An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication

Amanita phalloides is one of the most toxic mushrooms worldwide, and it is involved in the majority of human fatal cases of mushroom poisoning. alpha-Amanitin, the most deleterious toxin of A. phalloides to humans, inhibits RNA polymerase II (RNAPII), causing hepatic and renal failure. Previously, we have shown that polymyxin B (polB) reverts alpha-amanitin inhibition of RNAPII, although it was not able to guarantee the full survival of alpha-amanitin-intoxicated mice or prevent alpha-amanitin pro-inflammatory effects. alpha-Amanitin is also a substrate of the organic-anion-transporting polypeptide 1B3 (OATP1B3) and Na(+)-taurocholate cotransporter polypeptide (NTCP) transporters. Therefore, in the present work, we used a combination of polB [(2.5 mg/kg intraperitoneal (i.p.)] with the anti-inflammatory and NTCP inhibitor drug, methylprednisolone (MP) (10 mg/kg i.p.), as an attempt to fully revert alpha-amanitin-induced toxicity (0.33 mg/kg i.p.) in CD-1 mice. Results showed that the administration of the polB+MP combination, 4 h after alpha-amanitin, led to the full survival of the intoxicated animals, with a significant attenuation of alpha-amanitin-induced renal and hepatic necrosis. Also, the combination polB+MP led to a decrease of aminotransferase plasma levels, of the renal myeloperoxidase activity and of renal inflammatory cell infiltrate promoted by alpha-amanitin, although not preventing any of the hepatic pro-inflammatory effect of the toxin. The obtained results indicate that this combination may represent an important and valuable therapeutic approach to be used against alpha-amanitin intoxication.