EPO-Dependent Activation of PI3K/Akt/FoxO3a Signalling Mediates Neuroprotection in In Vitro and In Vivo Models of Parkinson’s Disease

Abstract

Erythropoietin (EPO) may become a potential therapeutic candidate for the treatment of the neurodegenerative disorder -- Parkinson's disease (PD), since EPO has been found to prevent neuron apoptosis through the activation of cell survival signalling. However, the underlying mechanisms of how EPO exerts its neuroprotective effect are not fully elucidated. Here we investigated the mechanism by which EPO suppressed 6-hydroxydopamine (6-OHDA)-induced neuron death in in vitro and in vivo models of PD. EPO knockdown conferred 6-OHDA-induced cytotoxicity. This effect was reversed by EPO administration. Treatment of PC12 cells with EPO greatly diminished the toxicity induced by 6-OHDA in a dose- and time-dependent manner. EPO effectively reduced apoptosis of striatal neurons and induced a significant improvement on the neurological function score in the rat models of PD. Furthermore, EPO increased the expression of phosphorylated Akt and phosphorylated FoxO3a, and abrogated the 6-OHDA-induced dysregulation of Bcl-2, Bax and Caspase-3 in PC12 cells and in striatal neurons. Meanwhile, the EPO-dependent neuroprotection was notably reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that PI3K/Akt/FoxO3a signalling pathway may be a possible mechanism involved in the neuroprotective effect of EPO in PD.

Resveratrol Protects PC12 Cells from High Glucose-Induced Neurotoxicity Via PI3K/Akt/FoxO3a Pathway

“…Insulin-like growth factor-1 can induce the phosphorylation of FoxO3a by the PI3K/Akt pathway and promote the survival of hippocampal neurons and PC-12 cells (Zheng et al 2000). Erythropoietin activates the PI3K/Akt/FoxO3a signaling pathway and protects neurons from 6-hydroxydopamine-induced apoptosis (Jia et al 2014). In addition, Wang et al (2013) reported that venlafaxine protects PC12 cells against corticosteroneinduced cell death by modulating the activity of the PI3K/ Akt/FoxO3a pathway.…”

FoxO3a and disease progression

“…For example, FoxO3a causes the induction of apoptosis in prostate cancer cells via upregulating PUMA [98] . Low levels of FoxO3a may link to chemotherapy resistance in liver cancer and FoxO3a appears to present antitumor properties in hepatocellular carcinoma [99][100][101] . FoxO3a also plays a role in the neuroprotective effect of the erythropoietin (EPO) role in Parkinson's disease via Akt [102] .…”

Sohlh2 inhibits the apoptosis of mouse primordial follicle oocytes via C-kit/PI3K/Akt/Foxo3a signalling pathway

“…Recently, Foxo3a was found to be involved in oocyte apoptosis in the neonatal rat ovary and SCF initiates anti-apoptotic signalling through PI3K/Akt cascades in the oocytes of primordial follicles (Jin et al, 2004;Liu et al, 2009). Foxo3a belongs to the subfamily of forkhead transcription factors and is one of the downstream effectors of the PI3K/Akt signalling pathway (Jia et al, 2014;Tran et al, 2003;Yoon et al, 2014). In Foxo3a-/-mice in contrast to normal mice, more primordial follicles were activated but eventually ended in follicle atresia and oocyte apoptosis.…”