Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels

Abstract

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3β (GSK-3β) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes. The present data suggest that thiamine precursors with high bioavailability might be useful as a complementary therapy in several neuropsychiatric disorders.

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

“…Although this coenzyme of central metabolism of glucose is widely known as the physiologically active derivative of thiamine, behavioral and biochemical changes in the brain may also be due to the action of non‐coenzyme forms of thiamine (Bunik & Aleshin, ; Mkrtchyan et al, ). This view is supported by no significant changes in the brain ThDP levels measured after administration of a high dose of thiamine, which did change stress reactions and hippocampal neurogenesis along with increased levels of thiamine, but not ThDP, in the brain cortex (Vignisse et al, ). It should be noted, however, that from the minor components of the pool, such as thiamine, its mono‐ and triphosphates, and adenylated thiamine triphosphate, only thiamine and its monophosphate are reliably detected in the brain.…”

“…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.…”

“…Taking into account that the excretion of exogenous thiamine in rats occurs in app. 48 hr (Pipkin & Stella, 1982), whereas daily administration of the doses of thiamine up to 200 mg/kg increased the brain thiamine levels and/or total thiamine pool in rodents killed 24 hr after the administration (Bettendorff, Weekers, Wins, & Schoffeniels, 1990;Vignisse et al, 2017), our protocol, where rats were killed 24 hr after administration of 400 mg/kg thiamine, should allow one to observe not only the systemic action of thiamine compounds, but also the effects of the elevated thiamine pool in the brain.…”

Advances in Research on the Relationship between Vitamins and Neuropathy

“…Vitamin B1: also known as thiamine, is one of the earliest found in vitamins, and its main phosphorylated derivative -dithiophosphoric acid (ThDP) is a necessary cofactor for glucose metabolism, and the energy source of the brain Mainly in the blood, which can affect the brain's energy metabolism, causing central nervous system disease; 2015, Wang D found that thiamine lack of involvement in the brain inflammatory process, including the promotion of microglia activation, CD40 / CD40L, Cytokines IL1, TNF, IL6 and arachidonic acid metabolites increased [6], and the excessive production of inflammatory mediators caused by neurotoxicity; 2017, Vignisse J found that thiamine deficiency can cause damage to brain function metabolism, but Thiamine precursors protect the hippocampal structure from the deleterious effects of free radicals and inflammatory factors, and play a neuroprotective role, and also play a beneficial role in neurodegenerative diseases such as Alzheimer's disease [7].…”

Thiamine diphosphate synthesis and redox state indicator in rat brain during of B(1) hypovitaminosis

“…At the same time, single thiamine administration was not enough for ThDP level rapid normalization in the brain tissue of Av-T rats. The data obtained may indicate that the primary reason for the disturbance of redox balance in thiamine deficiency may be a decrease in the intracellular pool of thiamine and its biologically active derivatives, which in themselves are capable to neutralize free-radical compounds [25,28]. However, this assumption requires further experimental proof.…”