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

Karina Barbosa De Queiroz,Flávia Lombardi Lopes,Gifone Aguiar Rocha,Vânia D’Almeida,Vanessa Cavalcante-Silva,Roney Santos Coimbra

doi:10.1186/s12974-020-01763-y

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, 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.MethodsEleven-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.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-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.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.

Highlights

Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children
Adjunctive therapy with B12 reduced apoptotic cell counts in the hippocampal dentate gyrus of infant rats with BM All animals infected with S. pneumoniae had BM after 18 h p.i., as evidenced by positive bacterial titers in the cerebrospinal fluid (CSF) (~ 1 × 108 cfu/mL)
The positive correlation found between hippocampal Hcy concentration and the apoptotic score in the dentate gyrus of infected animals treated with B12 supports the hypothesis that an imbalance in the sulfur amino acid homeostasis leading to Hcy accumulation may play a pivotal role in the neurodegenerative process associated to BM

Summary

Introduction

Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. Since the advent of anti-Hib vaccine in the late 90s, pneumococcus has become the most frequent cause of non-epidemic BM among children older than 1 year of age [2, 3]. BM is characterized by intense granulocytic inflammation within the subarachnoid and ventricular spaces, extending into the perilymphatic space of the inner ear. This granulocytic inflammation results in extensive neuronal damage, primarily in the brain cortex (CX) and hippocampus (HC). HC cells undergoing apoptosis are mostly post mitotic neurons and progenitor cells distributed along the inner granule cell layer of the dentate gyrus [10, 11]

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