Estrogen-induced Bcl-2 expression after spinal cord injury is mediated through phosphoinositide-3-kinase/Akt-dependent CREB activation.

Our previous study showed that, after spinal cord injury (SCI) in rats, estrogen provides neuroprotection through expression of Bcl-2. However, molecular targets that mediate estrogen-induced expression of Bcl-2 are not fully understood. Here, we investigated whether, after SCI, the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways are involved in estrogen-induced expression of Bcl-2. Both Akt and ERK were activated and peaked at 8 h after SCI. Treatment with estrogen significantly increased the level of phosphorylated Akt (pAkt) and ERK (pERK) after injury. Cyclic-AMP response element binding protein (CREB) transcription factor was also activated and peaked at 8 h after SCI. Treatment with estrogen significantly increased the level of phosphorylated CREB (pCREB) after injury. Administration of LY294002, an inhibitor of PI3K/Akt, decreased the level of pCREB after SCI, whereas PD98059, an inhibitor of ERK, showed no significant effect. Also, treatment with LY294002 significantly inhibited expression of Bcl-2, but PD98059 showed no significant effect. Furthermore, treatment with estrogen inhibited apoptotic cell death, whereas treatment with LY294002 or PD98059 increased apoptotic cell death after SCI. Together, these data indicate that estrogen's neuroprotection is mediated in part by induction of Bcl-2 through PI3K/Akt-dependent CREB activation.