Novel SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells

Yuequ Zhang, Shabnam Shaabani, Kirsty Vowinkel, Marina Trombetta-Lima, Angélica María Sabogal-Guáqueta, Tingting Chen, Jan Hoekstra, Jan Lembeck, Martina Schmidt, Niels Decher, Alexander Dömling*, Amalia M Dolga*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
31 Downloads (Pure)

Abstract

Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca 2+ uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca 2+ level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.

Original languageEnglish
Article number116163
Number of pages16
JournalBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Volume171
DOIs
Publication statusPublished - Feb-2024

Keywords

  • Mice
  • Animals
  • Small-Conductance Calcium-Activated Potassium Channels
  • Reactive Oxygen Species/metabolism
  • Ferroptosis
  • Neurons/metabolism
  • Mitochondria/metabolism

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