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Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats.
Toxicol Lett. 2018 Mar 15; 285:60-73.TL

Abstract

Recent studies have demonstrated that volatile anesthetic causes caspase-dependent neuroapoptosis and persistent cognitive deficits in young animals. Apoptosis-inducing factor (AIF) can trigger apoptosis by caspase-independent pathway. Whether isoflurane induces neuroapoptosis by activation of AIF and its possible mechanism are underdetermined. Rats at postnatal day 7 were exposed to 1.1% isoflurane for 4 h and the expression of AIF, cytochrome c, caspase-3, μ-calpain, m-calpain, Bcl-2 and Bax in the mitochondrial, cytosolic, and nuclear fraction, as well as the number of both AIF and TUNEL positive neurons in the cortices of rats were measured. Moreover, the effects of calpain inhibitor MDL-28170 or JNK inhibitor SP600125 on isoflurane-induced AIF release, caspase activation and cognitive deficits were assessed. We found isoflurane activated CytC-caspase-3 dependent apoptosis pathway mainly in the early phase (0-6 h after exposure). Moreover, isoflurane activated mitochondrial μ-calpain, induced AIF truncation during early phase and activated m-calpain, induced AIF release from the mitochondria to cytosol and translocation into the nucleus in the late phase (6-24 h after exposure). MDL-28170 attenuated the isoflurane-induced mitochondrial AIF truncation, release and nuclear translocation, but did not change the expression of cleaved-caspase-3 and mitochondrial Bax and Bcl-2 proteins. SP600125 attenuated isoflurane-induced neuroapoptosis by inhibiting both AIF and caspase-3 pathways and reduced cognitive impairment in neonatal rats. This is the first study to provide the evidence that isoflurane induced AIF-dependent neuroapoptosis by activation of mitochondrial μ-calpain and m-calpain in neonatal rats. JNK inhibition reversed isoflurane-induced neuroapoptosis and subsequent long-term neurocognitive impairment, acting via inhibiting activation of both AIF and caspase-3 pathways.

Authors+Show Affiliations

Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.Department of Anesthesiology, ChanCheng Center Hospital, Guangdong Medical College, Foshan, 528030, PR China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, 22908-0710, USA.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China. Electronic address: caofox5188@126.com.Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: liyuj@mail.sysu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29289695

Citation

Han, Xue, et al. "Calpain and JNK Pathways Participate in Isoflurane - Induced Nucleus Translocation of Apoptosis-inducing Factor in the Brain of Neonatal Rats." Toxicology Letters, vol. 285, 2018, pp. 60-73.
Han X, Liu C, Zhang K, et al. Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats. Toxicol Lett. 2018;285:60-73.
Han, X., Liu, C., Zhang, K., Guo, M., Shen, Z., Liu, Y., Zuo, Z., Cao, M., & Li, Y. (2018). Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats. Toxicology Letters, 285, 60-73. https://doi.org/10.1016/j.toxlet.2017.12.022
Han X, et al. Calpain and JNK Pathways Participate in Isoflurane - Induced Nucleus Translocation of Apoptosis-inducing Factor in the Brain of Neonatal Rats. Toxicol Lett. 2018 Mar 15;285:60-73. PubMed PMID: 29289695.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats. AU - Han,Xue, AU - Liu,Chuiliang, AU - Zhang,Kun, AU - Guo,Mingyan, AU - Shen,Zhiwen, AU - Liu,Yafang, AU - Zuo,Zhiyi, AU - Cao,Minghui, AU - Li,Yujuan, Y1 - 2017/12/28/ PY - 2017/10/08/received PY - 2017/12/11/revised PY - 2017/12/27/accepted PY - 2018/1/1/pubmed PY - 2018/2/20/medline PY - 2018/1/1/entrez KW - Apoptosis KW - Apoptosis-inducing factor (AIF) KW - C-Jun N-terminal kinase (JNK) KW - Calpain KW - Caspase-3 KW - Isoflurane SP - 60 EP - 73 JF - Toxicology letters JO - Toxicol. Lett. VL - 285 N2 - Recent studies have demonstrated that volatile anesthetic causes caspase-dependent neuroapoptosis and persistent cognitive deficits in young animals. Apoptosis-inducing factor (AIF) can trigger apoptosis by caspase-independent pathway. Whether isoflurane induces neuroapoptosis by activation of AIF and its possible mechanism are underdetermined. Rats at postnatal day 7 were exposed to 1.1% isoflurane for 4 h and the expression of AIF, cytochrome c, caspase-3, μ-calpain, m-calpain, Bcl-2 and Bax in the mitochondrial, cytosolic, and nuclear fraction, as well as the number of both AIF and TUNEL positive neurons in the cortices of rats were measured. Moreover, the effects of calpain inhibitor MDL-28170 or JNK inhibitor SP600125 on isoflurane-induced AIF release, caspase activation and cognitive deficits were assessed. We found isoflurane activated CytC-caspase-3 dependent apoptosis pathway mainly in the early phase (0-6 h after exposure). Moreover, isoflurane activated mitochondrial μ-calpain, induced AIF truncation during early phase and activated m-calpain, induced AIF release from the mitochondria to cytosol and translocation into the nucleus in the late phase (6-24 h after exposure). MDL-28170 attenuated the isoflurane-induced mitochondrial AIF truncation, release and nuclear translocation, but did not change the expression of cleaved-caspase-3 and mitochondrial Bax and Bcl-2 proteins. SP600125 attenuated isoflurane-induced neuroapoptosis by inhibiting both AIF and caspase-3 pathways and reduced cognitive impairment in neonatal rats. This is the first study to provide the evidence that isoflurane induced AIF-dependent neuroapoptosis by activation of mitochondrial μ-calpain and m-calpain in neonatal rats. JNK inhibition reversed isoflurane-induced neuroapoptosis and subsequent long-term neurocognitive impairment, acting via inhibiting activation of both AIF and caspase-3 pathways. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/29289695/Calpain_and_JNK_pathways_participate_in_isoflurane___induced_nucleus_translocation_of_apoptosis_inducing_factor_in_the_brain_of_neonatal_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(17)31532-1 DB - PRIME DP - Unbound Medicine ER -