15d-Prostaglandin J2 induced reactive oxygen species-mediated apoptosis during experimental visceral leishmaniasis.

Abstract

UNLABELLED:

15-Deoxy-delta (12,14)-prostaglandin J2 (15d-PgJ2) is a potent bioactive lipid mediator, known to possess several roles in cell regulation and differentiation along with antimicrobial efficacy against different bacterial and viral infections. In the present study, we investigated the therapeutic efficacy and mechanism of action of 15d-PgJ2 in vitro in Leishmania donovani promastigotes and infected J774 macrophages, and in vivo in Balb/c mice/golden hamster model of experimental visceral leishmaniasis. 15d-PgJ2 effectively killed L. donovani promastigotes and amastigotes in vitro with IC50 of 104.6 and 80.09 nM, respectively. At 2 mg/kg (mice) and 4 mg/kg (hamster) doses, 15d-PgJ2 decreased >90 % spleen and liver parasite burden. It significantly reduced interleukin (IL)-10 and transforming growth factor (TGF)-β synthesis in infected macrophages and splenocytes. 15d-PgJ2 induced reactive oxygen species (ROS)-dependent apoptosis of promastigotes by triggering phosphatidyl serine externalization, mitochondrial membrane damage and inducing caspase-like activity. In vitro drug interaction studies revealed an indifference to the synergistic association of 15d-PgJ2 with Miltefosine and Amphotericin-B (Amp-B). Moreover, when combined with sub-curative doses of Miltefosine and Amphotericin-B, 15d-PgJ2 resulted in >95 % parasite removal. Our results suggested that 15d-PgJ2 induces mitochondria-dependent apoptosis of L. donovani and is a good therapeutic candidate for adjunct therapy against experimental visceral leishmaniasis.

KEY MESSAGE:

15d-PgJ2 effectively eliminated both promastigotes and amastigotes form of L. donovani. 15d-PgJ2 decreased parasite burden from infected mice and hamsters with reduced Th2 cytokines. 15d-PgJ2 induced ROS-mediated mitochondrial apoptosis of L. donovani promastigotes. 15d-PgJ2 is a good therapeutic candidate for adjunct therapy with Miltefosine and Amp-B.

• Authors: Preeti Vishwakarma, Naveen Parmar, Pawan Kumar Yadav, Pragya Chandrakar, Susanta Kar
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 94 Issue 6 Pg. 695-710 (06 2016) ISSN: 1432-1440 [Electronic] Germany
• PMID: 26830627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxyprostaglandin J2
• Antiprotozoal Agents
• IL10 protein, mouse
• Reactive Oxygen Species
• Transforming Growth Factor beta
• Phosphorylcholine
• Interleukin-10
• miltefosine
• Amphotericin B
• Prostaglandin D2

Topics

• Amphotericin B (pharmacology)
• Animals
• Antiprotozoal Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cricetulus
• Disease Models, Animal
• Drug Administration Schedule
• Female
• Interleukin-10 (antagonists & inhibitors, biosynthesis, immunology)
• Leishmania donovani (drug effects, growth & development, metabolism)
• Leishmaniasis, Visceral (drug therapy, immunology, parasitology)
• Life Cycle Stages (drug effects)
• Liver (drug effects, immunology, parasitology)
• Macrophages (drug effects, immunology, parasitology)
• Male
• Mice
• Mice, Inbred BALB C
• Mitochondria (drug effects)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Reactive Oxygen Species (agonists, immunology)
• Spleen (drug effects, immunology, parasitology)
• Transforming Growth Factor beta (antagonists & inhibitors, biosynthesis, immunology)
• Treatment Outcome