title: Gypenosides protect primary cultures of rat cortical cells against oxidative neurotoxicity.
abstract: Gypenosides (GPs) were tested for their ability to protect primary cultures of immature cortical cells against oxidative glutamate toxicity. In immature neural cells, glutamate cytotoxicity is known to be mediated by the inhibition of cystine uptake, leading to depletion of intracellular glutathione (GSH). The depletion of GSH impairs cellular antioxidant defenses resulting in oxidative stress and cell death. We found that pretreatment with GPs (100-400 microg/ml) significantly protected cells from glutamate-induced cell death. It was therefore of interest to investigate whether GPs protect cortical cells against glutamate-induced oxidative injury through preventing GSH depletion. Results show that GPs significantly up-regulated mRNAs encoding gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione reductase (GR) and enhanced their activities for GSH synthesis as well as recycle. Furthermore, GPs lowered the consumption of GSH through decreased accumulation of intracellular peroxides, leading to an increase in the intracellular GSH content. GPs were also found to prevent lipid peroxidation and reduce the influx of Ca(2+) which routinely follows glutamate oxidative challenge. GPs treatment significantly blocked glutamate-induced decrease in levels of Bcl-2 and increase in Bax, leading to a decrease in glutamate-induced apoptosis. Thus, we conclude that GPs protect cortical cells by multiple antioxidative actions via enhancing intracellular GSH, suppressing glutamate-induced cytosolic Ca(2+) elevation and blocking glutamate-induced apoptosis. The novel role of GPs implies their remarkable preventative and therapeutic potential in treatment of neurological diseases involving glutamate and oxidative stress.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Shandong University, Jinan, PR China.
authors.forename: Linshan
authors.initials: L
authors.lastname: Shang
authors.forename: Jincheng
authors.initials: J
authors.lastname: Liu
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Feng
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.forename: Weipeng
authors.initials: W
authors.lastname: Cao
authors.forename: Hua
authors.initials: H
authors.lastname: Xin
mesh_terms: D000704:Analysis of Variance; D000814:Aniline Compounds; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D029774:Gynostemma; D015227:Lipid Peroxidation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014966:Xanthenes; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D018696:Neuroprotective Agents; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D014966:Xanthenes; D051028:bcl-2-Associated X Protein; C474918:gypenoside; C059715:Fluo-3; D018698:Glutamic Acid; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D002118:Calcium