KU0063794, a Dual mTORC1 and mTORC2 Inhibitor, Reduces Neural Tissue Damage and Locomotor Impairment After Spinal Cord Injury in Mice Marika Cordaro 1 & Irene Paterniti 1 & Rosalba Siracusa 1 & Daniela Impellizzeri 1 & Emanuela Esposito 1 & Salvatore Cuzzocrea 1,2 Received: 18 January 2016 /Accepted: 3 March 2016 # Springer Science+Business Media New York 2016 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 re- sponses associated to spinal cord injury (SCI) and plays a crucial role in secondary injury initiating a progressive degen- eration 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 inhib- itor 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 re- sults denote that the administration of KU0063794 produced a neuroprotective function at the lesion site following SCI, representing a novel therapeutic approach after SCI. Keywords KU0063794 . Temsirolimus . SCI . Autophagy . Inflammation Introduction Spinal cord injury (SCI) is one of the most primary reasons of long-term disability among young adults worldwide that consist of primary and secondary mechanisms that may explain the dif- ficulty in finding a suitable therapy [1] for the primary injury while the secondary injury is responsible for the extension of injury and produces further tissue loss and dysfunction, including a cascade of stress response. Plus the stress response, autophagy is a highly essential cellular response to damage and influences the improvement and progression of post-traumatic disease [2]. The term autophagy, from Greek Bself-eating^ refers to a range of processes, including chaperone-mediated autophagy, microautophagy, and macroautophagy, that regulated process of degradation and recycling of cellular constituents, partici- pated in organelle turnover and the bioenergetic management of starvation of spinal cord injury. The mammalian target of rapamycin (mTOR), a conserved serine/threonine kinase, is the catalytic subunit of two funda- mentally distinct complexes: complexes-mTOR complex 1 (mTORC1) and complexes-mTOR complex 2 (mTORC2) that individually plays an essential role in the control of cell proliferation. Both complexes localized to distinctive subcel- lular sections, thus affecting their initiation and role [3, 4]. The mTORC1 stimulate protein synthesis by mRNA translation Marika Cordaro and Irene Paterniti contributed equally to this work. * Salvatore Cuzzocrea salvator@unime.it 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy 2 Department of Pharmacological and Physiological Science, Saint Louis University, Saint Louis, MO, USA Mol Neurobiol DOI 10.1007/s12035-016-9827-0