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KU0063794, a Dual mTORC1 and mTORC2 Inhibitor, Reduces Neural Tissue Damage and Locomotor Impairment After Spinal Cord Injury in Mice

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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.

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Acknowledgments

The authors would like to thank Maria Antonietta Medici for her excellent technical assistance during this study and Mr Francesco Soraci for his secretarial and administrative assistance and Miss Valentina Malvagni for her editorial assistance with the manuscript.

This work was supported by L’Oréal award.

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    Authors and Affiliations

    1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166, Messina, Italy

      Marika Cordaro, Irene Paterniti, Rosalba Siracusa, Daniela Impellizzeri, Emanuela Esposito & Salvatore Cuzzocrea

    2. Department of Pharmacological and Physiological Science, Saint Louis University, Saint Louis, MO, USA

      Salvatore Cuzzocrea

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    1. Marika Cordaro
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    2. Irene Paterniti
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    3. Rosalba Siracusa
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    5. Emanuela Esposito
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    6. Salvatore Cuzzocrea
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    Corresponding author

    Correspondence to Salvatore Cuzzocrea.

    Ethics declarations

    The study was permitted by the University of Messina Review Board for the care of animals. All animal experiments complied with regulations in Italy (D.M. 116192) as well as the EU regulations (O.J. of E.C. L 358/1 12/18/1986).

    Competing Interests

    The authors declare that they have no competing interests.

    Additional information

    Marika Cordaro and Irene Paterniti contributed equally to this work.

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    Cordaro, M., Paterniti, I., Siracusa, R. et al. KU0063794, a Dual mTORC1 and mTORC2 Inhibitor, Reduces Neural Tissue Damage and Locomotor Impairment After Spinal Cord Injury in Mice. Mol Neurobiol 54, 2415–2427 (2017). https://doi.org/10.1007/s12035-016-9827-0

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    • DOI: https://doi.org/10.1007/s12035-016-9827-0

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