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Vargova I, Machova Urdzikova L, Karova K, et al. Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response. Biomedicines. 2021;9(6)doi: 10.3390/biomedicines9060593.
Vargova, I., Machova Urdzikova, L., Karova, K., Smejkalova, B., Sursal, T., Cimermanova, V., Turnovcova, K., Gandhi, C. D., Jhanwar-Uniyal, M., & Jendelova, P. (2021). Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response. Biomedicines, 9(6), . https://doi.org/10.3390/biomedicines9060593
Vargova, Ingrid, et al. "Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response." Biomedicines vol. 9,6 (2021). doi: https://doi.org/10.3390/biomedicines9060593
Vargova I, Machova Urdzikova L, Karova K, Smejkalova B, Sursal T, Cimermanova V, Turnovcova K, Gandhi CD, Jhanwar-Uniyal M, Jendelova P. Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response. Biomedicines. 2021 May 24;9(6). doi: 10.3390/biomedicines9060593. PMID: 34073791; PMCID: PMC8225190.
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Biomedicines. 2021 May 24;9(6). doi: 10.3390/biomedicines9060593.

Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response.

Biomedicines

Ingrid Vargova, Lucia Machova Urdzikova, Kristyna Karova, Barbora Smejkalova, Tolga Sursal, Veronika Cimermanova, Karolina Turnovcova, Chirag D Gandhi, Meena Jhanwar-Uniyal, Pavla Jendelova

Affiliations

  1. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska, 1083, 142 20 Prague, Czech Republic.
  2. 2nd Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague, Czech Republic.
  3. Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY 10595, USA.

PMID: 34073791 PMCID: PMC8225190 DOI: 10.3390/biomedicines9060593

Abstract

Traumatic spinal cord injury (SCI) is untreatable and remains the leading cause of disability. Neuroprotection and recovery after SCI can be partially achieved by rapamycin (RAPA) treatment, an inhibitor of mTORC1, complex 1 of the mammalian target of rapamycin (mTOR) pathway. However, mechanisms regulated by the mTOR pathway are not only controlled by mTORC1, but also by a second mTOR complex (mTORC2). Second-generation inhibitor, pp242, inhibits both mTORC1 and mtORC2, which led us to explore its therapeutic potential after SCI and compare it to RAPA treatment. In a rat balloon-compression model of SCI, the effect of daily RAPA (5 mg/kg; IP) and pp242 (5 mg/kg; IP) treatment on inflammatory responses and autophagy was observed. We demonstrated inhibition of the mTOR pathway after SCI through analysis of p-S6, p-Akt, and p-4E-BP1 levels. Several proinflammatory cytokines were elevated in pp242-treated rats, while RAPA treatment led to a decrease in proinflammatory cytokines. Both RAPA and pp242 treatments caused an upregulation of LC3B and led to improved functional and structural recovery in acute SCI compared to the controls, however, a greater axonal sprouting was seen following RAPA treatment. These results suggest that dual mTOR inhibition by pp242 after SCI induces distinct mechanisms and leads to recovery somewhat inferior to that following RAPA treatment.

Keywords: autophagy; dual inhibition; inflammation; mTOR; pp242; rapamycin; spinal cord injury

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