PMID- 26044641
OWN - NLM
STAT- MEDLINE
DCOM- 20160524
LR  - 20231213
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 97
DP  - 2015 Oct
TI  - Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and 
      hemichannels and can be prevented by octanol.
PG  - 289-305
LID - S0028-3908(15)00202-6 [pii]
LID - 10.1016/j.neuropharm.2015.05.021 [doi]
AB  - Oxaliplatin-induced neurotoxicity (OIN) is a common complication of chemotherapy 
      without effective treatment. In order to clarify the mechanisms of both acute and 
      chronic OIN, we used an ex-vivo mouse sciatic nerve model. Exposure to 25 muM 
      oxaliplatin caused a marked prolongation in the duration of the nerve evoked 
      compound action potential (CAP) by nearly 1200% within 300 min while amplitude 
      remained constant for over 20 h. This oxaliplatin effect was almost completely 
      reversed by the gap junction (GJ) inhibitor octanol in a concentration-dependent 
      manner. Further GJ blockers showed similar effects although with a narrower 
      therapeutic window. To clarify the target molecule we studied sciatic nerves from 
      connexin32 (Cx32) and Cx29 knockout (KO) mice. The oxaliplatin effect and 
      neuroprotection by octanol partially persisted in Cx29 better than in Cx32 KO 
      nerves, suggesting that oxaliplatin affects both, but Cx32 GJ channels more than 
      Cx29 hemichannels. Oxaliplatin also accelerated neurobiotin uptake in HeLa cells 
      expressing the human ortholog of Cx29, Cx31.3, as well as dye transfer between 
      cells expressing the human Cx32, and this effect was blocked by octanol. 
      Oxaliplatin caused no morphological changes initially (up to 3 h of exposure), 
      but prolonged nerve exposure caused juxtaparonodal axonal edema, which was 
      prevented by octanol. Our study indicates that oxaliplatin causes forced opening 
      of Cx32 channels and Cx29 hemichannels in peripheral myelinated fibers leading to 
      disruption of axonal K(+) homeostasis. The GJ blocker octanol prevents OIN at 
      very low concentrations and should be further studied as a neuroprotectant.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Kagiava, Alexia
AU  - Kagiava A
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, Nicosia, Cyprus.
FAU - Theophilidis, George
AU  - Theophilidis G
AD  - Laboratory of Animal Physiology, Department of Zoology, School of Biology, 
      Aristotle University of Thessaloniki, Thessaloniki, Greece.
FAU - Sargiannidou, Irene
AU  - Sargiannidou I
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, Nicosia, Cyprus.
FAU - Kyriacou, Kyriacos
AU  - Kyriacou K
AD  - Department of Molecular Pathology and Electron Microscopy, The Cyprus Institute 
      of Neurology and Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Kleopa, Kleopas A
AU  - Kleopa KA
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, Nicosia, Cyprus; Neurology Clinics, The Cyprus 
      Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, 
      Nicosia, Cyprus. Electronic address: kleopa@cing.ac.cy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150601
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Connexins)
RN  - 0 (GJC3 protein, human)
RN  - 0 (Gje1 protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Octanols)
RN  - 0 (Organoplatinum Compounds)
RN  - 04ZR38536J (Oxaliplatin)
RN  - RWP5GA015D (Potassium)
SB  - IM
MH  - Animals
MH  - Axons/drug effects/pathology/physiology
MH  - Connexins/antagonists & inhibitors/genetics/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Edema/drug therapy/pathology/physiopathology
MH  - HeLa Cells
MH  - Homeostasis/drug effects/physiology
MH  - Humans
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Nerve Tissue Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Octanols/*pharmacology
MH  - Organoplatinum Compounds/*toxicity
MH  - Oxaliplatin
MH  - Potassium/metabolism
MH  - Sciatic Nerve/*drug effects/pathology/physiopathology
MH  - Gap Junction beta-1 Protein
OTO - NOTNLM
OT  - Action potential
OT  - Chemotherapy-induced neuropathy
OT  - Cx29
OT  - Cx32
OT  - Gap junctions
OT  - Juxtaparanodes
OT  - Sciatic nerve
EDAT- 2015/06/06 06:00
MHDA- 2016/05/25 06:00
CRDT- 2015/06/06 06:00
PHST- 2014/10/30 00:00 [received]
PHST- 2015/04/16 00:00 [revised]
PHST- 2015/05/16 00:00 [accepted]
PHST- 2015/06/06 06:00 [entrez]
PHST- 2015/06/06 06:00 [pubmed]
PHST- 2016/05/25 06:00 [medline]
AID - S0028-3908(15)00202-6 [pii]
AID - 10.1016/j.neuropharm.2015.05.021 [doi]
PST - ppublish
SO  - Neuropharmacology. 2015 Oct;97:289-305. doi: 10.1016/j.neuropharm.2015.05.021. 
      Epub 2015 Jun 1.