An interventional approach to block brain damage caused by Shiga toxin-producing Escherichia coli infection, by use of a combination of phosphodiesterase inhibitors.
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.
Okayama
Akiko
A
Microbial Section, Nara Prefectural Institute for Hygiene and Environment, Nara, Japan.
Mikasa
Keiichi
K
Matsui
Norio
N
Higashi
Nobutaka
N
Miyamoto
Mamiko
M
Kita
Eiji
E
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*
D015295:Antigens, Tumor-Associated, Carbohydrate; D016207:Cytokines; C472766:Gb3 antigen; D010726:Phosphodiesterase Inhibitors; D022641:Shiga Toxin 2; D020889:Rolipram; D010431:Pentoxifylline