Abstract
Objective: This study aimed to investigate whether long noncoding RNA sprouty receptor tyrosine kinase signaling antagonist 4-intronic transcript 1 (SPRY4-IT1) is involved in the regulation of ketamine-induced neurotoxicity. Methods: Human embryonic stem cells (hESCs) were induced into neurons in vitro and treated with ketamine. Apoptosis and neurite degeneration assays were used to determine ketamine-induced neurotoxicity and qRT-PCR to determine SPRY4-IT1 expression. SPRY4-IT1 was downregulated in hESC-induced neurons to examine its regulation on ketamine-induced neurotoxicity. The correlation between enhancer of zeste homolog 2 (EZH2) and SPRY4-IT1 was also examined. EZH2 was upregulated in SPRY4-IT1-downregualted hESC-induced neurons to further examine its participation in SPRY4-IT1-mediated ketamine neurotoxicity. Results: Ketamine-induced dose-dependent apoptosis, neurite degeneration, and SPRY4-IT1 upregulation in hESC-induced neurons. Lentivirus-mediated SPRY4-IT1 downregulation protected ketamine neurotoxicity. EZH2 expression was positively correlated with SPRY4-IT1 in hESC-induced neurons. EZH2 overexpression markedly reversed the protective effects of SPRY4-IT1 knockdown on ketamine neurotoxicity. Conclusions: SPRY4-IT1 is involved in anesthesia-induced neurotoxicity, possibly through the regulation on EZH2 gene.
References
1.
Disma
N
, O’Leary
JD
, Loepke
AW
, Brambrink
AM
, Becke
K
, Clausen
NG
, et al. Anesthesia and the developing brain: a way forward for laboratory and clinical research
. Paediatr Anaesth
. 2018
;28
(9
):758
–63
. .2.
O'Leary
JD
. Human studies of anesthesia-related neurotoxicity in children: a narrative review of recent additions to the clinical literature
. Clin Perinatol
. 2019
;46
(4
):637
–45
. .3.
Ho
AM
, Fleming
ML
, Mizubuti
GB
. Anesthetic neurotoxicity and the developing brain
. CMAJ
. 2017
;189
(32
):E1028
–9
. .4.
Malinovsky
JM
, Cozian
A
, Lepage
JY
, Mussini
JM
, Pinaud
M
, Souron
R
. Ketamine and midazolam neurotoxicity in the rabbit
. Anesthesiology
. 1991
;75
(1
):91
–7
. .5.
Ubogu
EE
, Sagar
SM
, Lerner
AJ
, Maddux
BN
, Suarez
JI
, Werz
MA
. Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity
. Epilepsy Behav
. 2003
;4
(1
):70
–5
. .6.
Wei
H
. The role of calcium dysregulation in anesthetic-mediated neurotoxicity
. Anesth Analg
. 2011
;113
(5
):972
–4
. .7.
Wei
H
, Inan
S
. Dual effects of neuroprotection and neurotoxicity by general anesthetics: role of intracellular calcium homeostasis
. Prog Neuropsychopharmacol Biol Psychiatry
. 2013
;47
:156
–61
. .8.
Ito
H
, Uchida
T
, Makita
K
. Ketamine causes mitochondrial dysfunction in human induced pluripotent stem cell-derived neurons
. PLoS One
. 2015
;10
(5
):e0128445
. .9.
Zhu
X
, Li
P
, Hao
X
, Wei
K
, Min
S
, Luo
J
, et al. Ketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of neuroinflammation and soluble amyloid-beta peptide in depressive-like rats
. Neurosci Lett
. 2015
;599
:32
–7
. .10.
Li
Y
, Shen
R
, Wen
G
, Ding
R
, Du
A
, Zhou
J
, et al. Effects of ketamine on levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in the hippocampus of mice following acute or chronic administration
. Front Pharmacol
. 2017
;8
:139
. 11.
Maass
PG
, Luft
FC
, Bähring
S
. Long non-coding RNA in health and disease
. J Mol Med
. 2014
;92
(4
):337
–46
. .12.
Chen
X
, Yan
GY
. Novel human lncRNA-disease association inference based on lncRNA expression profiles
. Bioinformatics
. 2013
;29
(20
):2617
–24
. .13.
Wapinski
O
, Chang
HY
. Long noncoding RNAs and human disease
. Trends Cell Biol
. 2011
;21
(6
):354
–61
. .14.
Andersen
RE
, Lim
DA
. Forging our understanding of lncRNAs in the brain
. Cell Tissue Res
. 2018
;371
(1
):55
–71
. .15.
Ng
SY
, Johnson
R
, Stanton
LW
. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors
. EMBO J
. 2012
;31
(3
):522
–33
. .16.
Fan
MJ
, Zou
YH
, He
PJ
, Zhang
S
, Sun
XM
, Li
CZ
. Long non-coding RNA SPRY4-IT1 promotes epithelial-mesenchymal transition of cervical cancer by regulating the miR-101-3p/ZEB1 axis
. Biosci Rep
. 2019
;39
(6
). .17.
Wen
X
, Han
XR
, Wang
YJ
, Fan
SH
, Zhuang
J
, Zhang
ZF
, et al. Effects of long noncoding RNA SPRY4-IT1-mediated EZH2 on the invasion and migration of lung adenocarcinoma
. J Cell Biochem
. 2018
;119
(2
):1827
–40
. .18.
Zhou
M
, Zhang
XY
, Yu
X
. Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma
. Biomed Pharmacother
. 2017
;85
:348
–54
. .19.
Sun
M
, Liu
XH
, Lu
KH
, Nie
FQ
, Xia
R
, Kong
R
, et al. EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition
. Cell Death Dis
. 2014
;5
:e1298
. .20.
Bai
X
, Twaroski
D
, Bosnjak
ZJ
. Modeling anesthetic developmental neurotoxicity using human stem cells
. Semin Cardiothorac Vasc Anesth
. 2013
;17
(4
):276
–87
. .21.
Bai
X
, Yan
Y
, Canfield
S
, Muravyeva
MY
, Kikuchi
C
, Zaja
I
, et al. Ketamine enhances human neural stem cell proliferation and induces neuronal apoptosis via reactive oxygen species-mediated mitochondrial pathway
. Anesth Analg
. 2013
;116
(4
):869
–80
. .22.
Bosnjak
ZJ
, Yan
Y
, Canfield
S
, Muravyeva
MY
, Kikuchi
C
, Wells
CW
, et al. Ketamine induces toxicity in human neurons differentiated from embryonic stem cells via mitochondrial apoptosis pathway
. Curr Drug Saf
. 2012
;7
(2
):106
–19
. .23.
Zhao
X
, Shu
F
, Wang
X
, Wang
F
, Wu
L
, Li
L
, et al. Inhibition of microRNA-375 ameliorated ketamine-induced neurotoxicity in human embryonic stem cell derived neurons
. Eur J Pharmacol
. 2019
;844
:56
–64
. .24.
Liu
D
, Li
Y
, Luo
G
, Xiao
X
, Tao
D
, Wu
X
, et al. LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2
. Cancer Lett
. 2017
;388
:281
–91
. .25.
Zhang
SC
, Wernig
M
, Duncan
ID
, Brüstle
O
, Thomson
JA
. In vitro differentiation of transplantable neural precursors from human embryonic stem cells
. Nat Biotechnol
. 2001
;19
(12
):1129
–33
. .26.
Schuldiner
M
, Eiges
R
, Eden
A
, Yanuka
O
, Itskovitz-Eldor
J
, Goldstein
RS
, et al. Induced neuronal differentiation of human embryonic stem cells
. Brain Res
. 2001
;913
(2
):201
–5
. .27.
Itskovitz-Eldor
J
, Schuldiner
M
, Karsenti
D
, Eden
A
, Yanuka
O
, Amit
M
, et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers
. Mol Med
. 2000
;6
(2
):88
–95
. .28.
Xu
Y
, Yao
Y
, Jiang
X
, Zhong
X
, Wang
Z
, Li
C
, et al. SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma
. J Exp Clin Cancer Res
. 2018
;37
(1
):81
. .29.
Quan
Z
, Zheng
D
, Qing
H
. Regulatory roles of long non-coding RNAs in the central nervous system and associated neurodegenerative diseases
. Front Cell Neurosci
. 2017
;11
:175
. .30.
Yu
YL
, Chou
RH
, Chen
LT
, Shyu
WC
, Hsieh
SC
, Wu
CS
, et al. EZH2 regulates neuronal differentiation of mesenchymal stem cells through PIP5K1C-dependent calcium signaling
. J Biol Chem
. 2011
;286
(11
):9657
–67
. .© 2021 S. Karger AG, Basel
2021
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
