Influence of lipophilicity and stereochemistry at the C-7 position on the cardioprotective and antioxidant effect of ginkgolides during rat heart ischemia and reperfusion

The extent to which the cardioprotective effect of ginkgolides is related to their lipophilicity rather than to their anti-platelet activating factor (PAF) effect was addressed in isolated rat hearts submitted to ischemia and reperfusion. A new derivative of ginkgolide C (1), the 7-alpha-O-(4-methylphenyl) ginkgolide C (4) was synthesized and compared to 7-O-(4-n-methylphenyl) ginkgolide C (2) that had the same absolute configuration at C-7 as 1 for its lipophilicity, anti-PAF activity, and cardioprotective and antioxidant effects. Using reversed-phase high-performance liquid chromatography HPLC, 4 and 2 were found to be significantly more lipophilic (i.e., log k(w) of 3.42 +/- 0.05 and 3.64 +/- 0.07, respectively) than 1 (1.15 +/- 0.03) and the strong PAF inhibitor ginkgolide B (GkB; 1.65 +/- 0.03). The anti-PAF activities (IC50 values in mu M) were 8.2, 17.1, and 2.2 for 4, 1, and GkB, respectively, while 2 was inactive. In preischemic and/or reperfused hearts perfused with ginkgolides at 0.7 mu M: (i) 2 and 4 were more efficient in improving postischemic hemodynamic and metabolic recovery than 1, (ii) a key-step in cardioprotection Occurred during ischemia where 2 and 4 limited myocardial ATP depletion and contracture development, (iii) a strong anti-lipoperoxidant effect was observed with 2 and 4, but not 1. In vivo administration of 2 to rats (4 mg/kg/day for 20 days) was more effective than that of I regarding ischemic heart protection, suggesting a positive role for lipophilicity. It was concluded that a high lipophilicity is not an absolute prerequisite for a strong anti-PAF effect for ginkgolides, whereas it appears essential for cardioprotection. (c) 2005 Wiley-Liss, In

On the antioxidant properties of erythropoietin and its association with the oxidative-nitrosative stress response to hypoxia in humans

International audienceAim: The aim of this study was to examine if erythropoietin (EPO) has the potential to act as a biological antioxidant and determine the underlying mechanisms.Methods: The rate at which its recombinant form (rHuEPO) reacts with hydroxyl (HO˙), 2,2-diphenyl-1-picrylhydrazyl (DPPH˙) and peroxyl (ROO˙) radicals was evaluated in-vitro. The relationship between the erythopoietic and oxidative–nitrosative stress response to poikilocapneic hypoxia was determined separately in-vivo by sampling arterial blood from eleven males in normoxia and following 12 h exposure to 13% oxygen. Electron paramagnetic resonance spectroscopy, ELISA and ozone-based chemiluminescence were employed for direct detection of ascorbate (A˙) and N-tert-butyl-alpha-phenylnitrone spin-trapped alkyl (PBN-OR) radicals, 3-nitrotyrosine (3-NT) and nitrite (NO2 ).Results: We found rHuEPO to be a potent scavenger of HO˙ (kr = 1.03–1.66 x 10e11 M-1.s-1) with the capacity to inhibit Fenton chemistry through catalytic iron chelation. Its ability to scavenge DPPH˙ and ROO˙ was also superior compared to other more conventional antioxidants. Hypoxia was associated with a rise in arterial EPO and freeradical-mediated reduction in nitric oxide, indicative of oxidative–nitrosative stress. The latter was confirmed by an increased systemic formation of A˙, PBN-OR, 3-NT and corresponding loss of NO2 (P < 0.05 vs. normoxia). The erythropoietic and oxidative–nitrosative stress responses were consistently related (r = 0.52 to 0.68, P < 0.05)