Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil.
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Front Immunol. 2023 Oct 3;14:1250055. doi: 10.3389/fimmu.2023.1250055. eCollection 2023.
The interplay between bacterial virulence factors and the host innate immune response in pneumococcal meningitis (PM) can result in uncontrolled neuroinflammation, which is known to induce apoptotic death of progenitor cells and post-mitotic neurons in the hippocampal dentate gyrus, resulting in cognitive impairment. Vitamin B12 attenuates hippocampal damage and reduces the expression of some key inflammatory genes in PM, by acting as an epidrug that promotes DNA methylation, with increased production of S-adenosyl-methionine, the universal donor of methyl.
Eleven-day-old rats were infected with via intracisternal injection and then administered either vitamin B12 or a placebo. After 24 hours of infection, the animals were euthanized, and apoptosis in the hippocampal dentate gyrus, microglia activation, and the inflammatory infiltrate were quantified in one brain hemisphere. The other hemisphere was used for RNA-Seq and RT-qPCR analysis.
In this study, adjuvant therapy with B12 was found to modulate the hippocampal transcriptional signature induced by PM in infant rats, mitigating the effects of the disease in canonical pathways related to the recognition of pathogens by immune cells, signaling via NF-kB, production of pro-inflammatory cytokines, migration of peripheral leukocytes into the central nervous system, and production of reactive species. Phenotypic analysis revealed that B12 effectively inhibited microglia activation in the hippocampus and reduced the inflammatory infiltrate in the central nervous system of the infected animals. These pleiotropic transcriptional effects of B12 that lead to neuroprotection are partly regulated by alterations in histone methylation markings. No adverse effects of B12 were predicted or observed, reinforcing the well-established safety profile of this epidrug.
B12 effectively mitigates the impact of PM on pivotal neuroinflammatory pathways. This leads to reduced microglia activation and inflammatory infiltrate within the central nervous system, resulting in the attenuation of hippocampal damage. The anti-inflammatory and neuroprotective effects of B12 involve the modulation of histone markings in hippocampal neural cells.
肺炎链球菌性脑膜炎（PM）中细菌毒力因子与宿主固有免疫反应的相互作用可导致失控性神经炎症，已知这种炎症会诱导海马齿状回祖细胞和有丝分裂后神经元的凋亡死亡，从而导致认知障碍。维生素 B12 通过作为一种前药发挥作用，促进 DNA 甲基化，增加 S-腺苷甲硫氨酸（SAM）的产生，SAM 是甲基的通用供体，从而减轻 PM 中的海马损伤并降低一些关键炎症基因的表达，以此来减轻海马损伤并降低一些关键炎症基因的表达，从而减轻海马损伤并降低一些关键炎症基因的表达。
将 11 天大的大鼠通过脑室内注射感染 ，然后给予维生素 B12 或安慰剂。感染 24 小时后，处死动物，在一个大脑半球中定量分析海马齿状回的凋亡、小胶质细胞活化和炎症浸润。另一个大脑半球用于 RNA-Seq 和 RT-qPCR 分析。
在这项研究中，发现辅助用 B12 治疗可调节 PM 诱导的婴儿大鼠海马转录特征，减轻疾病对与免疫细胞识别病原体、NF-kB 信号转导、促炎细胞因子产生、外周白细胞向中枢神经系统迁移以及活性氧产生相关的经典途径的影响。表型分析表明，B12 可有效抑制感染动物海马中的小胶质细胞活化，并减少中枢神经系统中的炎症浸润。B12 的这些多效转录效应导致神经保护，部分受到组蛋白甲基化标记改变的调节。没有预测到或观察到 B12 的不良反应，这加强了这种前药良好的安全性。
B12 可有效减轻 PM 对关键神经炎症途径的影响。这导致小胶质细胞活化和中枢神经系统内炎症浸润减少，从而减轻海马损伤。B12 的抗炎和神经保护作用涉及海马神经细胞中组蛋白标记的调节。
