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.

The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells

“…Whether the activators of IK Ca channels or/and suppression of gap junction channels are effective at alleviating OXAL-induced neurotoxicity [23,34,41,43] necessitates further investigation.…”

Platinum-induced neurotoxicity: A review of possible mechanisms

“…Conversely, voltage-gated potassium channels are unlikely to be the primary target for oxaliplatin because patch-clamp studies failed to show any effect of oxaliplatin on Shaker-type potassium channels[ 36 ]. Kagiava et al[ 37 ] found some evidence indicating that potassium channel dysfunction during oxaliplatin treatment can occur due to malfunction of the gap junction (GJ) channels and hemichannels in myelinated fibers. According to their findings, oxaliplatin causes prolonged opening of GJ channels and hemichannels, leading to excessive potassium accumulation in the periaxonal space and its osmotic swelling.…”

Gap Junction Channels of Innexins and Connexins: Relations and Computational Perspectives

“…When using octanol for inhibiting GJC, connexon downregulation was demonstrated in different insects, like Oncopeltus, Hyalophora, Drosophila, Xylocopa, and Periplaneta [60,61,62,63]. In addition, GJC was inhibited in rodents to better understand the function of proteins and transcriptional regulators, as well as the mechanism of function of these inhibitors on cell communication [64,65,66]. A review of gap junction blockers in animal models in relation to seizures which includes a comprehensive list of inhibitors, can be found in [51].…”

“…Chemical mechanisms excel at reversibly blocking GJC, although these blockers are non-specific for different innexins and connexins and need a precise concentration to properly inhibit GJC [65].…”