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

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

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.

Highlights

Neuroprotection and recovery after Spinal cord injury (SCI) can be partially achieved by rapamycin (RAPA) treatment, an inhibitor of mTOR complex 1 (mTORC1), complex 1 of the mammalian target of rapamycin pathway
Our study demonstrated how RAPA and pp242 treatments altered the levels of substrates of the mTOR pathway from spinal cord tissue after acute SCI (Figure 6)
The present study assessed the mechanisms via two mTOR pathway inhibitors, RAPA and pp242, which influenced the acute phase of SCI in rats

Summary

Introduction

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. 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. 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, 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.

Methods

Results

Discussion

Conclusion