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Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway.
Biomed Pharmacother. 2018 Dec; 108:1469-1476.BP

Abstract

As one of the most popular anesthetics, sevoflurane is widely used in pediatric anesthesia. Unfortunately, an increasing number of studies have demonstrated that sevoflurane has potential neurotoxic effects on the developing brain and cognition, even in adolescence. Connexin 43 (Cx43) has been documented to contribute to cognitive dysfunction. The present study hypothesized that Cx43 may participate in sevoflurane-induced neuroinjury and investigated the underlying mechanisms in young Sprague Dawley (SD) rats. Seven-day-old SD rats (P7) were exposed to 3% sevoflurane for 4 h. The levels of Cx43,mitogen-activated protein kinase (MAPK) signaling pathway components(including total and phosphorylated p38, extracellular signal-regulated kinase (ERK), and c-Jun n-terminal kinase (JNK) and activator protein 1(AP-1) transcription factors (including total and phosphorylated c-Fos, and c-Jun) were assessed by Western blot analysis. Neuronal apoptosis was detected using immunohistochemistry (IHC). The Morris water maze (MWM) was performed to evaluate cognitive function from P28 to P33. The results showed that anesthesia with 3% sevoflurane for 4 h increased Cx43 levels in the rat hippocampus from 6 h to 3 d, and compared with sevoflurane exposure in the control group rats, exposure in P7 SD rats also increased the ratios of phosphorylated JNK to JNK and, phosphorylated c-Jun to c-Jun in the hippocampus from 6 h to 3 d. All these effects could be alleviated by pretreatment with the JNK inhibitor SP600125 (10 mg/kg). Neuroapoptosis was similarly increased from 6 h to 1 d after inhaled sevoflurane exposure. Finally, the MWM indicated that sevoflurane could increase the escape latency and, decrease the number of platform crossings from P28 to P33. Overall, our findings suggested that sevoflurane increased Cx43 expression and induced to apoptosis by activating the JNK/c-Jun signaling pathway in the hippocampus of P7 rats. This finding may reveal a new strategy for preventing sevoflurane-induced neuronal dysfunction.

Authors+Show Affiliations

Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China; Department of Anesthesiology, Dalian Central Hospital, Dalian, China.Department of Anesthesiology, Dalian Central Hospital, Dalian, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China. Electronic address: 2895364359@qq.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30372849

Citation

Bi, Congjie, et al. "Sevoflurane Induces Neurotoxicity in the Developing Rat Hippocampus By Upregulating Connexin 43 Via the JNK/c-Jun/AP-1 Pathway." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 108, 2018, pp. 1469-1476.
Bi C, Cai Q, Shan Y, et al. Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. Biomed Pharmacother. 2018;108:1469-1476.
Bi, C., Cai, Q., Shan, Y., Yang, F., Sun, S., Wu, X., & Liu, H. (2018). Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 108, 1469-1476. https://doi.org/10.1016/j.biopha.2018.09.111
Bi C, et al. Sevoflurane Induces Neurotoxicity in the Developing Rat Hippocampus By Upregulating Connexin 43 Via the JNK/c-Jun/AP-1 Pathway. Biomed Pharmacother. 2018;108:1469-1476. PubMed PMID: 30372849.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. AU - Bi,Congjie, AU - Cai,Qiuping, AU - Shan,Yangyang, AU - Yang,Fan, AU - Sun,Shiwei, AU - Wu,Xiuying, AU - Liu,Hongtao, Y1 - 2018/10/08/ PY - 2018/05/30/received PY - 2018/09/11/revised PY - 2018/09/19/accepted PY - 2018/10/31/pubmed PY - 2019/3/12/medline PY - 2018/10/31/entrez KW - AP-1 KW - Connexin 43 KW - JNK KW - MAPK KW - Neurotoxicity KW - Sevoflurane SP - 1469 EP - 1476 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 108 N2 - As one of the most popular anesthetics, sevoflurane is widely used in pediatric anesthesia. Unfortunately, an increasing number of studies have demonstrated that sevoflurane has potential neurotoxic effects on the developing brain and cognition, even in adolescence. Connexin 43 (Cx43) has been documented to contribute to cognitive dysfunction. The present study hypothesized that Cx43 may participate in sevoflurane-induced neuroinjury and investigated the underlying mechanisms in young Sprague Dawley (SD) rats. Seven-day-old SD rats (P7) were exposed to 3% sevoflurane for 4 h. The levels of Cx43,mitogen-activated protein kinase (MAPK) signaling pathway components(including total and phosphorylated p38, extracellular signal-regulated kinase (ERK), and c-Jun n-terminal kinase (JNK) and activator protein 1(AP-1) transcription factors (including total and phosphorylated c-Fos, and c-Jun) were assessed by Western blot analysis. Neuronal apoptosis was detected using immunohistochemistry (IHC). The Morris water maze (MWM) was performed to evaluate cognitive function from P28 to P33. The results showed that anesthesia with 3% sevoflurane for 4 h increased Cx43 levels in the rat hippocampus from 6 h to 3 d, and compared with sevoflurane exposure in the control group rats, exposure in P7 SD rats also increased the ratios of phosphorylated JNK to JNK and, phosphorylated c-Jun to c-Jun in the hippocampus from 6 h to 3 d. All these effects could be alleviated by pretreatment with the JNK inhibitor SP600125 (10 mg/kg). Neuroapoptosis was similarly increased from 6 h to 1 d after inhaled sevoflurane exposure. Finally, the MWM indicated that sevoflurane could increase the escape latency and, decrease the number of platform crossings from P28 to P33. Overall, our findings suggested that sevoflurane increased Cx43 expression and induced to apoptosis by activating the JNK/c-Jun signaling pathway in the hippocampus of P7 rats. This finding may reveal a new strategy for preventing sevoflurane-induced neuronal dysfunction. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/30372849/Sevoflurane_induces_neurotoxicity_in_the_developing_rat_hippocampus_by_upregulating_connexin_43_via_the_JNK/c_Jun/AP_1_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(18)33537-6 DB - PRIME DP - Unbound Medicine ER -