Neuroprotective effects of NV-31, a bilobalide-derived compound: evidence for an antioxidative mechanism.
In previous studies we have already shown that the extract of Ginkgo biloba, and some of its constituents, such as ginkgolide B and bilobalide, protected cultured neurons against apoptotic and excitotoxic damage and reduced the infarct volume after focal cerebral ischemia in mice and rats. In this work, we determined the neuroprotective and antioxidative effects of 4-hydroxy-4-tert-butyl-2,3,5,6-tetrahydrothiopyran-1-oxide (NV-31), a stable compound which was synthesized to mimic the pharmacological activity profile of bilobalide. In pure neuronal cultures from chick embryo telencephalon, damage was induced by serum deprivation (24 h) and exposure to staurosporine (200 nM, 24 h) which caused an increase in the percentage of apoptotic neurons from 14 (controls) to 30 and 55%, respectively. NV-31 (1-100 nM) protected dose-dependently chick neurons against both serum deprivation- and staurosporine-induced apoptosis. Similarly, NV-31 (100 nM) reduced staurosporine (300 nM, 24 h)-induced neuronal damage in mixed cultures of neurons and astrocytes from neonatal rat hippocampus. The cellular ROS content increased 6-fold 4 h after serum deprivation as well as 4 h after the exposure to staurosporine and this increase was reduced by 50% in the presence of 10 and 100 nM NV-31, respectively. In mice, a treatment with 10 and 20 mg/kg NV-31 60 min before and immediately after focal cerebral ischemia, respectively, significantly reduced the infarct area compared with vehicle-treated animals. In the present study, we show that NV-31 promotes neuronal survival and we suggest that its antioxidative property contributes to the mechanism of neuroprotection.
Ahlemeyer
B
B
Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der Philipps-Universität Marburg, Ketzerbach 63, D-35032 Marburg, Germany. ahlemeye@mailer.uni-marburg.de
Junker
V
V
Hühne
R
R
Krieglstein
J
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D020441:Ginkgo biloba / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D008517:Phytotherapy; D010936:Plant Extracts; D010946:Plants, Medicinal; D011714:Pyrans / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013687:Telencephalon / Q000187:drug effects / Q000378:metabolism; D000096983:Ginkgo Extract
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018696:Neuroprotective Agents; D010936:Plant Extracts; D011714:Pyrans; D017382:Reactive Oxygen Species; D019311:Staurosporine; C427345:4-hydroxy-4-tert-butyl-2,3,5,6-tetrahydrothiopyran-1-oxide; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract