Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and hemichannels and can be prevented by octanol

Oxaliplatin-inducedneurotoxicity(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 25μM oxaliplatin caused a marked prolongation in the duration of the nerve evoked compound action potential (CAP) by nearly 1200% within 300min while amplitude remained constant for over 20h. This oxaliplatin effect was almost completely reversed by thegapjunction(GJ) inhibitoroctanolin 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 byoctanolpartially persisted in Cx29 better than in Cx32 KO nerves, suggesting that oxaliplatin affects both, but Cx32 GJchannelsmore than Cx29hemichannels. 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 byoctanol. Oxaliplatin caused no morphological changes initially (up to 3h of exposure), but prolonged nerve exposure caused juxtaparonodal axonal edema, which waspreventedbyoctanol. Our study indicates that oxaliplatin causes forced opening of Cx32channelsand Cx29hemichannelsin peripheral myelinated fibers leading to disruption of axonal K(+) homeostasis. The GJ blockeroctanolprevents OIN at very low concentrations and should be further studied as a neuroprotectant.