Vitamin B12 is neuroprotective in experimental pneumococcal meningitis through modulation of hippocampal DNA methylation

Abstract

Background Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. The Hcy pathway controls bioavailability of methyl, and its homeostasis can be modulated by vitamin B12, a cofactor of the methionine synthase enzyme. Herein, the neuroprotective potential and the underlying mode of action of vitamin B12 adjuvant therapy were assessed in an infant rat model of BM. Methods Eleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B12 or placebo, and, 24 h after infection, their hippocampi were analyzed for apoptosis in the dentate gyrus, sulfur amino acids content, global DNA methylation, transcription, and proximal promoter methylation of candidate genes. Differences between groups were compared using 2-way ANOVA followed by Bonferroni post hoc test. Correlations were tested with Spearman’s test. Results B12 attenuated BM-induced hippocampal apoptosis in a Hcy-dependent manner (r = 0.80, P < 0.05). BM caused global DNA hypomethylation; however, B12 restored this parameter. Accordingly, B12 increased the methylation capacity of hippocampal cells from infected animals, as inferred from the ratio S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) in infected animals. BM upregulated selected pro-inflammatory genes, and this effect was counteracted by B12, which also increased methylation of CpGs at the promoter of Ccl3 of infected animals. Conclusion Hcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B12 shows an anti-inflammatory and neuroprotective action through methyl-dependent epigenetic mechanisms.

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

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“…In general, DNA hypomethylation in gene promoters is associated with the activated state of their expression ( 12 ). It is already known that promoters of genes encoding cytokines are rapidly demethylated (~6 hours) after T cell activation ( 13 ) and that several genes encoding key cytokines and chemokines have increased systemic expression in patients with COVID-19 ( 14 ) are regulated by the methylation of CpGs in their promoters or enhancers ( 15 – 18 ). The ability of RNA viruses to hijack the epigenome of host immune cells in order to evade antiviral defense is widely acknowledged ( 19 , 20 ).…”

Suitability of Banana and Plantain Fruits in Modulating Neurodegenerative Diseases: Implicating the In Vitro and In Vivo Evidence from Neuroactive Narratives of Constituent Biomolecules

“…Cobalamin (Vitamin B 12 ) contributes to the protection of nerve fibers through myelin sheath synthesis [ 171 ]. In a recent study, vitamin B 12 was experimentally demonstrated to have modulatory neuroprotective and anti-inflammatory activities against pneumococcal meningitis and hippocampus damage [ 172 ]. In addition, hippocampus apoptosis, triggered by bacterial meningitis, was diminished by vitamin B 12 treatment (10 µL intramuscular dosage) [ 172 ].…”