The neuroprotective effect of baicalein is generally attributed to inhibition of
12/15-lipoxygenase (12/15-LOX) and suppression of oxidative stress, but recent
studies showed that baicalein also activates hypoxia-inducible factor-α (HIF1α)
through inhibition of prolyl hydrolase 2 (PHD2) and activation of the
phosphatidylinositide-3 kinase (PI3K)/Akt signaling pathway. Yet, the
significance and regulation of prosurvival cytokines erythropoietin (Epo) and
vascular endothelial growth factor (VEGF), two transcriptional targets of HIF1α,
in baicalein-mediated neuroprotection in neurons and astrocytes remains unknown.
Here we investigated the causal relationship between the PI3K/Akt signaling
pathway and Epo/VEGF expression in baicalein-mediated neuroprotection in primary
rat cortical neurons and astrocytes. Our results show that baicalein induced Epo
and VEGF expression in a HIF1α- and PI3K/Akt-dependent manner in neurons.
Baicalein also protected neurons against excitotoxicity in a PI3K- and
Epo/VEGF-dependent manner without affecting neuronal excitability. In contrast,
at least a 10-fold higher concentration of baicalein was needed to induce
Epo/VEGF production and PI3K/Akt activity in astrocytes for protection of
neurons. Moreover, only baicalein-induced astrocytic VEGF, but not Epo
expression requires HIF1α, while PI3K/Akt signaling had little role in
baicalein-induced astrocytic Epo/VEGF expression. These results suggest distinct
mechanisms of baicalein-mediated Epo/VEGF production in neurons and astrocytes
for neuroprotection, and provide new insights into the mechanisms and potential
of baicalein in treating brain injury in vivo.