Vitamin B₁₂is neuroprotective in experimental pneumococcal meningitis through modulation of hippocampal DNA methylation

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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 B<jats:sub>12</jats:sub>, cofactor of the methionine synthase enzyme. Herein, the neuroprotective potential and the underlying mode of action of vitamin B<jats:sub>12</jats:sub> adjuvant therapy were assessed in an infant rat model of BM.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Eleven-day old rats were intracysternally infected with <jats:italic>Streptococcus pneumoniae</jats:italic> serotype 3, or saline, treated with B<jats:sub>12</jats:sub> 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 Spearman’s test.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>B<jats:sub>12</jats:sub> attenuated BM-induced hippocampal apoptosis in a Hcy dependent manner (r = 0.80, <jats:italic>P</jats:italic> &lt; 0.05). BM caused global DNA hypomethylation, however B<jats:sub>12</jats:sub> restored this parameter. Accordingly, B<jats:sub>12</jats:sub> 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 B<jats:sub>12</jats:sub>, which also increased methylation of CpGs at the promoter of <jats:italic>Ccl3</jats:italic> of infected animals.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Hcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B<jats:sub>12</jats:sub> shows an anti-inflammatory and neuroprotective action through methyl-dependent epigenetic mechanisms.</jats:p></jats:sec>

Vitamin B12 and gut-brain homeostasis in the pathophysiology of ischemic stroke

“…While the precise mechanisms by which VB12 deficiency induces neuropsychiatric conditions remains unclear, several vital functions of VB12 are likely to be relevant. VB12 protects against oxidative injury and inflammatory stress by directly scavenging free radical species and suppressing oxidation-induced injury, supporting glutathione activity, reducing endoplasmic reticulum stress and resisting neuronal apoptosis in several models of neurological disease [10].…”

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

“…B12 supplementation has also been shown to promote DNA methylation changes and affect the antidepressant response in a mouse model [ 161 ]. Supplementation also restores hippocampal DNA methylation levels in rats with bacterial meningitis [ 162 ]. These studies suggest that B12 supplementation could be explored in scenarios where increased methylation potential is required, analogous to the FA supplementation of pregnant women to prevent NTDs.…”

MBP‐activated autoimmunity plays a role in arsenic‐induced peripheral neuropathy and the potential protective effect of mecobalamin

“…Besides, as a therapeutic drug of Alzheimer's disease‐related cognitive disorder, MeCbl treatment significantly decreased homocysteine level in blood, which was an indicator of neuroinflammation 68 . Coimbra and colleagues suggested that the repressive effect of MeCbl on neuroinflammtion was partly through modulation of DNA methylation of certain inflammatory cytokines 69 . However, the underlying mechanism for the anti‐inflammatory effect of MeCbl on AIPN is warranted for further research.…”

“…68 Coimbra and colleagues suggested that the repressive effect of MeCbl on neuroinflammtion was partly through modulation of DNA methylation of certain inflammatory cytokines. 69 However, the underlying mechanism for the anti-inflammatory effect of MeCbl on AIPN is warranted for further research.…”