title: KU0063794, a Dual mTORC1 and mTORC2 Inhibitor, Reduces Neural Tissue Damage and Locomotor Impairment After Spinal Cord Injury in Mice.
abstract: Autophagy is an intracellular catabolic mechanism for the degradation of cytoplasmic constituents in the autophagosomal-lysosomal pathway. This mechanism plays an important role in homeostasis and it is defective in certain diseases. Preceding studies have revealed that autophagy is developing as an important moderator of pathological responses associated to spinal cord injury (SCI) and plays a crucial role in secondary injury initiating a progressive degeneration of the spinal cord. Thus, based on this evidence in this study, we used two different selective inhibitors of mTOR activity to explore the functional role of autophagy in an in vivo model of SCI as well as to determine whether the autophagic process is involved in spinal cord tissue damage. We treated animals with a novel synthetic inhibitor temsirolimus and with a dual mTORC1 and mTORC2 inhibitor KU0063794 matched all with the well-known inhibitor of mTOR the rapamycin. Our results demonstrated that mTOR inhibitors could regulate the neuroinflammation associated to SCI and the results that we obtained evidently demonstrated that rapamycin and temsirolimus significantly diminished the expression of iNOS, COX2, GFAP, and re-established nNOS levels, but the administration of KU0063794 is able to blunt the neuroinflammation better than rapamycin and temsirolimus. In addition, neuronal loss and cell mortality in the spinal cord after injury were considerably reduced in the KU0063794-treated mice. Accordingly, taken together our results denote that the administration of KU0063794 produced a neuroprotective function at the lesion site following SCI, representing a novel therapeutic approach after SCI.
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Cordaro
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Siracusa
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy. salvator@unime.it.|Department of Pharmacological and Physiological Science, Saint Louis University, Saint Louis, MO, USA. salvator@unime.it.
authors.forename: Salvatore
authors.identifier: 0000-0001-6131-3690
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009417:Nerve Tissue / Q000187:drug effects / Q000473:pathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D009025:Morpholines; D046912:Multiprotein Complexes; D009573:Nitrites; D011743:Pyrimidines; C401859:temsirolimus; C541932:Ku 0063794; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Autophagy; Inflammation; KU0063794; SCI; Temsirolimus