Neuroinflammation regulates the balance between hippocampal neuron death and neurogenesis in an ex vivo model of thiamine deficiency

Abstract

Background Thiamine (vitamin B1) is a cofactor for enzymes of central energy metabolism and its deficiency (TD) impairs oxidative phosphorylation, increases oxidative stress, and activates inflammatory processes that can lead to neurodegeneration. Wernicke–Korsakoff syndrome (WKS) is a consequence of chronic TD, which leads to extensive neuronal death, and is associated with neuropathological disorders, including cognitive deficits and amnesia. The hippocampus is one of the brain areas most affected by WKS. B1 replacement may not be enough to prevent the irreversible cognitive deficit associated with WKS. Materials and methods An organotypic hippocampal slice culture (OHC) model was developed to investigate, using immunofluorescence and confocal microscopy and transcriptome analysis, the molecular mechanisms underlying the neurodegeneration associated with TD. The effect of anti-inflammatory pharmacological intervention with resveratrol (RSV) was also assessed in B1-deprived OHCs. Results In OHCs cultured without B1, neuronal density decayed after 5 days and, on the 7th day, the epigenetic markings H3K4me3 and H3K9me3 were altered in mature neurons likely favoring gene transcription. Between the 7th and the 14th day, a pulse of neurogenesis was observed followed by a further massive neuron loss. Transcriptome analysis at day nine disclosed 89 differentially expressed genes in response to B1 deprivation. Genes involved in tryptophan metabolism and lysine degradation KEGG pathways, and those with Gene Ontology (GO) annotations related to the organization of the extracellular matrix, cell adhesion, and positive regulation of synaptic transmission were upregulated. Several genes of the TNF and FoxO signaling pathways and with GO terms related to inflammation were inhibited in response to B1 deprivation. Nsd1, whose product methylates histone H3 lysine 36, was upregulated and the epigenetic marking H3K36me3, associated with negative regulation of neurogenesis, was increased in neurons. Treating B1-deprived OHCs with RSV promoted an earlier neurogenesis pulse. Conclusion Neuroregeneration occurs in B1-deficient hippocampal tissue during a time window. This phenomenon depends on reducing neuroinflammation and, likely, on metabolic changes, allowing acetyl-CoA synthesis from amino acids to ensure energy supply via oxidative phosphorylation. Thus, neuroinflammation is implicated as a major regulator of hippocampal neurogenesis in TD opening a new search space for treating WKS.

Organotypic Hippocampal Culture Model Reveals Differential Responses to highly similar Zika virus isolates

“…OHC were immune stained as previously described (27). The density of mature neurons in OHC 8h, 24h, 48h, 5, 7 and 10 days post infection (p.i.)…”

Alcohol withdrawal syndrome

“…Thiamine (vitamin B-1) is a cofactor for synthesizing neurotransmitters, enhancing neuronal function, and converting carbohydrates into energy 10,11. Thiamine is not manufactured in the body and must be acquired from the diet 10,11.…”

“…Thiamine deficiency may occur in AUD from poor intake or absorption, leading to severe headaches, paresthesia, neuropathy, gait imbalance, visual disturbances, anxiety, cognitive impairment, confusion, and dementia, known as Wernicke-Korsakoff (WK) Syndrome 10,11. Thiamine deficiency often coexists with AWS and thiamine is administered to help glucose form adenosine triphosphate (ATP) to enhance neurotransmission and energy 10,11. Acetylcholine, an excitatory neurotransmitter, and ATP are synthesized simultaneously to facilitate the conduction of other neurotransmitters (see Function of select neurotransmitters ) 10,11…”

“…coexists with AWS and thiamine is administered to help glucose form adenosine triphosphate (ATP) to enhance neurotransmission and energy. 10,11 Acetylcholine, an excitatory neurotransmitter, and ATP are synthesized simultaneously to facilitate the conduction of other neurotransmitters (see Function of select neurotransmitters). 10,11 Gamma-aminobutyric acid (GABA), glutamate, and dopamine are major neurotransmitters impacted by EAC.…”

“…10,11 Acetylcholine, an excitatory neurotransmitter, and ATP are synthesized simultaneously to facilitate the conduction of other neurotransmitters (see Function of select neurotransmitters). 10,11 Gamma-aminobutyric acid (GABA), glutamate, and dopamine are major neurotransmitters impacted by EAC. 6,7,12 GABA is an inhibitory neurotransmitter that decreases cell excitability and produces a calming effect in a person who has not consumed alcohol.…”