Berberine chloride causes a caspase-independent, apoptotic-like death in Leishmania donovani promastigotes.
Berberine chloride, a quarternary isoquinoline alkaloid, is a promising anti-leishmanial compound, IC(50) being 7.1 microM in L. donovani promastigotes. This leishmanicidal activity was initiated by its pro-oxidant effect, evidenced by enhanced generation of reactive oxygen intermediates that was accompanied by depletion of thiols; pre-incubation in N-acetyl cysteine, attenuated its cell viability, corroborating that generation of free radicals triggered its parasiticidal activity. Externalization of phosphatidylserine and elevation of intracellular calcium preceded depolarization of the mitochondrial membrane potential, which translated into an increase in the sub G(0)/G(1) population and was accompanied by DNA laddering, hallmarks of apoptosis. Berberine chloride failed to induce caspase activity and anti-leishmanial activity in the presence of a pan caspase inhibitor, Z-Val-Ala-DL-Asp (methoxy)-fluoromethylketone remained unchanged, which indicated that the apoptosis was caspase independent. Collectively, the data indicates that Berberine chloride triggers an apoptosis-like death following enhanced generation of reactive oxygen species, thus meriting further pharmacological investigations.
Saha
Piu
P
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya JC Bose Road, Kolkata, 700 020, India.
Sen
Rupashree
R
Hariharan
Chellaram
C
Kumar
Deepak
D
Das
Padma
P
Chatterjee
Mitali
M
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001599:Berberine / Q000494:pharmacology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D006801:Humans; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D000981:Antiprotozoal Agents; D061945:Caspase Inhibitors; D017382:Reactive Oxygen Species; D001599:Berberine; D020169:Caspases