Proanthocyanidins and related compounds: Antileishmanial activity and modulatory effects on nitric oxide and tumor necrosis factor-alpha-release in the murine macrophage-like cell line RAW 264.7

A series of 17 proanthocyanidins and structurally related compounds was tes ted for activity against Leishmania donovani amastigotes and promastigotes in vitro. Most of the polyphenols significantly inhibited the intracellular survival of L. donovani amastigotes (EC50 0.8-10.6 nM) when compared with the antileishmanial drug Pentostam((R)) (EC50 10.6 nM), but all were inacti ve against the extracellular form (EC50 7.8 to > 86 nM). Noteworthy is that all compounds exhibited only moderate or no cytotoxicity against the murin e host cells (EC50 7.8 to > 56nm; > 25 mug/ml). These polyphenols were furt her evaluated for immunomodulatory effects on macrophage functions, includi ng release of nitric oxide (NO), tumor necrosis factor-alpha (TNT) and inte rferon (IFN)-like properties using several functional assays. The results s howed that all compounds induced murine RAW 264.7 cells only moderately to release NO (7-26 muM) relative to the reference stimulus IFN-gamma /LPS (11 9 muM). The TNF-inducing potential of the polyphenols producing 50% lysis i n murine L929 cells ranged from absent to 138 U/ml at the host cell subtoxi c concentration of 50 mug/ml. The highest TNF-inducing activity was associa ted with those fla-van-3-ols with galloyl groups (98-127 U/ml). For proanth ocyanidins, it appeared that an increase in the flavanyl chain length did n ot enhance the induction of TNF-release (32-86 U/ml and below detection lim its for oligomers and polymers, respectively). With interferon-like activit ies, phylloflavan and a prodelphinidin polymer showed appreciable cytoprote ctive effects, as reflected by the inhibition of the cytopathic effect of e ncephalomyocarditis virus on L929 fibroblast cells (38 and 36 U/ml, respect ively). All remaining compounds displayed only negligible or moderate prote ctive effects at subtoxic concentrations up to 25 mug/ml (<5 to 12 U/ml). T hese results indicate that proanthocyanidins and related compounds have fav orable antileishmanial activity in vitro and might be considered as benefic ial immunological response modifiers provided there are no bioavailability problems.