Introduction and Objective: Diabetic peripheral neuropathy remains a major therapeutic challenge, with over 50% of patients responding inadequately to existing non-opioid therapies (gabapentinoids, SNRIs, TCAs). Dorsal root ganglion (DRG) neurons serve as the primary sites for injury-induced plasticity underlying painful peripheral pathophysiologies. Voltage-gated sodium channels (VGSC), specifically Nav1.8, are highly expressed in DRGs and are critical for generation of nociceptive signals. However, the viability of targeting Nav1.8 for neuropathic pain conditions remains unclear.Methods: We opted to target membrane delimited protein-protein interactions between scaffold proteins and Nav1.8. Therefore, we developed the MM-3000 series, a family of short lipidated peptidomimetics (SLiP) based on a unique protein-binding domain found in Nav1.8. MM-3000 was a provided inital proof-of-concept and MM-3001 was a second generation iteration with improved pharmacokinetic parameters. Techniques used include calcium imaging, whole cell patch clamp, and behavioral studies. In vitro experiments were conducted using mouse embryonic DRG (eDRG) neurons, human DRG neurons, and in vivo experiments were conducted in rodents and minipigs.Results: In electrophysiology experiments, the MM-3000 series selectively reduced Nav1.8 currents in hyperexcitable neurons. Additionally, action potentials of nociceptors that received the MM-3000 series were shorter and narrower, indicative of loss of Nav1.8. We also observed a significant reduction in action potential firing and increase in rheobase. When tested in vivo, systemic administration of the MM-3000 series produced significant, dose-dependent reductions in neuropathic pain-like behaviors in multiple preclinical models.Conclusion: These data suggest that Nav1.8-scaffold protein complexes play a critical role in regulating the intrinsic excitability of DRG neurons and that these complexes provide an attractive target for pharmacologic treatment of chronic neuropathy.
R. Powell: None.
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