Delayed Influence of Spinal Cord Injury on the Amino Acids of NO• Metabolism in Rat Cerebral Cortex Is Attenuated by Thiamine

Abstract

Severe spinal cord injuries (SCIs) result in chronic neuroinflammation in the brain, associated with the development of cognitive and behavioral impairments. Nitric oxide (NO•) is a gaseous messenger involved in neuronal signaling and inflammation, contributing to nitrosative stress under dysregulated production of reactive nitrogen species. In this work, biochemical changes induced in the cerebral cortex of rats 8 weeks after SCI are assessed by quantification of the levels of amino acids participating in the NO• and glutathione metabolism. The contribution of the injury-induced neurodegeneration is revealed by comparison of the SCI- and laminectomy (LE)-subjected animals. Effects of the operative interventions are assessed by comparison of the operated (LE/SCI) and non-operated animals. Lower ratios of citrulline (Cit) to arginine (Arg) or Cit to ornithine and a more profound decrease in the ratio of lysine to glycine distinguish SCI animals from those after LE. The data suggest decreased NO• production from both Arg and homoarginine in the cortex 8 weeks after SCI. Both LE and SCI groups show a strong decrease in the level of cortex glutathione. The neurotropic, anti-inflammatory, and antioxidant actions of thiamine (vitamin B1) prompted us to study the thiamine effects on the SCI-induced changes in the NO• and glutathione metabolism. A thiamine injection (400 mg/kg intraperitoneally) within 24 h after SCI abrogates the changes in the cerebral cortex amino acids related to NO•. Thiamine-induced normalization of the brain glutathione levels after LE and SCI may involve increased supply of glutamate for glutathione biosynthesis. Thus, thiamine protects from sequelae of SCI on NO•-related amino acids and glutathione in cerebral cortex.

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

“…As mentioned earlier, the GDH reactivity to the (de)acetylating agents could be additionally affected by endogenous levels of the GDH ligands in the (de)acetylation medium, which are known to change during the day (Fustin et al, ; Reinke & Asher, ). Thiamine administration may also change the brain metabolome (Boyko et al, ; Tsepkova et al, ). Therefore, further assessment of the daytime‐ and thiamine‐dependent changes in the GDH function has been done after removal of endogenous low molecular mass compounds from GDH of the brain homogenates through gel filtration on a HiTrap column.…”

“…It is worth noting that the thiamine‐induced change in the physiological regulation of brain GDH by acetylation may be exploited to correct pathological states, where the acetylation and/or diurnal rhythms are disturbed. In this regard, the demonstrated action of thiamine administration on the acetylation of brain proteins may contribute to the known neuroprotective action of thiamine in pathological states (Aleshin et al, ; Boyko et al, ; Mkrtchyan, Üçal, et al, ).…”

“…The thiamine‐treated group of animals (Figure ) obtained 400 mg of thiamine per kg as a single intraperitoneal injection of thiamine*HCl (prepared fresh as a 200 mg/ml water solution with pH adjusted to 6.7–6.9 with NaOH), as in previous studies (Boyko et al, ; Mkrtchyan, Üçal, et al, ; Tsepkova et al, ). The control group of animals received a similar injection of physiological solution (0.9% sodium chloride) which mimics the ionic properties of the administered thiamine solution better than water.…”

“…As a result, studies of the brain action of thiamine and even its membrane-permeable derivatives usually employ administration of high doses of these compounds (Bettendorff et al, 1990;Boyko et al, 2017;Mkrtchyan, Üçal, et al, 2018b;Tsepkova et al, 2017;Vignisse et al, 2017), also modeling clinical applications of thiamine to treat neurodegenerative disorders (reviewed in (Aleshin et al, 2019;Bunik, 2014). In humans, the doses up to 500 mg thiamine thrice a day (Galvin et al, 2010), or of 500 mg thiamine daily during a month (Hawk, Oser, & Summerson, 1955) are reported to be safe.…”

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

“…Arguably, the association originates from an essential role of OGDHC in the amino acid metabolism ( Santos et al, 2006 ; Bunik and Fernie, 2009 ; Graf et al, 2009 , 2020 ; Trofimova et al, 2012 ; Araujo et al, 2013 ) and immune response ( Diaz-Munoz et al, 2015 ), i.e., the pathways known or implied to be changed in the chronic phases of CNS damage. In particular, changed metabolism of amino acids may underlie such important metabolic features of the damage as perturbed glutathione and nitric oxide (NO ⋅ ) homeostasis, which are linked to cognitive perturbations ( Aquilani et al, 2003 ; Gahm et al, 2006 ; Ploder et al, 2008 ; Vuille-Dit-Bille et al, 2012 ; Yi et al, 2016 ; Boyko et al, 2018 ; Xing et al, 2018 ). In our previous study of a rat model of severe SCI, a single dose of thiamine after SCI have attenuated long-term changes in the levels of the NO ⋅ - and glutathione-related amino acids in the brain cerebral cortex ( Boyko et al, 2018 ).…”