title: JNK pathway may be involved in isoflurane-induced apoptosis in the hippocampi of neonatal rats.
abstract: Previous studies have demonstrated that isoflurane, a commonly used volatile anesthetic, can induce widespread apoptosis in the neonatal animal brains and result in persistent cognitive impairment. Isoflurane-induced cytosolic Ca(2+) overload and activation of mitochondrial pathway of apoptosis may be involved in this neurodegeneration. The c-Jun N-terminal kinase (JNK) signaling can regulate the expression of the Bcl-2 family members that modulates mitochondrial membrane integrity. Therefore, we hypothesize that JNK signaling pathway activation contributes to isoflurane-induced apoptosis in the brain. In this study, Sprague-Dawley neonatal rats at postnatal day 7 were exposed to 1.1% isoflurane or air for 4h. The JNK inhibitor SP600125 at 5 μg, 10 μg, 20 μg, 30 μg or the vehicle was intraventricularly administered before the exposure. Neuronal apoptosis in the hippocampi of neonatal rats was detected by TUNEL 6h after isoflurane or air exposure. The protein expression of phospho-JNK, phospho-c-Jun, and caspase-3 as well as the antiapoptotic protein Bcl-xL and Akt/glycogen synthase kinase (GSK)-3β pathway was detected by Western blotting. Isoflurane significantly increased apoptotic cells in the hippocampal CA1, CA3, and DG regions. The JNK inhibitor SP600125 dose-dependently inhibited isoflurane-induced neuronal apoptosis and increase of caspase-3 and phospho-JNK. SP600125 also attenuated isoflurane-induced down-regulation of Bcl-xL and maintained the activated Akt level to increase the phosphorylation of GSK-3β at Ser9. Our results indicate that JNK activation contributes to isoflurane-induced neuroapoptosis in the developing brain. Maintaining Bcl-xL and Akt activation may be involved in the neuroprotective effects of SP600125.
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. yujuan_04@yahoo.com.cn
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Chuiliang
authors.initials: C
authors.lastname: Liu
authors.forename: Minting
authors.initials: M
authors.lastname: Zeng
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Huaqiao
authors.initials: H
authors.lastname: Wang
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018685:Anesthetics, Inhalation; D000873:Anthracenes; C432165:pyrazolanthrone; D007530:Isoflurane; D048670:MAP Kinase Kinase 4