4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway.
4-Methylcatechol (4MC), a stimulator of the synthesis of neurotrophin family members in various cells, was able to up-regulate the expression of heme oxygenase (HO)-1, a redox-sensitive inducible stress protein, in neural stem/progenitor cells (NS/PCs). RT-PCR analysis showed that 4MC induced HO-1 mRNA expression in a dose- and a time-dependent manner. The increase in HO-1 mRNA was followed by an increase in HO-1 protein content, which was confirmed by ELISA and Western blotting analysis. When NS/PCs were pretreated with 4MC before exposure to hydrogen peroxide (H(2)O(2)), most of the cells were rescued from the H(2)O(2)-induced death. 4MC enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) and Akt in a time-dependent manner. Pretreatment of cultures with a selective inhibitor of PI3 kinase (PI3K)/Akt, but not with one of MAPK/ERK, inhibited both the 4MCinduced HO-1 expression and neuroprotective effect, demonstrating that PI3K/Akt signaling pathway played a significant role in 4MC-induced HO-1 induction and neuroprotection. Taken together, our results suggest that 4MC activates the expression of HO-1 through the PI3K/Akt signaling pathway and that the HO-1 protein inhibits the death of NS/PCs induced by oxidative stress.
Furukawa
Yoshiko
Y
Gifu Pharmaceutical University, Japan. furukawa@cc.matsuyama-u.ac.jp
Urano
Tomomi
T
Minamimura
Misato
M
Nakajima
Mitsunari
M
Okuyama
Satoshi
S
Furukawa
Shoei
S
D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D013997:Time Factors
D002396:Catechols; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C018599:4-methylcatechol; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases