Bilobalide prevents apoptosis through activation of the PI3K/Akt pathway in SH-SY5Y cells

Abstract

Bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, has been proposed to exert protective and trophic effects on neurons. However, mechanisms underlying the protective effects of bilobalide remain unclear. Using human SH-SY5Y neuroblastoma cells and primary hippocampal neurons, this study investigated the neuroprotective effects of bilobalide. We mimicked aging-associated neuronal impairments by applying external factors (beta amyloid protein (Abeta) 1-42, H(2)O(2) and serum deprivation) consequently inducing cell apoptosis. As markers for apoptosis, cell viability, DNA fragmentation, mitochondrial membrane potential and levels of cleaved caspase 3 were measured. We found that, bilobalide prevented Abeta 1-42-, H(2)O(2)- and serum deprivation-induced apoptosis. To better understand the neuroprotective effects of bilobalide, we also tested the ability of bilobalide to modulate pro-survival signaling pathways such as protein kinase C (PKC), extracellular-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. It was found that, bilobalide dose-dependently increased PI3K activity and levels of phosphorylated Akt (p-Akt Ser473 and Thr308), which could be maintained up to at least 2 h after bilobalide withdrawal in cells treated with or without Abeta 1-42, H(2)O(2) or serum-free medium. In addition, application of PI3K/Akt inhibitor LY294002 could abrogate both the protective effects of bilobalide against Abeta 1-42-, H(2)O(2)- and serum deprivation-induced apoptotic cell damage and bilobalide-induced increase in PI3K activity and levels of p-Akt (Ser473 and Thr308). In contrast, application of PKC inhibitor staurosporine (STS) did not affect the protective effects of bilobalide. Moreover, no change in levels of phosphorylated ERK1/2 (p-ERK1/2) was observed in bilobalide-treated cells. These results further suggested that the PI3K/Akt pathway might be involved in the protective effects of bilobalide. Since modern technology allows production of purified bilobalide with high bioavailability, bilobalide may be useful in developing therapy for diseases involving age-associated neurodegeneration.

Alleviation of spinal cord injury by Ginkgolide B via the inhibition of STAT1 expression

“…The secondary inflammation reaction in the spinal cord is even more severe than in brain tissue. Some studies have tried to manipulate the composition of inflammatory cells in mouse models of SCI but did not obtain satisfactory results (Shi et al, 2010;Lukáš et al, 2011), suggesting the necessity for the development of alternative treatments for secondary SCI. The JAK/STAT signaling pathway is activated immediately after SCI and is accompanied with morphological changes and cell apoptosis (Cayli et al, 2004).…”

Dietary anthocyanins protect endothelial cells against peroxynitrite-induced mitochondrial apoptosis pathway and Bax nuclear translocation: an in vitro approach

“…**P \ 0.01 [(Cy3glc ? ONOO -) versus ONOO -at the same incubation time] implications of both PI3 K and Akt in prevention of apoptosis [32,49,50] and recently, the inactivation of the PI3 K/Akt pathway has been reported as an important feature in peroxynitrite-induced PC12 cell apoptosis [32], not related with a direct effect on the enzyme system. Actually, it has been recognized that PI3 K/Akt activity is essential for retaining Bax in the cytoplasma, preventing its translocation into mitochondria [32,49].…”

The Phosphatidyl Inositol 3 Kinase-Glycogen Synthase Kinase 3β Pathway Mediates Bilobalide-Induced Reduction in Amyloid β-Peptide

“…An increasing number of studies, based on in vitro and in vivo models, have demonstrated its neuroprotective effects [4][5][6][7][8]. The neuroprotective mechanisms of BB are, however, not clearly known.…”

“…The neuroprotective mechanisms of BB are, however, not clearly known. Recent evidence has suggested that some members of intracellular signaling cascades may be involved in the neuroprotective effects of BB [8]. For example, BB protected against neuronal apoptosis by inhibiting the up-regulation of c-myc, p53, Bax as well as the activated caspase 3 [6].…”