Vargova Ingrid, Machova Urdzikova Lucia, Karova Kristyna, Smejkalova Barbora, Sursal Tolga, Cimermanova Veronika, Turnovcova Karolina, Gandhi Chirag D, Jhanwar-Uniyal Meena, Jendelova Pavla
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska, 1083, 142 20 Prague, Czech Republic.
2nd Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague, Czech Republic.
Biomedicines. 2021 May 24;9(6):593. doi: 10.3390/biomedicines9060593.
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.
创伤性脊髓损伤（SCI）目前无法治愈，仍然是导致残疾的主要原因。雷帕霉素（RAPA）是哺乳动物雷帕霉素靶蛋白（mTOR）途径复合物1（mTORC1）的抑制剂，对SCI后的神经保护和恢复有一定作用。然而，mTOR途径调控的机制不仅受mTORC1控制，还受第二种mTOR复合物（mTORC2）控制。第二代抑制剂pp242可同时抑制mTORC1和mTORC2，这促使我们探究其在SCI后的治疗潜力，并与RAPA治疗进行比较。在大鼠SCI球囊压迫模型中，观察了每日给予RAPA（5mg/kg；腹腔注射）和pp242（5mg/kg；腹腔注射）对炎症反应和自噬的影响。通过分析p-S6、p-Akt和p-4E-BP1水平，我们证实了SCI后mTOR途径受到抑制。在接受pp242治疗的大鼠中，几种促炎细胞因子水平升高，而RAPA治疗则导致促炎细胞因子水平降低。与对照组相比，RAPA和pp242治疗均导致LC3B上调，并在急性SCI中促进了功能和结构恢复，然而，RAPA治疗后轴突发芽更为明显。这些结果表明，SCI后pp242双重抑制mTOR会诱导不同的机制，导致恢复效果略逊于RAPA治疗。
