Trypanosuppresive effects of ellagic acid and amelioration of the trypanosome-associated pathological features coupled with inhibitory effects on trypanosomal sialidase in vitro and in silico.

BACKGROUND: The search for novel antitrypanosomal agents had previously led to the isolation of ellagic acid as a bioactive antitrypanosomal compound using in vitro studies. However, it is not known whether this compound will elicit antitrypanosomal activity in in vivo condition which is usually the next step in the drug discovery process.

PURPOSE: Herein, we investigated the in vivo activity of ellagic acid against bloodstream form of Trypanosoma congolense and its ameliorative effects on trypanosome-induced anemia and organ damage as well as inhibitory effects on trypanosomal sialidase.

METHODS: Rats were infected with T. congolense and were treated with 100 and 200mg/kg body weight (BW) of ellagic acid for fourteen days. The levels of parasitemia, packed cell volume and biochemical parameters were measured. Subsequently, T. congolense sialidase was partially purified on DEAE cellulose column and the mode of inhibition of ellagic acid on the T. congolense sialidase determined. Molecular docking study was also conducted to determine the mode of interaction of the ellagic acid to the catalytic domain of T. rangeli sialidase.

RESULTS: At a dose of 100 and 200mg/kg (BW), ellagic acid demonstrated significant (P < 0.05) trypanosuppressive effect for most of the 24 days experimental period. Further, the ellagic acid significantly (P < 0.05) ameliorated the trypanosome-induced anemia, hepatic and renal damages as well as hepatomegaly, splenomegaly and renal hypertrophy. The trypanosome-associated free serum sialic acid upsurge alongside the accompanied membrane bound sialic acid reduction were also significantly (P < 0.05) prevented by the ellagic acid treatment. The T. congolense sialidase was purified to a fold of 6.6 with a yield of 83.8%. The enzyme had a KM and Vmax of 70.12mg/ml and 0.04µmol/min respectively, and was inhibited in a non-competitive pattern by ellagic acid with an inhibition binding constant of 1986.75μM. However, in molecular docking study, ellagic acid formed hydrogen bonding interaction with major residues R(39), R(318), and W(124) at the active site of T. rangeli sialidase with a predicted binding free energy of -25.584kcal/mol.

CONCLUSION: We concluded that ellagic acid possesses trypanosuppressive effects and could ameliorate the trypanosome-induced pathological alterations.