The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase C.
An excess of the free radical nitric oxide (NO) is viewed as a deleterious factor involved in various CNS disorders. Numerous studies have shown that the Ginkgo biloba extract EGb 761 is a NO scavenger with neuroprotective properties. However, the mechanisms underlying its neuroprotective ability remain to be fully established. Thus, we investigated the effect of different constituents of EGb 761, i.e., flavonoids and terpenoids, against toxicity induced by NO generators on cells of the hippocampus, a brain area particularly susceptible to neurodegenerative damage. Exposure of rat primary mixed hippocampal cell cultures to either sodium nitroprusside (SNP; 100 microM) or 3-morpholinosydnonimine resulted in both a decrease in cell survival and an increase in free radical accumulation. These SNP-induced events were blocked by either EGb 761 (10-100 microg/ml) or its flavonoid fraction CP 205 (25 microg/ml), as well as by inhibitors of protein kinase C (PKC; chelerythrine) and L-type calcium channels (nitrendipine). In contrast, the terpenoid constituents of EGb 761, known as bilobalide and ginkgolide B, as well as inhibitors of phospholipases A [3-[(4-octadecyl)benzoyl]acrylic acid (OBAA)] and C (U-73122), failed to display any significant effects. Moreover, EGb 761 (50 microm) CP 205 (25 microg/ml), and chelerythrine were also able to rescue hippocampal cells preexposed to SNP (up to 1 mM). Finally, EGb 761 (100 microg/ml) was shown to block the activation of PKC induced by SNP (100 microM). These data suggest that the protective and rescuing abilities of EGb 761 are not only attributable to the antioxidant properties of its flavonoid constituents but also via their ability to inhibit NO-stimulated PKC activity.
Bastianetto
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Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Verdun, Québec, Canada.
Zheng
W H
WH
Quirion
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D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D053119:Benzophenanthridines; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002478:Cells, Cultured; D004224:Diterpenes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D020441:Ginkgo biloba; D046934:Ginkgolides; D006624:Hippocampus / Q000166:cytology; D054833:Isoindoles; D007783:Lactones / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000633:toxicity; D009599:Nitroprusside / Q000633:toxicity; D016566:Organoselenium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010617:Phenanthridines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010936:Plant Extracts; D010946:Plants, Medicinal; D011493:Protein Kinase C / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014665:Vasodilator Agents / Q000633:toxicity; D000096983:Ginkgo Extract
D000470:Alkaloids; D000975:Antioxidants; D001393:Azoles; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004224:Diterpenes; D004791:Enzyme Inhibitors; D004963:Estrenes; D005419:Flavonoids; D016166:Free Radical Scavengers; D046934:Ginkgolides; D054833:Isoindoles; D007783:Lactones; D008981:Molsidomine; D018696:Neuroprotective Agents; D009568:Nitrendipine; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D016566:Organoselenium Compounds; D010617:Phenanthridines; D010726:Phosphodiesterase Inhibitors; D010936:Plant Extracts; D011493:Protein Kinase C; D011760:Pyrrolidinones; D014665:Vasodilator Agents; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C042986:ebselen; C002385:linsidomine; C045856:ginkgolide B; C016299:chelerythrine