title: Involvement of caspase-3/PTEN signaling pathway in isoflurane-induced decrease of self-renewal capacity of hippocampal neural precursor cells.
abstract: Evidence has shown that children exposed to isoflurane anesthesia in early childhood display long-term cognitive abnormalities, and decreased self-renewal capacity of hippocampal neural precursor cells (NPCs), which are associated with cognition impairment. Caspase-3 has long been considered as a mediator in isoflurane-induced neuroapoptosis. However, accumulating data indicate that caspase-3 also plays a non-apoptotic negative regulatory role in NPCs self-renewal. In this study we used in vitro NPC cultures to test whether caspase-3 and its downstream signaling effectors were involved in isoflurane-induced impairment of the self-renewal capacity of hippocampal NPCs. We showed that isoflurane exposure induced a decrease in the self-renewal capacity of hippocampal NPCs by decreasing proliferation and increasing neuronal differentiation. Furthermore, we found that isoflurane exposure significantly increased the levels of active caspase-3 and decreased the levels of phospho-PTEN under both proliferation and differentiation conditions. Inhibition of either caspase-3 with Z-DEVD-fmk or PTEN with BPV (phen) in NPCs, attenuated the isoflurane-induced decrease of their proliferation and increase of neuronal differentiation. Application of Z-DEVD-fmk also attenuated isoflurane-induced decrease in phospho-PTEN expression. Taken together, our in vitro results reveal a previously uncharacterized involvement of caspase-3/PTEN signaling in the isoflurane-induced impairment of NPCs self-renewal, and contribute to the identification of novel targets for maintaining NPCs self-renewal in isoflurane-induced cognitive dysfunction.
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: alluo@tjh.tjmu.edu.cn.
authors.forename: Ailin
authors.initials: A
authors.lastname: Luo
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D007530:Isoflurane / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000777:Anesthetics; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D009942:Organometallic Compounds; D010618:Phenanthrolines; D009418:S100 Proteins; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D007530:Isoflurane; D007770:L-Lactate Dehydrogenase; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D053148:Caspase 3
keywords: Caspase-3; Isoflurane; Neural precursor cell; PTEN