title: Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and hemichannels and can be prevented by octanol.
abstract: 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 μM 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.
authors.affiliation: Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
authors.forename: Alexia
authors.initials: A
authors.lastname: Kagiava
authors.affiliation: Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Theophilidis
authors.affiliation: Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
authors.forename: Irene
authors.initials: I
authors.lastname: Sargiannidou
authors.affiliation: Department of Molecular Pathology and Electron Microscopy, The Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Kyriacou
authors.affiliation: 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.
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000442:Octanols / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D011188:Potassium / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000442:Octanols; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011188:Potassium; D000097002:Gap Junction beta-1 Protein; C464674:GJC3 protein, human; C464673:Gje1 protein, mouse
keywords: Action potential; Chemotherapy-induced neuropathy; Cx29; Cx32; Gap junctions; Juxtaparanodes; Sciatic nerve