Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases †
Abstract
:1. Introduction
2. Transport and Metabolism of Thiamine Derivatives
3. Coenzyme Function of Thiamine Diphosphate
3.1. ThDP-Dependent Enzymes in Mammals
3.2. ThDP Mediated Catalysis
4. Thiamine Status in Humans and Inter-Organ Homeostasis
4.1. Thiamine Status in Humans
4.2. Thiamine Transport across the Blood–Brain Barrier Is Limited by Trans-Stimulation
4.3. TPK Is Regulated by Retroinhibition of ThDP
5. Development of Synthetic Thiamine Derivatives with High Bioavailability
- Disulfides, among which the most prominent representative is SuBT and its product of hydrolysis thiamine disulfide [63];
6. BFT in Animal Studies
6.1. Administration of BFT in Mice Does Not Significantly Increase Brain ThDP Levels
6.2. BFT Has Beneficial Effects in Animal Models of Neurodegenerative Diseases, Stress, and Anxiety
- The administration of BFT decreased aggression, reversed ultrasound-induced changes in GluA1 and GluA2 subunit expression, and reversed the decreased expression of plasticity markers [74];
- BFT (more efficiently than thiamine) counteracted the predator stress-induced decrease in the proliferation and survival of newborn immature neurons in the subgranular zone of the dentate gyrus [75].
6.3. BFT Has Coenzyme-Independent Antioxidant and Anti-Inflammatory Properties
7. BFT in Human Clinical Studies
7.1. Thiamine Homeostasis Is Disrupted in Patients with Alzheimer’s Disease
7.2. Therapeutic Effects of BFT on Patients with Alzheimer’s Disease
8. O,S-Dibenzoylthiamine, a Promising New Thiamine Prodrug
8.1. DBT Has Strong Antioxidant and Anti-Inflammatory Properties in Cultured Cells
8.1.1. DBT Has Powerful Antioxidant Effects Mediated by Glutathione
8.1.2. DBT Has Powerful Anti-Inflammatory Effects Mediated by NF-κB
8.2. DBT Protects from Motor Neuron Degeneration in a Transgenic Mouse Model of ALS
9. Hypotheses on the Mechanisms of Action of Synthetic Thiamine Derivatives
9.1. The Pharmacological Effects of BFT and DBT Are Most Probably ThDP-Independent
- Most of the studies were conducted in non-deficient cells or animals. Normal chow is rich in thiamine, and it must be understood that thiamine prodrugs are administered under conditions of thiamine saturation, where thiamine-dependent enzymes are saturated with ThDP. Indeed, when tested, ThDP-dependent enzymes are not or, at best, minimally increased [15,93];
- Many studies claim that BFT activates TK [67,99,100]. It is not clear how this could happen in the absence of a thiamine deficiency as, under normal conditions, TK is close to saturation with ThDP (see point 1). One possibility is that TK expression is upregulated at the mRNA level. Such mechanisms cannot be excluded as TK expression is controlled by Nrf2 [101]. However, using cultured neuroblastoma cells, we observed antioxidant effects of BFT and DBT, though neither TK activity nor expression was increased [93].
9.2. If Not ThDP, What Is the Active Metabolite of BFT and DBT?
- BFT requires extracellular dephosphorylation to S-BT (occurring in the intestine in vivo). S-BT, as well as DBT and SuBT, cross plasma membranes by simple diffusion. Intracellular S-BT is subject to the action of thioesterases to yield the open thiol form of thiamine [77]. In an aqueous medium, S-BT spontaneously undergoes an intramolecular rearrangement to O-BT, probably as a result of acyl-migration from sulfur to oxygen [10]. O-BT is then spontaneously converted to thiamine. The conversion of S-BT to O-BT is favored by alkaline pH. Though O-BT can be enzymatically converted to thiamine in most tissues, it does not seem to be more efficient than thiamine in raising tissue thiamine content [102]. O-BT has not been pharmacologically tested, but its spontaneous synthesis from BFT has been reported [10], and docking studies suggested that O-BT might be a good ligand for Keap1, competing for Nrf2 and favoring the translocation of Nrf2 to the nucleus [15]. Therefore, it is not excluded that O-BT might be pharmacologically active. Thiochrome, an oxidized form of thiamine present in small amounts in cells, was not increased by treatment of Neuro2a cells with BFT [77];
- DBT can either be hydrolyzed to S-BT or yield O-BT through the action of thioesters. O-BT might be transformed to S-BT by acyl migration from an O to an S atom [10]. S-BT can then proceed further to the open thiol form;
- SuBT, which was not discussed here as it has not been tested in neurodegenerative diseases [63], requires hydrolysis to thiamine disulfide, which must be reduced to the open thiol form. The reductant could be reduced glutathione (GSH) which is the most abundant intracellular thiol [103], or NADPH in a reaction of the type catalyzed by glutathione reductase [104]. SuBT has antioxidant [77] and weak anti-inflammatory [93] properties at a level similar to BFT but, for the latter, did not match DBT;
- All three thiamine prodrugs considered here will ultimately yield an open thiol form before being processed into thiamine [66]. The formation of the open thiol form from thiamine is unlikely under physiological conditions, but it is a thermodynamically stable form at alkaline pH (pH > 10) [105]. Nevertheless, a challenging hypothesis would be that there exist enzymes able to catalyze the formation of the open form from thiamine [105,106].
9.3. Which Are the Targets of BFT and DBT?
- BFT and DBT (and, to a lesser extent, SuBT and thiamine) have strong antioxidant properties both in vitro [75,77,93] and in vivo [15,17,79]. In cultured neuroblastoma cells, thiamine prodrugs normalized paraquat reduced NADPH and GSH levels in cultured neuroblastoma cells but were independent of TK activity and expression or Nrf2/ARE signaling. These prodrugs clearly seem to be involved in maintaining a high [GSH]/[GSSG] ratio and high NADPH concentrations. These results might be explained by an effect on glucose 6-phosphate dehydrogenase (G6PD). Indeed, this rate-limiting enzyme of the PPP is highly regulated, both at the level of transcription and post-translation [108,109]. However, it must be kept in mind that in addition to the oxidative part of the PPP, other sources of NADPH, such as cytosolic dehydrogenases and mitochondrial trans-hydrogenase, exist [103,109];
- Decreases in GSK-3β expression or activity regularly turn out after BFT or DBT treatment, in particular in in vivo studies [74,75,76,110] (but [15]). GSK-3β is a pleiotropic serine-threonine protein kinase able to phosphorylate over 100 substrates and play a role in numerous cellular functions affected in Alzheimer’s disease [111]. Decreased activity of GSK-3β activity by phosphorylation on Ser 9 may be responsible for changes in brain plasticity observed [17,74,77]. In addition, GSK-3β might be involved in the antioxidant response by activating Nrf2, an upstream regulator of G6PD and TK [112,113];
- BFT and, in particular DBT, have strong anti-inflammatory properties that seem to be mediated by NF-κB. Indeed, these compounds block the translocation of its p65 subunit to the nucleus and suppress LPS-induced iNOS expression and cytokine release [79,93]. This is of particular interest in view of the recent results showing that cytokines decrease thiamine transporter expression and activity and that the expression of these transporters is reduced in the brains of Alzheimer’s disease patients [89]. According to our data, DBT is a much more potent anti-inflammatory agent than BFT (and SuBT) in cultured BV-2 cells. We have no explanation for this difference, especially as it does not seem to be more efficient in raising intracellular thiamine concentrations. The differences may be related to different metabolization schemes with different proportions of intermediates O-BT, open thiol form) generated (Figure 9). This might also suggest that antioxidant and anti-inflammatory properties are mediated via different molecular targets;
- A significant amount of prodrug is already transformed into thiamine in the intestine, thereby affecting the gut microbiome. This might affect the enteric nervous system and, indirectly, the central nervous system. Indeed, thiamine affects the relative abundance of bacterial populations favoring those producing short-chain fatty acids [114]. A very appealing hypothesis would be that BFT corrects gut dysbiosis in Alzheimer’s patients, reducing inflammation and oxidative stress in the brain through the microbiota-gut-brain axis [115,116]. Interestingly NF-κB and Nrf2, both potential targets of BFT, seem to be involved in these processes. However, the gut microbiome hypothesis alone is not sufficient to explain the antioxidant and anti-inflammatory properties of BFT and DBT, as such effects were also observed in cell cultures, suggesting that other mechanisms coexist, as illustrated in Figure 10.
10. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AGE | Advanced Glycation end products |
ALS | Amyotrophic lateral sclerosis |
BBB | Blood–brain barrier |
BFT | Benfotiamine |
DBT | O,S-Dibenzoylthiamine |
GSH | Reduced glutathione |
G6PD | Glucose 6-phosphate dehydrogenase |
O-BT | O-Benzoylthiamine |
OGDHC | 2-Oxoglutarate dehydrogenase complex |
PDHC | Pyruvate dehydrogenase complex |
PPP | Pentose phosphate pathway |
S-BT | S-Benzoylthiamine |
SuBT | Sulbutiamine |
ThDP | Thiamine diphosphate |
ThMP | Thiamine monophosphate |
TK | Transketolase |
TPK | Thiamine pyrophosphokinase |
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Species (Tissue) | Thiamine | ThMP | ThDP |
---|---|---|---|
Plasma (nmol/L) | |||
Human 1 | 7.1 ± 1.6 | 5.8 ± 0.6 | - |
Blood (nmol/L) | |||
Human 2 | 4 ± 3 | 10 ± 4 | 138 ± 33 |
Rat 3 | 188 ± 72 | 718 ± 90 | 1127 ± 55 |
Mouse 4 | 73 ± 10 | 103 ± 37 | 737 ± 97 |
Cerebral cortex (pmol/mg protein) | |||
Human 2 | 0.2 ± 0.3 | 3.5 ± 2.6 | 21 ± 5 |
Baboon (P. papio) 5 | 8 ± 2 | 2.6 ± 0.4 | 43 ± 7 |
Rat 6 | 3.1 ± 1.0 | 4.0 ± 0.4 | 79 ± 5 |
Mouse 4 | 6 ± 0.8 | 8.1 ± 4.6 | 90 ± 8 |
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Bettendorff, L. Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases. Int. J. Mol. Sci. 2023, 24, 11296. https://doi.org/10.3390/ijms241411296
Bettendorff L. Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases. International Journal of Molecular Sciences. 2023; 24(14):11296. https://doi.org/10.3390/ijms241411296
Chicago/Turabian StyleBettendorff, Lucien. 2023. "Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases" International Journal of Molecular Sciences 24, no. 14: 11296. https://doi.org/10.3390/ijms241411296