatment significantly reduced mTOR signaling, neuronal death, and microglial activation, coincident with enhanced expression of Beclin‐1 and LC3II, markers of autophagy induction. KU0063794 was able to blunt the neuroinflammation (evaluated as iNOS, COX2, GFAP and NOS expression) better than rapamycin and temsirolimus. mTOR pathway inhibition prevented neuronal death and diminished neuroinflammation in this model of SCI. Persistent mTOR signaling following SCI suggests a failure of autophagy induction, which may contribute to neuronal death. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in SCI. Support or Funding Information No funding