Cell type-specific signaling mechanism of baicalein-induced endogenous Epo and VEGF production from neurons and astrocytes for neuroprotection.

<p>Baicalein treatment in neurons activates class I PI3K/Akt to induce HIF1α-mediated Epo/VEGF expression with a minimal effective concentration at 35 nM. Its direct inhibition of 12/15-LOX additionally contributes to the induction of neuronal VEGF, but not Epo. In astrocytes where PHD2 is in low abundance and 12/15-LOX is lacking, high concentration of baicalein (35 μM in minimum) is required to activate class I PI3K/Akt. However, baicalein-induced upregulation of astrocytic Epo/VEGF is sensitive to LY294002 (LY) but not the selective class I PI3K inhibitors, suggesting that other LY294002-inhibitable protein kinases (PKs) mediate the effect. Furthermore, baicalein-induced astrocytic Epo expression is HIF1α-independent and possibly by HIF2α that reportedly mediates astrocytic Epo gene transcription and can also be stabilized when PHD2 is inhibited. Since brain neurons and astrocytes may access nanomolar and micromolar concentration of baicalein respectively when the compound is applied peripherally, the increased production of Epo and VEGF from both cell types may thus be converged to provide neuroprotection against excitotoxic or other neurotoxic insults.