title: 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.
abstract: 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.
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China; Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China; Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America; Department of Clinic Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States of America; Department of Perio, Diagnostic Sciences & Biomedical Sciences, School of Dentistry, University of Southern California, Los Angeles, CA, 93003, United States of America; Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles, CA, 93003, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Zhong
authors.affiliation: Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Hoffman
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China; Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, United States of America.
authors.forename: Sheng-He
authors.initials: SH
authors.lastname: Huang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D008559:Memantine / Q000627:therapeutic use*; D020814:Meningitis, Escherichia coli / Q000188:drug therapy*; D051379:Mice; D008969:Molecular Sequence Data; D009538:Nicotine / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D008559:Memantine