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Understanding the molecular, cellular, and physiological components of neurodegenerative diseases (NDs) is paramount for developing accurate diagnostics and efficacious therapies. However, the complexity of ND pathology and the limitations associated with conventional analytical methods undermine research. Fortunately, microfluidic technology can facilitate discoveries through improved biomarker quantification, brain organoid culture, and small animal model manipulation. Because this technology can increase experimental throughput and the number of metrics that can be studied in concert, it demands more sophisticated computational tools to process and analyze results. Advanced analytical algorithms and machine learning platforms can address this challenge in data generated from microfluidic systems, but they can also be used outside of devices to discern patterns in genomic, proteomic, anatomical, and cognitive data sets. We discuss these approaches and their potential to expedite research discoveries and improve clinical outcomes through ND characterization, diagnosis, and treatment platforms.

In native tissue, Kv4.2 channels associate with the ancillary subunits Kv channels interacting proteins (KChIPs) and dipeptidyl peptidase-related proteins (DPPs) to evoke rapidly activating/inactivating currents in the heart (I to ) and brain (I A ). Despite extensive knowledge of Kv4.2 biophysical modulation by auxiliary subunits, the pharmacological effects, especially those related to the co-expressed subunit and the state-dependent drug binding, remain unknown. Here, we investigated the effects of co-expressing KChIP2c or DPP6 on the pharmacological inhibition of Kv4.2 channels by riluzole. Riluzole inhibited Kv4.2, Kv4.2/DPP6, and Kv4.2/KChIP2c channels in a voltage-independent manner, with potency ranked as Kv4.2/DPP6 > Kv4.2 > Kv4.2/KChIP2c. Additionally, to a dissimilar extent, riluzole inhibited the channels from the closed state, left-shifted the inactivation curves, and enhanced the closed-state inactivation (differently modifying the rate constants of this latter). More divergent effects were observed: the inactivation kinetics was accelerated in Kv4.2 and Kv4.2/KChIP2c but not in Kv4.2/DPP6; only in Kv4.2/KChIP2c, the activation curve was left-shifted and the recovery from inactivation was decelerated; and the closed-state inactivation developed faster in Kv4.2 and Kv4.2/DPP6 but was slower in Kv4.2/KChIP2c channels. Notably, inhibition from the closed-inactivated state was more rapid than from the closed state for the three channels. We conclude that riluzole can elicit differential effects on native Kv4.2 channels depending on the presence of distinct ancillary subunits. These findings contribute to our understanding of the interplay between auxiliary subunits and pharmacological regulation of α-subunits of ion channels, highlighting the role of the former by modulating the organ-specific effects of channel-interacting drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel Na V 1.7. We previously identified compound 194 as an indirect inhibitor of Na V 1.7 by preventing SUMOylation of the Na V 1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of Na V 1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of Na V 1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194., (Copyright © 2024 International Association for the Study of Pain.)