POMEGRANATE ELLAGITANNINS ANTAGONIZE IN VITRO THE INFLAMMATORY RESPONSE INVOLVED IN MALARIA

Malaria is the infectious disease that causes more deaths worldwide, approximately 2 million deaths each year and about 250 million infected individuals. The eastern province of Orissa (India) is an area endemic for both Plasmodium falciparum (Pf) and Plasmodium vivax. Malaria patients receive a herbal preparation named OMARIA (Orissa Malaria Research Indigenous Attempt), made of sun-dried rind of the immature P. granatum fruits (Pg). The effect could be attributed to different constituents of a fraction enriched in tannins (Pg-FET), namely ellagic acid (EA), and punicalagin (Punic), which inhibited in vitro the growth of Pf asexual blood stages. Severe malaria is an inflammatory cytokine driven disease. There is remarkable evidence that tumour necrosis factor (TNF) and interleukin-1 are important contributors to the systemic disease caused by the infectious agent Pf. It was not clear which of the compounds present in Pg-FET or ellagitannins could antagonize the host inflammatory response.Pg-FET and its constituents inhibited the Hz induced-MMP-9 secretion (Table 1 A and B). Punicalagin at 1 and 10 μM inhibited the release of MMP-9 by 38% and 79%; the MMP-9 mRNA levels decreased accordingly (Table 1 C and D). EA at 1 and 10 μM inhibited the release of MMP-9 by 52 and 66%, respectively, and the MMP-9 expression by 56 and 65% (Table 1 E and F). EA inhibited Hz-induced promoter activity by 38% and 50% at 1 and 10 μM, respectively, while the inhibitory effect of punicalagin was only statistically significant at 10 μM (-65%). The in vitro beneficial effects of the fruit rind of Punica granatum L. for the treatment of malaria include, in addition to the anti-parasitic activity, the ability to limit the excessive inflammatory response in the host, thus possibly limiting the risk of progression to the more severe form of the disease, including the onset of cerebral malaria.