The inhibition of mammalian target of rapamycin (mTOR) in improving inflammatory response after traumatic brain injury.

Abstract

Traumatic brain injury (TBI) provokes primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) manages numerous aspects of cellular growth, and it is up-regulated after moderate to severe traumatic brain injury (TBI). Currently, the significance of this increased signalling event for the recovery of brain function is unclear; therefore, we used two different selective inhibitors of mTOR activity to discover the functional role of mTOR inhibition in a mouse model of TBI performed by a controlled cortical impact injury (CCI). Treatment with KU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin as well-known inhibitor of mTOR, was performed 1 and 4 hours subsequent to TBI. Results proved that mTOR inhibitors, especially KU0063794, significantly improved cognitive and motor recovery after TBI, reducing lesion volumes. Also, treatment with mTOR inhibitors ameliorated the neuroinflammation associated with TBI, showing a diminished neuronal death and astrogliosis after trauma. Our findings propose that the involvement of selective mTORC1/2 inhibitor may represent a therapeutic strategy to improve recovery after brain trauma.

• Authors: Michela Campolo, Giovanna Casili, Marika Lanza, Alessia Filippone, Marika Cordaro, Alessio Ardizzone, Sarah Adriana Scuderi, Salvatore Cuzzocrea, Emanuela Esposito, Irene Paterniti
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 16 Pg. 7855-7866 (08 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 34245104 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Enzyme Inhibitors
• Immunosuppressive Agents
• MTOR Inhibitors
• Morpholines
• Pyrimidines
• Ku 0063794
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Brain Injuries, Traumatic (complications)
• Cell Death
• Cell Proliferation
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Immunosuppressive Agents (pharmacology)
• MTOR Inhibitors (pharmacology)
• Male
• Mice
• Morpholines (pharmacology)
• Neuroinflammatory Diseases (drug therapy, etiology, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Pyrimidines (pharmacology)
• Signal Transduction
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)