PMID- 31187143
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230412
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 171
IP  - 1
DP  - 2019 Sep 1
TI  - Both GSK-3beta/CRMP2 and CDK5/CRMP2 Pathways Participate in the Protection of 
      Dexmedetomidine Against Propofol-Induced Learning and Memory Impairment in 
      Neonatal Rats.
PG  - 193-210
LID - 10.1093/toxsci/kfz135 [doi]
AB  - Dexmedetomidine has been reported to ameliorate propofol-induced neurotoxicity in 
      neonatal animals. However, the underlying mechanism is still undetermined. 
      Glycogen synthase kinase-3beta (GSK-3beta), cycline-dependent kinase-5 (CDK5), and 
      Rho-kinase (RhoA) pathways play critical roles in neuronal development. The 
      present study is to investigate whether GSK-3beta, CDK5, and RhoA pathways are 
      involved in the neuroprotection of dexmedetomidine. Seven-day-old (P7) Sprague 
      Dawley rats were anesthetized with propofol for 6 h. Dexmedetomidine at various 
      concentrations were administered before propofol exposure. Neuroapoptosis, the 
      neuronal proliferation, and the level of neurotransmitter in the hippocampus were 
      evaluated. The effects of GSK-3beta inhibitor SB415286, CDK5 inhibitor roscovitine, 
      or RhoA inhibitor Y276321 on propofol-induced neurotoxicity were assessed. 
      Propofol-induced apoptosis in the hippocampal neurons and astrocytes, inhibited 
      neuronal proliferation in the dentate gyrus region, down-regulated the level of 
      gamma-aminobutyric acid and glutamate in the hippocampus, and impaired long-term 
      cognitive function. These harmful effects were reduced by pretreatment with 50 
      mug.kg-1 dexmedetomidine. Moreover, propofol-activated GSK-3beta and CDK5 pathways, 
      but not RhoA pathway, by reducing the phosphorylation of GSK-3beta (ser 9), 
      increasing the expression of CDK5 activator P25 and increasing the 
      phosphorylation of their target sites on collapsin response mediator protein 2 
      (CRMP2) shortly after exposure. These effects were reversed by pretreatment with 
      50 mug.kg-1 dexmedetomidine. Furthermore, SB415286 and roscovitine, not Y276321, 
      attenuated the propofol-induced neuroapoptosis, brain cell proliferation 
      inhibition, gamma-aminobutyric acid and glutamate downregulation, and learning and 
      memory dysfunction. Our results indicate that dexmedetomidine reduces 
      propofol-induced neurotoxicity and neurocognitive impairment via inhibiting 
      activation of GSK-3beta/CRMP2 and CDK5/CRMP2 pathways in the hippocampus of neonatal 
      rats.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      Society of Toxicology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Li, Junhua
AU  - Li J
AUID- ORCID: 0000-0003-1245-3333
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
AD  - Laboratory of RNA and Major Diseases of Brain and Hearts, Sun Yat-sen Memorial 
      Hospital, Sun Yat-sen University, Guangzhou 510120, China.
FAU - Guo, Mingyan
AU  - Guo M
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
AD  - Laboratory of RNA and Major Diseases of Brain and Hearts, Sun Yat-sen Memorial 
      Hospital, Sun Yat-sen University, Guangzhou 510120, China.
FAU - Liu, Yafang
AU  - Liu Y
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
AD  - Laboratory of RNA and Major Diseases of Brain and Hearts, Sun Yat-sen Memorial 
      Hospital, Sun Yat-sen University, Guangzhou 510120, China.
FAU - Wu, Guiyun
AU  - Wu G
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
FAU - Miao, Liping
AU  - Miao L
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
FAU - Zhang, Jing
AU  - Zhang J
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
FAU - Zuo, Zhiyi
AU  - Zuo Z
AD  - Department of Anesthesiology, University of Virginia Health System, 
      Charlottesville, Virginia 22908-0710.
FAU - Li, Yujuan
AU  - Li Y
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, 510120, China.
AD  - Laboratory of RNA and Major Diseases of Brain and Hearts, Sun Yat-sen Memorial 
      Hospital, Sun Yat-sen University, Guangzhou 510120, China.
AD  - Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School 
      of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
SB  - IM
OTO - NOTNLM
OT  - collapsin response mediator protein 2
OT  - cycline-dependent kinase-5
OT  - dexmedetomedine
OT  - glycogen synthase kinase-3beta
OT  - neuroapoptosis
OT  - propofol
EDAT- 2019/06/13 06:00
MHDA- 2019/06/13 06:01
CRDT- 2019/06/13 06:00
PHST- 2019/06/13 06:01 [medline]
PHST- 2019/06/13 06:00 [pubmed]
PHST- 2019/06/13 06:00 [entrez]
AID - 5514061 [pii]
AID - 10.1093/toxsci/kfz135 [doi]
PST - ppublish
SO  - Toxicol Sci. 2019 Sep 1;171(1):193-210. doi: 10.1093/toxsci/kfz135.