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

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.

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.

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.

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.