A Novel Hydrogen Polysulfide Donor Alleviates Neuropathic Pain by Enhancing A-Type Potassium Currents via LIMK1-Cofilin Mediated Interaction between Filamin A and Kv4.2
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Hydrogen persulfide (H 2 S 2 ) is an important endogenous signaling molecule, holding significant therapeutic potential across diverse disease models due to its potent antioxidant and redox-regulating properties. Herein, we report the synthesis, characterization, and in vivo evaluation of an esterase responsive H 2 S 2 donor, HPD1 . It reduced mechanical and cold allodynia at 14 mg/kg (i.p.) in chronic constriction injury and paclitaxel-induced neuropathic pain models. Moreover, HPD1 exhibited negligible systemic toxicity and behavioral side effects even at 28 mg/kg. Electrophysiological tests showed that HPD1 suppressed PTX-induced hyperexcitability in dorsal root ganglion (DRG) neurons by specifically potentiating A-type potassium currents ( I A ). Mechanistically, we demonstrate that HPD1 activates LIMK1, which inactivates cofilin and stabilizes F-actin, thereby promoting the interaction between the actin-binding protein Filamin A and Kv4.2. Furthermore, both the HPD1 -induced increase in Filamin A-Kv4.2 co-localization and the subsequent restoration of I A density in DRG neurons, as well as the analgesic effect of HPD1 were dampened by pharmacological inhibition of LIMK1 with BMS-5. This work has developed a new generation of H 2 S 2 donors, demonstrated the analgesic efficacy of HPD1 , and uncovered the novel LIMK1-cofilin-Filamin A-Kv4.2 dependent mechanism that restores I A , thus providing a reliable therapeutic strategy for neuropathic pain based on H 2 S 2 donors.
