Severe Spinal Cord Injury in Rats Induces Chronic Changes in the Spinal Cord and Cerebral Cortex Metabolism, Adjusted by Thiamine That Improves Locomotor Performance.

Alexandra Boyko,Artem Artiukhov,Garik Mkrtchyan,Anastasia Graf,Vasily Aleshin,Polina Tsepkova,Lyudmila Baratova,Alexander Ksenofontov,Victoria Bunik,Sergey Ryabov

doi:10.3389/fnmol.2021.620593

Abstract

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.

Highlights

Severe spinal cord injury (SCI) causes long-term consequences, similar to the traumatic brain injury (TBI)
Using the amino acids profiling of the cerebral cortex as an integral marker of the SCIinduced metabolic perturbation in the brain, we show that a pleiotropic regulator thiamine, whose coenzyme form, thiamine diphosphate (ThDP), is required for the oxoglutarate dehydrogenase complex (OGDHC) function in particular, attenuates the changes in the known metabolic markers of the OGDHC downregulation in the brain
We show that the observed metabolic changes are associated with the changed expression of the major metabolic regulators linked to OGDHC function, i.e.,p53 and sirtuin 5

Summary

Introduction

Severe spinal cord injury (SCI) causes long-term consequences, similar to the traumatic brain injury (TBI). A strong link between mitochondrial metabolism and immunity is clearly demonstrated by the fact that immune response is impaired upon inhibition of 2-oxoglutarate dehydrogenase multienzyme complex (OGDHC) (Diaz-Munoz et al, 2015), limiting the tricarboxylic acid (TCA) cycle flux (reviewed by Bunik and Fernie, 2009). Perturbed homeostasis of intracellular Ca2+, known to occur early after the CNS injuries and associated with increased levels of the reactive oxygen and nitrogen species (Verweij et al, 1997; Xiong et al, 1997; Scholpa and Schnellmann, 2017), may be mediated by OGDHC, as Ca2+ ions activate OGDHC, stimulating the enzymatic production of both the energy intermediates and reactive oxygen species (reviewed in Bunik, 2019)

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