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<p>Understanding the role of ion channels in regulating the membrane potential (<i>Vm</i>) is essential to understanding neurodegenerative disorders. Potassium channels, particularly the Kv7.2–Kv7.3 complex, are essential for maintaining neuronal excitability and network stability. Disruption of Kv ion channels can lead to excitotoxicity, interneuron loss, and progressive cognitive decline. The present study investigates 4-Isopropylbenzoic acid (4-IPBA), a naturally occurring compound, for its potential to rectify neuronal ion channel dysfunction, which can lead to dementia. Density Functional Theory calculations and experimental studies were performed to investigate structural, electronic, and pharmacological properties. Pharmacokinetic analysis suggests good brain permeability, oral absorption, and metabolic stability. Molecular docking analysis suggests that 4-IPBA can interact with the Kv7.2–Kv7.3 potassium channel, providing preliminary computational support for the ion channel rectification hypothesis in neurodegenerative disease. In vitro cytotoxicity assays (L929, SH-SY5Y) and antioxidant indicate low cellular toxicity across the tested concentration range and support a protective role against oxidative stress. This study hypothesizes that rectifying ion channel dysfunction to restore <i>Vm</i> may support neuronal signaling and interneuron stability, with potential relevance to cognitive decline, a rationale previously proposed by the same authors in cancer therapy. The dual mechanism, ion channel rectification and oxidative stress mitigation, may strengthen the neuroprotective hypothesis. Overall, the findings support the hypothesis that 4-IPBA may be associated with membrane potential–related ion channel behavior and neuronal protection, suggesting a potential strategy for further investigation in dementia research.</p>

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A hypothesis on restoring neuronal membrane potential in dementia: early hit identification of 4-IPBA as a potential ion-channel modulator

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • E. Eunice,
  • Johanan Christian Prasana

摘要

Understanding the role of ion channels in regulating the membrane potential (Vm) is essential to understanding neurodegenerative disorders. Potassium channels, particularly the Kv7.2–Kv7.3 complex, are essential for maintaining neuronal excitability and network stability. Disruption of Kv ion channels can lead to excitotoxicity, interneuron loss, and progressive cognitive decline. The present study investigates 4-Isopropylbenzoic acid (4-IPBA), a naturally occurring compound, for its potential to rectify neuronal ion channel dysfunction, which can lead to dementia. Density Functional Theory calculations and experimental studies were performed to investigate structural, electronic, and pharmacological properties. Pharmacokinetic analysis suggests good brain permeability, oral absorption, and metabolic stability. Molecular docking analysis suggests that 4-IPBA can interact with the Kv7.2–Kv7.3 potassium channel, providing preliminary computational support for the ion channel rectification hypothesis in neurodegenerative disease. In vitro cytotoxicity assays (L929, SH-SY5Y) and antioxidant indicate low cellular toxicity across the tested concentration range and support a protective role against oxidative stress. This study hypothesizes that rectifying ion channel dysfunction to restore Vm may support neuronal signaling and interneuron stability, with potential relevance to cognitive decline, a rationale previously proposed by the same authors in cancer therapy. The dual mechanism, ion channel rectification and oxidative stress mitigation, may strengthen the neuroprotective hypothesis. Overall, the findings support the hypothesis that 4-IPBA may be associated with membrane potential–related ion channel behavior and neuronal protection, suggesting a potential strategy for further investigation in dementia research.