Ginsenoside Re blocks Bay k-8644-induced neurotoxicity via attenuating mitochondrial dysfunction and PKCδ activation in the hippocampus of mice: Involvement of antioxidant potential.

Although the anticonvulsant effects of ginsenosides are recognized, little is known about their effects on the convulsive behaviors induced by the activation of L-type Ca2+ channels. Here, we investigated whether ginsenoside Re (GRe) modulates excitotoxicity induced by the L-type Ca2+ channel activator Bay k-8644. GRe significantly attenuated Bay k-8644-induced convulsive behaviors and hippocampal oxidative stress in mice. GRe-mediated antioxidant potential was more pronounced in the mitochondrial fraction than cytosolic fraction. As L-type Ca2+ channels are thought to be targets of protein kinase C (PKC), we investigated the role of PKC under excitotoxic conditions. GRe attenuated Bay k-8644-induced mitochondrial dysfunction, PKCδ activation, and neuronal loss. The PKCδ inhibition and neuroprotection mediated by GRe were comparable to those by the ROS inhibitor N-acetylcysteine, the mitochondrial protectant cyclosporin A, the microglial inhibitor minocycline, or the PKCδ inhibitor rottlerin. Consistently, the GRe-mediated PKCδ inhibition and neuroprotection were counteracted by the mitochondrial toxin 3-nitropropionic acid or the PKC activator bryostatin-1. GRe treatment did not have additional effects on PKCδ gene knockout-mediated neuroprotection, suggesting that PKCδ is a molecular target of GRe. Collectively, our results suggest that GRe-mediated anticonvulsive/neuroprotective effects require the attenuation of mitochondrial dysfunction and altered redox status and inactivation of PKCδ.

Protective effects of 5(S)-5-carboxystrictosidine on myocardial ischemia-reperfusion injury through activation of mitochondrial KATP channels.

5(S)-5-carboxystrictosidine (5-CS) is a compound found in Mappianthus iodoides Hand.-Mazz., root, a traditional Chinese medicine used for the treatment of coronary artery disease. In this study, we investigated whether 5-CS protects heart against I/R injury. Sprague-Dawley rats were treated with 5-CS intraperitoneally for 7 days before the experiment. Hearts were perfused for 20 min global ischemia and 180 min reperfusion. 5-CS significantly inhibited an increase in the post-ischemic left ventricular end-diastolic pressure (LVEDP) and improved the post-ischemic left ventricular developed pressure (LVDP), dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow as compared with sham group. Pretreatment with 5-hydroxydecanoic acid (5-HD), an inhibitor of mitochondrial KATP channel, for 10 min before ischemia attenuated the improvement of LVEDP, LVDP, dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow induced by 5-CS. 5-CS markedly decreased the infarct size and attenuated the increased lactate dehydrogenase (LDH) level in effluent during reperfusion. Pretreatment with 5-HD also blocked these protective effects of 5-CS. 5-CS increased Mn-SOD, catalase, and HO-1 levels decreased by I/R injury and pretreatment of 5-HD blocked the 5-CS effects. Increases in Bax, cleaved caspase-3 and cytochrome c levels, caspase-3 and caspase-9 activity, and decrease in Bcl-2 level by I/R injury were attenuated by 5-CS treatment and pretreatment of 5-HD blocked its effects. These results suggest that the protective effects of 5-CS against myocardial I/R injury may be partly related to activating antioxidant enzymes and suppressing apoptosis through opening mitochondrial KATP channels.