Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways

Abstract

SummaryPhencyclidine is an N-methyl D-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3β activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3β at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3β inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3β and activation of CREB. KeywordsPCP (phencyclidine); NMDAR (N-methyl-D-aspartate receptor); BDNF (brain-derived neurotrophic factor); PI-3K (phosphoinositide-3 kinase); ERK (extracellular signal-regulated kinase); GSK-3β (Glycogen Synthase Kinase 3 β);

Targeted Brain Derived Neurotropic Factors (BDNF) Delivery across the Blood-Brain Barrier for Neuro-Protection Using Magnetic Nano Carriers: An In-Vitro Study

“…Our aim was to evaluate and compare if the efficiency of bound BDNF is similar to free BDNF. Since BDNF has been shown to prevent apoptosis in different cells including brain cells [31], we wanted to check the efficiency of nanofurmulation by evaluating its ability to suppress apoptosis induced by morphinein PBMC. As expected, morphine (10 −7 M) induced apoptosis (55%) in PBMC compared to untreated cells (p = 0.006) as shown in figure 3A.…”

Overexpression of Human Arginine Decarboxylase Rescues Human Mesenchymal Stem Cells against H2O2Toxicity through Cell Survival Protein Activation

“…Once activated, it phosphorylates CREB (33), which in turn, switches on the expression of BDNF (34). Conversely, BDNF per se phosphorylates AKT and CREB to promote cell survival against the insults (35). In support, all of AKT, CREB, and BDNF have shown to suppress the activation of caspase 3 and the occurrence of apoptotic death in various pathologic conditions (36-38).…”

Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

“…Our data indicate that multiple molecular pathways are involved, including the mTORC1, PI 3-kinase and MAP-kinase pathways. These are also downstream of brain-derived neurotrophic factor (Chen et al, 2009; Xia et al, 2010), which has been shown to induce cholesterol synthesis and synapse development in primary cultured neurons (Suzuki et al, 2007). Insulin action on GSK3β and other pathways has also been shown to play a role in controlling Tau phosphorylation in the CNS (Lucas et al, 2001; Schubert et al, 2004) and neural progenitor homeostasis (Kim et al, 2009).…”