Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli-Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

• Published in: PloS one 2015-05, Vol.10 (5), p.e0121911-e0121911
• Main Authors: Yu, Jing-Yi, Zhang, Bao, Peng, Liang, Wu, Chun-Hua, Cao, Hong, Zhong, John F, Hoffman, Jill, Huang, Sheng-He
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alzheimer's disease; Ampicillin; Analysis; Animal models; Animals; Animals, Newborn; Antibacterial activity; Antibacterial agents; Antibiotics; Antimicrobial agents; Bacteremia; Bacteria; Bacterial infections; Biomarkers; Birth weight; Blood-Brain Barrier; Brain research; Chemical compounds; Data processing; Drugs; E coli; Endothelium; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - growth & development; Escherichia coli - pathogenicity; Gene expression; Gene sequencing; Genetic research; Health aspects; Hospitals; Infants; Infections; Infectious diseases; Inflammation; Interleukin 1; Laboratories; Medical treatment; Medicine; Memantine; Memantine - therapeutic use; Meningitis; Meningitis, Escherichia coli - drug therapy; Mice; Microbiology; Molecular Sequence Data; Morbidity; Neonates; Nervous system agents; Newborn babies; NF-κB protein; Nicotine - pharmacology; Pediatrics; Pharmacology; Public health; Ribonucleic acid; RNA; Sepsis; Sequence Analysis, RNA; Stromelysin 2; Transcriptome; Tropical diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121911

Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer's disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.