Abstract
Thiamine precursors, the most studied being benfotiamine (BFT), have protective effects in mouse models of neurodegenerative diseases. BFT decreased oxidative stress and inflammation, two major characteristics of neurodegenerative diseases, in a neuroblastoma cell line (Neuro2a) and an immortalized brain microglial cell line (BV2). Here, we tested the potential antioxidant and anti-inflammatory effects of the hitherto unexplored derivative O,S-dibenzoylthiamine (DBT) in these two cell lines. We show that DBT protects Neuro2a cells against paraquat (PQ) toxicity by counteracting oxidative stress at low concentrations and increases the synthesis of reduced glutathione and NADPH in a Nrf2-independent manner. In BV2 cells activated by lipopolysaccharides (LPS), DBT significantly decreased inflammation by suppressing translocation of NF-κB to the nucleus. Our results also demonstrate the superiority of DBT over thiamine and other thiamine precursors, including BFT, in all of the in vitro models. Finally, we show that the chronic administration of DBT arrested motor dysfunction in FUS transgenic mice, a model of amyotrophic lateral sclerosis, and it reduced depressive-like behavior in a mouse model of ultrasound-induced stress in which it normalized oxidative stress marker levels in the brain. Together, our data suggest that DBT may have therapeutic potential for brain pathology associated with oxidative stress and inflammation by novel, coenzyme-independent mechanisms.
Highlights
10% of fetal bovine serum (FBS) was 10 nM, which is enough for normal cell growth as Neuro2a cells cells and switching the cells to the Dulbecco’s modified Eagle’s medium (DMEM) thiamine-restricted medium did not induce a sensible possess high-affinity thiamine transporters [38]
Our results clearly show that DBT protects Neuro2a cells against oxidative stress and that this protection might be coupled to NADPH/GSH
Our results show that content is content increasedisinindeed the hippocampus subjectedofto the ultrasound and that malonaldehyde increased of in the theanimals hippocampus animalsstress subjected to it was decreased by DBT, which seemed to be more effective than thiamine (Supplemental ultrasound stress and that it was decreased by DBT, which seemed to be more effective than thiamine (Supplemental Figure S15)
Summary
Is anisessential micronutrient, indispensable for oxidative metabolism, Thiamine(vitamin It is the precursor of thiamine metabolism, which is especially important for neuronal activity and survival. It is the precursor of diphosphate (ThDP), an important coenzyme for pyruvate and oxoglutarate dehydrogenases, thiamine diphosphate (ThDP), an important coenzyme for pyruvate and oxoglutarate for transketolase (TKT1). Coenzyme) roles of thiamine in the nervous system have been suggested [2,3,4,5]
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