title: An interventional approach to block brain damage caused by Shiga toxin-producing Escherichia coli infection, by use of a combination of phosphodiesterase inhibitors.
abstract: We tested the combination of phosphodiesterase (PDE) 3 and PDE4 inhibitors as an interventional approach to prevent the development of brain damage after Shiga toxin (Stx)-producing Escherichia coli (STEC) infection, using mice with protein calorie malnutrition. The combination consisted of pentoxifylline and rolipram; the dose of each inhibitor was 7.5 mg/kg. Treatment with this combination, which was administered intraperitoneally twice daily at 12-h intervals, increased serum concentrations of each inhibitor to >2 microg/mL and afforded significant levels of protection when it was continued for 3 days, starting on day 2 (95% survival rate; P<.001) or day 3 (63% survival rate; P<.01) of infection. The treatment reduced plasma levels of Stx2; consequently, immunoreactions of Stx2 were not found in the brain, and survivors did not show neurologic symptoms. Protection was associated with decreased levels of tumor necrosis factor (TNF)- alpha and increased production of interleukin-10 in serum, the brain, and the cecum. Although the combination at doses >2 microg/mL reduced Gb3 content of and Stx2 binding to Caco-2 cells, its ability to suppress production of TNF- alpha seemed to be more important for the decrease in cell-bound Stx2 in intestinal epithelial cells. Therefore, the combination of PDE3 and PDE4 inhibitors might be used as an interventional approach to prevent brain damage caused by STEC infection.
authors.affiliation: Microbial Section, Nara Prefectural Institute for Hygiene and Environment, Nara, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Okayama
authors.forename: Keiichi
authors.initials: K
authors.lastname: Mikasa
authors.forename: Norio
authors.initials: N
authors.lastname: Matsui
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Higashi
authors.forename: Mamiko
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Kita
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D001927:Brain Diseases / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D002432:Cecum / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011502:Protein-Energy Malnutrition / Q000150:complications; D020889:Rolipram / Q000008:administration & dosage / Q000627:therapeutic use*; D022641:Shiga Toxin 2 / Q000378:metabolism*
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D016207:Cytokines; C472766:Gb3 antigen; D010726:Phosphodiesterase Inhibitors; D022641:Shiga Toxin 2; D020889:Rolipram; D010431:Pentoxifylline