PMID- 32847971
OWN - NLM
STAT- MEDLINE
DCOM- 20210806
LR  - 20210806
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 19
IP  - 10
DP  - 2020 Oct
TI  - Dysregulation of EAAT2 and VGLUT2 Spinal Glutamate Transports via Histone 
      Deacetylase 2 (HDAC2) Contributes to Paclitaxel-induced Painful Neuropathy.
PG  - 2196-2209
LID - 10.1158/1535-7163.MCT-20-0006 [doi]
AB  - Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain 
      unavailable. Given the significance of spinal cord glutamate transporters in 
      neuronal plasticity and central sensitization, this study investigated the role 
      of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate 
      transporter 2 (VGLUT2) in the development of paclitaxel-induced painful 
      neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced 
      long-lasting mechanical allodynia (>28 days) with increased glutamate 
      concentration and decreased EAAT2 expression with no changes in GABA/glycine or 
      VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression 
      was upregulated and coexpressed with enhanced synaptophysin, characterizing 
      nociceptive afferent sprouting and new synapse formation of glutamatergic neurons 
      in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also 
      upregulated, and their interaction and colocalization were confirmed following 
      paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of 
      HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated 
      paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, 
      glutamate accumulation, and the corresponding changes in 
      EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings 
      indicate that loss of the balance between glutamate release and reuptake due to 
      dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays 
      an important role in the development of paclitaxel-induced neuropathic pain. 
      HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, 
      which can potentially be a therapeutic target to relieve CIPN by reversing 
      central sensitization of spinal nociceptive neurons.
CI  - (c)2020 American Association for Cancer Research.
FAU - Wang, Xiao-Min
AU  - Wang XM
AD  - Laboratory and Clinical Research Institute for Pain, Department of 
      Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China. 
      cheucw@hku.hk xmwang1@hku.hk.
FAU - Gu, Pan
AU  - Gu P
AD  - Laboratory and Clinical Research Institute for Pain, Department of 
      Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China.
FAU - Saligan, Leorey
AU  - Saligan L
AD  - National Institute of Nursing Research, Division of Intramural Research, NIH, 
      Bethesda, Maryland.
FAU - Iadarola, Michael
AU  - Iadarola M
AD  - Anesthesiology Research Laboratories, Department of Perioperative Medicine, 
      Clinical Center, NIH, Bethesda, Maryland.
FAU - Wong, Stanley Sau Ching
AU  - Wong SSC
AD  - Laboratory and Clinical Research Institute for Pain, Department of 
      Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China.
AD  - Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, 
      China.
FAU - Ti, Lian Kah
AU  - Ti LK
AUID- ORCID: 0000-0003-0424-286X
AD  - Department of Anaesthesia, Yong Loo Lin School of Medicine, National University 
      of Singapore, Singapore.
FAU - Cheung, Chi Wai
AU  - Cheung CW
AD  - Laboratory and Clinical Research Institute for Pain, Department of 
      Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, China. 
      cheucw@hku.hk xmwang1@hku.hk.
AD  - Department of Anaesthesiology, The University of Hong Kong, Hong Kong, SAR, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200826
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Slc17a6 protein, rat)
RN  - 0 (Slc1a2 protein, rat)
RN  - 0 (Vesicular Glutamate Transport Protein 2)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 3.5.1.98 (Hdac2 protein, rat)
RN  - EC 3.5.1.98 (Histone Deacetylase 2)
RN  - P88XT4IS4D (Paclitaxel)
RN  - Neuropathy, Painful
SB  - IM
MH  - Animals
MH  - Excitatory Amino Acid Transporter 2/*metabolism
MH  - Glutamic Acid/metabolism
MH  - Histone Deacetylase 2
MH  - Male
MH  - Paclitaxel/*adverse effects
MH  - Pain/*chemically induced/metabolism
MH  - Peripheral Nervous System Diseases/*chemically induced/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Vesicular Glutamate Transport Protein 2/*metabolism
EDAT- 2020/08/28 06:00
MHDA- 2021/08/07 06:00
CRDT- 2020/08/28 06:00
PHST- 2020/01/05 00:00 [received]
PHST- 2020/04/24 00:00 [revised]
PHST- 2020/08/05 00:00 [accepted]
PHST- 2020/08/28 06:00 [pubmed]
PHST- 2021/08/07 06:00 [medline]
PHST- 2020/08/28 06:00 [entrez]
AID - 1535-7163.MCT-20-0006 [pii]
AID - 10.1158/1535-7163.MCT-20-0006 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2020 Oct;19(10):2196-2209. doi: 10.1158/1535-7163.MCT-20-0006. 
      Epub 2020 Aug 26.