PMID- 31999428 OWN - NLM STAT- MEDLINE DCOM- 20210303 LR - 20210303 IS - 1948-7193 (Electronic) IS - 1948-7193 (Linking) VI - 11 IP - 4 DP - 2020 Feb 19 TI - Dexmedetomidine Alleviates Neurogenesis Damage Following Neonatal Midazolam Exposure in Rats through JNK and P38 MAPK Pathways. PG - 579-591 LID - 10.1021/acschemneuro.9b00611 [doi] AB - Midazolam, a widely used anesthetic, inhibits proliferation of neural stem cells (NSCs) and induces neuroapoptosis in neonates. Dexmedetomidine, an effective auxiliary medicine in clinical anesthesia, protects the developing brain against volatile anesthetic-induced neuroapoptosis. Whether dexmedetomidine protects against neurogenesis damage induced by midazolam remains unknown. This study aims to clarify the protective effect of dexmedetomidine on midazolam-induced neurogenesis damage and explore its potential mechanism. Postnatal 7-day-old Sprague-Dawley (SD) rats and cultured NSCs were treated with either normal saline, midazolam, or dexmedetomidine combined with midazolam. The rats were sacrificed at 1, 3, and 7 days after treatment. Cell proliferation was assessed by 5-bromodeoxyurdine (BrdU) incorporation. Cell viability was determined using MTT assay. Cell differentiation and apoptosis were detected by immunofluorescent staining and terminal dUTP nick-end labeling (TUNEL), respectively. The protein levels of p-JNK, p-P38, and cleaved caspase-3 were quantified using Western blotting. Midazolam decreased cell proliferation and increased cell apoptosis in the subventricular zone (SVZ), the subgranular zone (SGZ) of the hippocampus, and cultured NSCs. Moreover, midazolam decreased cell viability and increased the expression of p-JNK and p-P38 in cultured NSCs. Co-treatment with dexmedetomidine attenuated midazolam-induced changes in cell proliferation, viability, apoptosis, and protein expression of p-JNK and p-P38 in cultured NSCs. Midazolam and dexmedetomidine did not affect the differentiation of the cultured NSCs. These results indicate that dexmedetomidine alleviated midazolam-induced neurogenesis damage via JNK and P38 MAPK pathways. FAU - Lei, Shan AU - Lei S AUID- ORCID: 0000-0002-2505-3059 AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Lu, Pan AU - Lu P AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Lu, Yang AU - Lu Y AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Zheng, Juan AU - Zheng J AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Li, Weisong AU - Li W AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Wang, Ning AU - Wang N AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Zhang, Hong AU - Zhang H AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Li, Rong AU - Li R AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Wang, Kui AU - Wang K AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Wen, Jieqiong AU - Wen J AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Wei, Haidong AU - Wei H AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Zhang, Yuanyuan AU - Zhang Y AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Qiu, Zhengguo AU - Qiu Z AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Xu, Jing AU - Xu J AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. FAU - Lv, Haixia AU - Lv H AD - Institute of Neurobiology , National Key Academic Subject of Physiology of Xi'an Jiaotong University , Xi'an 710016 , China. FAU - Chen, Xinlin AU - Chen X AD - Institute of Neurobiology , National Key Academic Subject of Physiology of Xi'an Jiaotong University , Xi'an 710016 , China. FAU - Liu, Yong AU - Liu Y AD - Institute of Neurobiology , National Key Academic Subject of Physiology of Xi'an Jiaotong University , Xi'an 710016 , China. FAU - Zhang, Pengbo AU - Zhang P AD - Department of Anesthesiology , The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710004 , China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200210 PL - United States TA - ACS Chem Neurosci JT - ACS chemical neuroscience JID - 101525337 RN - 0 (Neuroprotective Agents) RN - 67VB76HONO (Dexmedetomidine) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - R60L0SM5BC (Midazolam) SB - IM MH - Animals MH - Cell Differentiation/*drug effects MH - Cell Proliferation/*drug effects MH - Dexmedetomidine/metabolism/*pharmacology MH - Hippocampus/drug effects/metabolism MH - Midazolam/metabolism/*pharmacology MH - Neural Stem Cells/drug effects MH - Neurogenesis/*drug effects/physiology MH - Neurons/drug effects MH - Neuroprotective Agents/pharmacology MH - Rats MH - p38 Mitogen-Activated Protein Kinases/drug effects/metabolism OTO - NOTNLM OT - apoptosis OT - dexmedetomidine OT - differentiation OT - midazolam OT - neurogenesis OT - proliferation EDAT- 2020/01/31 06:00 MHDA- 2021/03/04 06:00 CRDT- 2020/01/31 06:00 PHST- 2020/01/31 06:00 [pubmed] PHST- 2021/03/04 06:00 [medline] PHST- 2020/01/31 06:00 [entrez] AID - 10.1021/acschemneuro.9b00611 [doi] PST - ppublish SO - ACS Chem Neurosci. 2020 Feb 19;11(4):579-591. doi: 10.1021/acschemneuro.9b00611. Epub 2020 Feb 10.