Targeting KCNN4 channels modulates microglial activation and apoptosis in a PD-relevant inflammatory model

Parkinson's disease (PD) is characterized by chronic neuroinflammation and progressive dopaminergic neurodegeneration, driven primarily by the activation of microglia and associated apoptotic pathways. The intermediate-conductance calcium-activated potassium channel KCNN4 has recently emerged as a potential therapeutic target, yet its role in chronic neurodegenerative conditions remains underexplored. In this study, we investigated whether pharmacological inhibition of KCNN4 using TRAM-34 can modulate both inflammatory and apoptotic responses in an LPS-induced mouse model of PD. Our in vivo findings demonstrate that TRAM-34 suppressed microglial activation, evidenced by reduced COX-2 and lower TLR4 relative to LPS, together with attenuated IL-1β; striatal Iba1 morphology at Day 86 also indicated mitigated activation. Furthermore, TRAM-34 treatment preserved dopaminergic neurons, as shown by increased tyrosine hydroxylase immunoreactivity, and mitigated apoptotic signaling by decreasing phosphorylated p53, cytochrome c release, and cleaved PARP-1 levels. Importantly, [¹ ⁸F]FE-PE2I PET at Day 30 showed partial restoration of striatal DAT, aligning with the Day-86 immunohistochemistry. In parallel, behavioral assessments using the rotarod test demonstrated that TRAM-34 significantly ameliorated LPS-induced motor deficits, further supporting its functional neuroprotective effects. In vitro studies further revealed that KCNN4 inhibition attenuates microglial overactivation and suppresses downstream inflammatory and pro-apoptotic signaling pathways. These dual effects suggest that TRAM-34 attenuates PD progression by simultaneously targeting neuroinflammation and apoptosis. This study underscores the therapeutic potential of KCNN4 channel inhibition in modulating microglial function and preventing neuronal loss in PD. By bridging molecular mechanisms with translational outcomes, our findings pave the way for KCNN4-targeted strategies to mitigate neurodegeneration and improve patient outcomes in PD.