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.

中文翻译：

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维生素B ₁₂通过调节海马DNA甲基化对实验性肺炎球菌性脑膜炎具有神经保护作用

细菌性脑膜炎（BM）导致海马凋亡，同型半胱氨酸（Hcy）积累到儿童脑脊液中的神经毒性水平。Hcy途径控制甲基的生物利用度，其稳态可通过蛋氨酸合酶的辅因子维生素B12来调节。本文中，在BM的新生大鼠模型中评估了维生素B12辅助治疗的神经保护潜力和潜在的作用方式。对11日龄的大鼠进行了膀胱内感染3型肺炎链球菌或生理盐水的治疗，并用B12或安慰剂处理，感染后24小时，分析了海马的齿状回中的细胞凋亡，硫氨基酸含量，总体DNA甲基化，转录和候选基因的近端启动子甲基化。两组之间的差异使用2通ANOVA和Bonferroni事后检验进行比较。相关性用Spearman检验进行了检验。B12以Hcy依赖性方式减弱了BM诱导的海马细胞凋亡（r = 0.80，P <0.05）。BM引起整体DNA低甲基化；但是，B12恢复了该参数。因此，从受感染动物中S-腺苷甲硫氨酸（SAM）∶S-腺苷同型半胱氨酸（SAH）之比推断，B12增加了受感染动物海马细胞的甲基化能力。BM上调了选定的促炎基因，B12抵消了这种作用，B12也增加了感染动物Ccl3启动子上CpGs的甲基化。在BM的新生大鼠模型中，Hcy可能在海马损伤中起重要作用，