title: Cell type-specific dependency on the PI3K/Akt signaling pathway for the endogenous Epo and VEGF induction by baicalein in neurons versus astrocytes.
abstract: 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.
authors.affiliation: Division of Neurology, Department of Pediatrics, the Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.forename: Shang-Hsuan
authors.initials: SH
authors.lastname: Lin
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lin
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Hung
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Yen-Chu
authors.initials: YC
authors.lastname: Lin
authors.forename: Kuo-Sheng
authors.initials: KS
authors.lastname: Hung
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Lien
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D044950:Flavanones; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; C006680:baicalein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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