Biomaterial Database

Uncovering the neuroprotective effect of vitamin B12 in pneumococcal meningitis: insights into its pleiotropic mode of action at the transcriptional level. 2023

Larissa Marcely Gomes Cassiano, and Marina da Silva Oliveira, and Karina Barbosa de Queiroz, and Alice Muglia Thomaz da Silva Amancio, and Anna Christina de Matos Salim, and Gabriel da Rocha Fernandes, and Cláudia Martins Carneiro, and Roney Santos Coimbra

Neurogenômica, Imunopatologia, Instituto René Rachou (IRR), Fiocruz, Belo Horizonte, MG, Brazil.

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 S. pneumoniae 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.

UI	MeSH Term	Description	Entries
D008586	Meningitis, Pneumococcal	An acute purulent infection of the meninges and subarachnoid space caused by Streptococcus pneumoniae, most prevalent in children and adults over the age of 60. This illness may be associated with OTITIS MEDIA; MASTOIDITIS; SINUSITIS; RESPIRATORY TRACT INFECTIONS; sickle cell disease (ANEMIA, SICKLE CELL); skull fractures; and other disorders. Clinical manifestations include FEVER; HEADACHE; neck stiffness; and somnolence followed by SEIZURES; focal neurologic deficits (notably DEAFNESS); and COMA. (From Miller et al., Merritt's Textbook of Neurology, 9th ed, p111)	Meningitis, Streptococcus pneumoniae,Experimental Pneumococcal Meningitis,Meningitis, Pneumococcal, Experimental,Meningitis, Pneumococcal, Penicillin-Resistant,Meningitis, Pneumococcal, Recurrent,Experimental Pneumococcal Meningitides,Meningitides, Streptococcus pneumoniae,Meningitis, Experimental Pneumococcal,Pneumococcal Meningitides,Pneumococcal Meningitides, Experimental,Pneumococcal Meningitis,Pneumococcal Meningitis, Experimental,Streptococcus pneumoniae Meningitides,Streptococcus pneumoniae Meningitis
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D006657	Histones	Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.	Histone,Histone H1,Histone H1(s),Histone H2a,Histone H2b,Histone H3,Histone H3.3,Histone H4,Histone H5,Histone H7
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013296	Streptococcus pneumoniae	A gram-positive organism found in the upper respiratory tract, inflammatory exudates, and various body fluids of normal and/or diseased humans and, rarely, domestic animals.	Diplococcus pneumoniae,Pneumococcus
D014805	Vitamin B 12	A cobalt-containing coordination compound produced by intestinal micro-organisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. INTRINSIC FACTOR is important for the assimilation of vitamin B 12.	Cobalamin,Cyanocobalamin,Cobalamins,Eritron,Vitamin B12,B 12, Vitamin,B12, Vitamin
D051381	Rats	The common name for the genus Rattus.	Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D018696	Neuroprotective Agents	Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.	Neuroprotectant,Neuroprotective Agent,Neuroprotective Drug,Neuroprotectants,Neuroprotective Drugs,Neuroprotective Effect,Neuroprotective Effects,Agent, Neuroprotective,Agents, Neuroprotective,Drug, Neuroprotective,Drugs, Neuroprotective,Effect, Neuroprotective,Effects, Neuroprotective