UNIGE document Scientific Article
previous document  unige:10535  next document
add to browser collection
Title

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

Authors
Billottet, L.
Culcasi, M.
Drieu, K.
Pietri, S.
Published in Drug Development Research. 2005, vol. 64, no. 3, p. 157-171
Abstract 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, Inc
Stable URL http://archive-ouverte.unige.ch/unige:10535
Full text
Article - document accessible for UNIGE members only Limited access to UNIGE
Structures
99 hits and 3 downloads since 2010-08-06
Update
Export document
Format :
Citation style :