Ginsenoside Rd Attenuates Mitochondrial Permeability Transition and Cytochrome c Release in Isolated Spinal Cord Mitochondria: Involvement of Kinase-Mediated Pathways

Abstract

Ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. However, the effects of Rd on spinal cord mitochondrial dysfunction and underlying mechanisms are still obscure. In this study, we sought to investigate the in vitro effects of Rd on mitochondrial integrity and redox balance in isolated spinal cord mitochondria. We verified that Ca2+ dissipated the membrane potential, provoked mitochondrial swelling and decreased NAD(P)H matrix content, which were all attenuated by Rd pretreatment in a dose-dependent manner. In contrast, Rd was not able to inhibit Ca2+ induced mitochondrial hydrogen peroxide generation. The results of Western blot showed that Rd significantly increased the expression of p-Akt and p-ERK, but had no effects on phosphorylation of PKC and p38. In addition, Rd treatment significantly attenuated Ca2+ induced cytochrome c release, which was partly reversed by antagonists of Akt and ERK, but not p-38 inhibitor. The effects of bisindolylmaleimide, a PKC inhibitor, on Rd-induced inhibition of cytochrome c release seem to be at the level of its own detrimental activity on mitochondrial function. Furthermore, we also found that pretreatment with Rd in vivo (10 and 50 mg/kg) protected spinal cord mitochondria against Ca2+ induced mitochondrial membrane potential dissipation and cytochrome c release. It is concluded that Rd regulate mitochondrial permeability transition pore formation and cytochrome c release through protein kinases dependent mechanism involving activation of intramitochondrial Akt and ERK pathways.

Ginsenoside-Rd Promotes Neurite Outgrowth of PC12 Cells through MAPK/ERK- and PI3K/AKT-Dependent Pathways

“…All these data suggested that neurite or axon outgrowth or regeneration required the involvement of ERK, AKT, or PKC signals. Since previous studies have demonstrated that Rd can exert its protective effects via activating ERK and AKT pathways [ 11 , 36 , 37 , 38 , 39 ], we examined whether ERK or AKT was responsible for Rd-induced neurite outgrowth in PC12 cells as well. As expected, our results showed that Rd could activate the ERK and AKT signaling pathways, and application of their respective antagonists PD98059 and LY294002 partially inhibited Rd-elicited neurite outgrowth ( Figure 4 and Figure 5 ).…”

Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs

“…On a similar note, GRg1 reduces the Aβ-associated generation of ROS and cell death (Wang and Du, 2009 ). Correspondingly, many publications show protective effect of ginseng constituents on brain mitochondrial activity under multiple toxic conditions, including ischemia (Ye et al, 2011 ), calcium treatment (Tian et al, 2009 ; Zhou et al, 2014 ), hydrogen peroxide treatment (Tian et al, 2009 ), and even incubation of cells with Aβ in vitro (Ma et al, 2014 ).…”

COX6B1 relieves hypoxia/reoxygenation injury of neonatal rat cardiomyocytes by regulating mitochondrial function

“…A large number of studies have shown that myocardial I/R could cause structural and functional abnormalities of mitochondria, which would lead to impairments of other organelles and cell homeostasis, and therefore further aggravate myocardial injury (Wang et al 2015b ; Maneechote et al 2017 ). Myocardial injury can lead to not only the opening of a large number of mitochondrial permeabilization transition pores (mPTPs), but also the disruption of the mitochondrial outer membrane, thereby resulting in the release of cytochrome c from the mitochondrial intermembrane space and leading to increased apoptosis (Zhou et al 2014 ; Wiczer et al 2014 ; Kumazawa et al 2014 ). Mitochondria-initiated apoptosis and necrosis are two major factors causing cell death during myocardial reperfusion (Dalla Via et al 2014 ).…”