Boyko Alexandra, Tsepkova Polina, Aleshin Vasily, Artiukhov Artem, Mkrtchyan Garik, Ksenofontov Alexander, Baratova Lyudmila, Ryabov Sergey, Graf Anastasia, Bunik Victoria
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
Front Mol Neurosci. 2021 Mar 29;14:620593. doi: 10.3389/fnmol.2021.620593. eCollection 2021.
Our study aims at developing knowledge-based strategies minimizing chronic changes in the brain after severe spinal cord injury (SCI). The SCI-induced long-term metabolic alterations and their reactivity to treatments shortly after the injury are characterized in rats. Eight weeks after severe SCI, significant mitochondrial lesions outside the injured area are demonstrated in the spinal cord and cerebral cortex. Among the six tested enzymes essential for the TCA cycle and amino acid metabolism, mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) is the most affected one. SCI downregulates this complex by 90% in the spinal cord and 30% in the cerebral cortex. This is associated with the tissue-specific changes in other enzymes of the OGDHC network. Single administrations of a pro-activator (thiamine, or vitamin B1, 1.2 mmol/kg) or a synthetic pro-inhibitor (triethyl glutaryl phosphonate, TEGP, 0.02 mmol/kg) of OGDHC within 15-20 h after SCI are tested as protective strategies. The biochemical and physiological assessments 8 weeks after SCI reveal that thiamine, but not TEGP, alleviates the SCI-induced perturbations in the rat brain metabolism, accompanied by the decreased expression of (acetyl)p53, increased expression of sirtuin 5 and an 18% improvement in the locomotor recovery. Treatment of the non-operated rats with the OGDHC pro-inhibitor TEGP increases the p53 acetylation in the brain, approaching the brain metabolic profiles to those after SCI. Our data testify to an important contribution of the OGDHC regulation to the chronic consequences of SCI and their control by p53 and sirtuin 5.
我们的研究旨在制定基于知识的策略，以尽量减少严重脊髓损伤（SCI）后大脑的慢性变化。在大鼠中对SCI诱导的长期代谢改变及其在损伤后不久对治疗的反应性进行了表征。严重SCI八周后，在脊髓和大脑皮层中发现损伤区域外存在明显的线粒体损伤。在三羧酸循环和氨基酸代谢必需的六种测试酶中，线粒体2-氧代戊二酸脱氢酶复合体（OGDHC）受影响最大。SCI使脊髓中的该复合体下调90%，大脑皮层中下调30%。这与OGDHC网络中其他酶的组织特异性变化有关。在SCI后15-20小时内单次给予OGDHC的前激活剂（硫胺素，即维生素B1，1.2 mmol/kg）或合成前抑制剂（三乙基戊二酰膦酸酯，TEGP，0.02 mmol/kg）作为保护策略进行测试。SCI八周后的生化和生理评估表明，硫胺素而非TEGP可减轻SCI诱导的大鼠脑代谢紊乱，同时伴有（乙酰基）p53表达降低、沉默调节蛋白5表达增加以及运动恢复改善18%。用OGDHC前抑制剂TEGP处理未手术的大鼠会增加大脑中的p53乙酰化，使大脑代谢谱接近SCI后的情况。我们的数据证明了OGDHC调节对SCI慢性后果的重要贡献以及p53和沉默调节蛋白5对其的控制作用。
