An Interventional Approach to Block Brain Damage Caused by Shiga Toxin-Producing Escherichia coli Infection, by Use of a Combination of Phosphodiesterase Inhibitors

• Published in: The Journal of infectious diseases 2004-12, Vol.190 (12), p.2129-2136
• Main Authors: Okayama, Akiko, Mikasa, Keiichi, Matsui, Norio, Higashi, Nobutaka, Miyamoto, Mamiko, Kita, Eiji
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Tumor-Associated, Carbohydrate - metabolism; Bacteria; Biological and medical sciences; Brain damage; Brain Diseases - microbiology; Brain Diseases - pathology; Brain Diseases - prevention & control; Caco 2 cells; Cecum - metabolism; Cells, Cultured; Cytokines; Cytokines - metabolism; Dosage; Dose-Response Relationship, Drug; Drug Therapy, Combination; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Infections - drug therapy; Escherichia coli O157; Feces - chemistry; Female; Fundamental and applied biological sciences. Psychology; Humans; Infections; Infectious diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbiology; Nephrons; Neuroglia; Pentoxifylline - administration & dosage; Pentoxifylline - therapeutic use; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - therapeutic use; Protein-Energy Malnutrition - complications; Rolipram - administration & dosage; Rolipram - therapeutic use; Shiga Toxin 2 - metabolism; Shiga toxins; Vehicles
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/425982

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 μg/mL and afforded significant levels of protection when it was continued for 3 days, starting on day 2 (95% survival rate; ) or P 2 μg/ mL reduced Gb3 content of and Stx2 binding to Caco-2 cells, its ability to suppress production of TNF-α 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.