Doctoral thesis (Dissertations and theses)
Mécanisme des effets neuroprotecteurs de la thiamine et de précurseurs à plus haute biodisponibilité
Vignisse, Julie
2016
 

Files


Full Text
These.doctorat.Julie.Vignisse.pdf
Author postprint (24.33 MB)
Download

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
stress; sulbutiamine; S-benzoylthiamine; benfotiamine; neuogenèse; neurogenesis; BDNF; ThDP
Abstract :
[fr] Thiamine is very important for brain functioning and its deficiency causes specific lesions. This is mainly due to decreased levels of its diphosphorylated derivative thiamine diphosphate (ThDP), an essential cofactor for key enzymes in brain energy metabolism. Brain thiamine deficiency is not only the result of reduced thiamine intake, but also a consequence of chronic alcoholism, gastrointestinal diseases, diabetes, absorption of anti-thiamine factors, aging or reduced transport activity. As thiamine transport across the blood-brain barrier is relatively slow, thiamine precursors with higher bioavailability have been developed. One such compound is benfotiamine (BFT). After oral intake, BFT is dephosphorylated by intestinal alkaline phosphatase to the lipophilic S-benzoylthiamine, which freely diffuses across the intestinal mucosa and is transformed to thiamine. After administration of BFT, much higher blood thiamine levels are reached than after administration of an equivalent amount of thiamine. BFT was first shown to be efficient against diabetes-related complications. More recently, it was shown to have highly beneficial effects in mouse models of neurodegenerative diseases. In particular, it decreases brain amyloid deposits and tau hyperphosphorylation. The aim of our thesis was to investigate the mechanisms involved in central nervous system effects of BFT. In a first part, using the mouse neuroblastoma cell line N2a, we demonstrated that BFT indeed requires prior dephosphorylation to S-benzoylthiamine in order to enter the cells and raise intracellular thiamine concentrations. Surprisingly, when orally administered to mice, BFT strongly increased blood thiamine concentration but did not increase brain ThDP levels, suggesting that potential central nervous system effects are cofactor-independent. It has been suggested that treatment with benfotiamine induces an increase in brain GSK-3ß phosphorylation, thereby decreasing its activity. As GSK-3ß is in part responsible for tau hyperphosphorylation, such a mechanism might explain a reduced formation of neurofibrillary tangles in the above-mentioned models of neurodegeneration. Using N2a cells, we indeed confirm a stimulation of the RTK – PI3K – Akt pro-survival pathway. As it is known that benfotiamine treatment has potent beneficial effects in 2 different mouse models of neurodegeneration and that exposure of WT mice to intense stress is also harmful for the hippocampus, we investigated the effects of predator stress on adult hippocampal neurogenesis. The latter has been shown to be impaired by stress in rodents. We therefore tested the effects of thiamine and BFT treatment on hippocampal neurogenesis in predator-stressed mice. Our results show that both thiamine and BFT prevented the reduction of neurogenesis induced by stress, benfotiamine being most effective. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and increase of anxiety-like behavior. Both treatments elevated brain levels of thiamine, but not of the coenzyme thiamine diphosphate (ThDP), again suggesting that the beneficial effects observed are not linked to the cofactor role of ThDP. Our study demonstrates for the first time that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes, probably by non-cofactor-dependent mechanisms. The use of thiamine precursors might thus be considered as a complementary therapy in several neuropsychiatric disorders, especially depression caused by chronic stress.
Disciplines :
Biochemistry, biophysics & molecular biology
Neurosciences & behavior
Author, co-author :
Vignisse, Julie ;  Université de Liège - ULiège > MEPR - Médecine - Département des sciences précliniques
Language :
French
Title :
Mécanisme des effets neuroprotecteurs de la thiamine et de précurseurs à plus haute biodisponibilité
Alternative titles :
[en] Mechanism of neuroprotective effets of thiamine and precursors with higher bioavaibility
Defense date :
15 June 2016
Institution :
Université de Liège
Degree :
Doctorat en sciences biomédicales et pharmaceutiques
Promotor :
STREKALOVA, Tatiana
BETTENDORFF, Lucien  
President :
SEUTIN, Vincent
Jury member :
SALMON, Eric
GRISAR, Thierry
GRISAR, Laurence
LIEGEOIS, Jean-François
LEPRINCE, Pierre
HEUSCHLING, Paul
Available on ORBi :
since 27 March 2024

Statistics


Number of views
27 (0 by ULiège)
Number of downloads
31 (0 by ULiège)

Bibliography


Similar publications



Contact ORBi