Eliglustat as a possible strategy to prevent the detrimental effects of Shiga toxin type 2: Preliminary results in vivo

GOMEZ FERNANDO; SACERDOTI F; TOYTOYNDJIAN E; IBARRA C; AMARAL MM

Buenos Aires

Congreso; Reunión de las Sociedades de Biociencias. Modalidad virtual.; 2020

SAIC. SAI.

Typical Hemolytic Uremic Syndrome (HUS) is a complication of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection and the most frequent cause of acute renal failure in children in Argentina. Stx2 binds to globotriaosylceramide (Gb3) receptor and causes direct damage on human renal microvascular endothelial cells (HGEC).Previously, we found that Eliglustat (EG), a Gb3 synthesis inhibitor, prevents the cytotoxic effects of Stx2 on HGEC. In this work, we evaluated the action of EG against the effects of Stx2 in vivo. MaleBALB/c mice at weaning (17-21 days) received 3 doses of EG (0.6 mg/g body weight (bwt) administered intraperitoneally (i.p.) every 24 h. After a rest period of 5 days, mice were i.p. injected with a lethal (1ng/g bwt) or sublethal (0.1 ng/g bwt) dose of Stx2 (EG+Stx2) or PBS (EG). Two additional groups of mice without EG pre-treatment were injected one with PBS (Ctrl) and another with Stx2 (Stx2).Survival, body weight (Δ weight= body weight after Stx2 or PBS injection-body weight at a day before injection) and food intake were registered daily. EG did not affect body weight gain (Δ weight: EG: 0.61 ± 0.07 g vs. Ctrl: 0.76 ± 0.09 g; n=3, ns). After Stx2 lethal dose treatment, EG+Stx2 mice showed a body weight decrease and a survival time (48-72 h) similar to Stx2 mice. On the contrary, after 3 days of Stx2 sublethal dose injection, while Stx2 mice exhibited piloerection and inactivity and body weight loss, EG+Stx2 mice did not show signs of illness and gained weight (Δ weight: EG+Stx2: 0.81 ± 0.09 vs. Stx2: -0.65 ± 0.05 g; n=3, p