Résumé
Introduction: Acute peripheral neuropathy (OIPN), a common adverse effect of the anticancer agent oxaliplatin [1], negatively influences quality of life, may lead to therapy discontinuation and to date there is no treatment available. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed along the pain pathway and common HCN blockers have been shown to reverse pain symptoms in OIPN rodent models [2], but their cardiac side effects limit their clinical use. Interestingly, TRIP8b, an auxiliary subunit regulating surface expression and function of HCN channel is not expressed in the heart [3], suggesting that disrupting HCN-TRIP8b interaction could decrease OIPN symptoms, without any cardiac effect. The aim of our project is to (i) study HCN-TRIP8b co-expression in DRG tissues and (ii) find new compounds targeting HCN-TRIP8b interaction with a clear pharmacological efficacy in decreasing acute pain symptoms.Material and methods: Protein levels and localization of HCN channels isoforms (HCN1-4) as well as TRIP8b subunits in DRG neurons from acute OIPN mice have been assessed with specific antibodies using Western Blot and immunohistochemistry technics. Series of peptoids (synthetic oligomers mimicking peptides) targeting HCN-TRIP8b interaction have been synthesized by the Institute of Chemistry of Clermont-Ferrand (ICCF) and their compounds efficacy on pain behavioural tests and pharmacokinetic profile were checked in acute OIPN animals.Results: HCN1/HCN2 isoforms co-localized with TRIP8b subunit in small and large DRG neurons. Western Blot analysis showed an increased expression of all proteins in DRG tissues from OIPN animals. Among all tested compounds, a hit peptoid demonstrated a dose-dependent antihyperalgic effect in acute OIPN that correlated with a concentration of the compound in the micromolar range in DRG tissues.Discussion/Conclusion: Our results provide the proof of concept that pharmacological disruption of TRIP8b-HCN interaction is analgesic in a model of acute OIPN, while, contrary to non-selective HCN channel blockers, it did not affect cardiac HCN currents.References:[1] Attal N et al. Epub. 2009;144:245-2522.[2] Descoeur J et al. EMBO Mol. Med. 2011;3:266-2783.[3] Han Y et al. J. Biomol. Screen. 2015;20(9):1124-1131.