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bioRxiv · 10.1101/2020.01.08.898635

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

de Queiroz, K. B.·Cavalcante-Silva, V.·Lopes, F. L.·Rocha, G. A.·D'Almeida, V.·Coimbra, R. S.
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Abstract

BackgroundBacterial 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, 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. MethodsEleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B12 or placebo, and, 24h 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 2-way followed by Bonferroni post-hoc test. Correlations were tested with Spearmans test. ResultsB12 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-adenosyl methionine (SAM):S-adenosyl homocysteine (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. ConclusionHcy 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.

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de Queiroz, K. B., Cavalcante-Silva, V., Lopes, F. L., Rocha, G. A., D'Almeida, V., Coimbra, R. S.. 2020-01-09. Vitamin B12 is neuroprotective in experimental pneumococcal meningitis through modulation of hippocampal DNA methylation. https://doi.org/10.1101/2020.01.08.898635

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