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 activa...

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Veröffentlicht in:Food and chemical toxicology 2023-08, Vol.178, p.113869-113869, Article 113869
Hauptverfasser: Tran, Ngoc Kim Cuong, Jeong, Ji Hoon, Sharma, Naveen, Nguyen, Yen Nhi Doan, Tran, Hoang-Yen Phi, Dang, Duy-Khanh, Park, Jung Hoon, Byun, Jae Kyung, Jin, Dezhong, Xiaoyan, Zeng, Ko, Sung Kwon, Nah, Seung-Yeol, Kim, Hyoung-Chun, Shin, Eun-Joo
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Bay k-8644 neurotoxicity involves mitochondrial dysfunction and mitochondrial oxidative stress.•Bay k-8644-induced mitochondrial dysfunction and neuroinflammation accompany PKCδ activation.•GRe provides neuroprotection against Bay k-8644 neurotoxicity in the mouse hippocampus.•GRe effects require the inhibition of mitochondrial dysfunction, oxidative stress, and PKCδ.
ISSN:0278-6915
1873-6351
DOI:10.1016/j.fct.2023.113869