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 μg/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)-α and increased production of interleukin-10 in serum, the brain, and the cecum. Although the combination at doses >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.