ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1624224
Validation of Hv1 channel functions in BV2 microglial cells using small molecule modulators
Provisionally accepted
Ashutosh Sharma1,2
Nandini B Kale1,2
Priyanka Yadav1,2Shivani Yadav1,2Madhavi Ranawat1,2Valmik S Shinde1,2
Aravind Singh Kshatri1,2*- 1Central drug research institute, Lucknow, India
- 2AcSIR, Ghaziabad, India
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Microglia are the first responders to insults or damages in the brain where they display both beneficial and detrimental effects. Excessively activated microglia aggravate the secondary damage by producing several proinflammatory mediators. Voltage-gated proton channels, Hv1 are selectively expressed in the microglia where they modulate microglial activation. Therefore, Hv1 has emerged as a tractable target for treating a number of conditions, ranging from pain, neurological disorders to cancer. Due to the absence of a suitable Hv1 inhibitor, the pathophysiological roles of Hv1 channels has been exemplified using preclinical Hv1 knockout (KO) mice models. Thus, we characterized and validated the microglial Hv1 channel's functions using the recently reported Hv1 inhibitor (YHV98-4) and a novel Hv1 activator (S-023-0515) in a model of lipopolysaccharide (LPS)-induced neuroinflammation. In LPS-stimulated BV2 microglial cells, treatment with YHV98-4 alleviated the proinflammatory cytokines such as TNF-IL-6 & iNOS. Direct activation of Hv1 channels using S-023-0515 resulted in an increase in microglial M1 like polarisation, proinflammatory mediators, phagocytic capacity and mitochondrial ROS levels but did not alter the cellular ROS production. Analysis of the signalling pathway indicated that YHV98-4 and S-023-0515 exerted their protective and deleterious effects, respectively via phosphorylation of NF-, which serves as an upstream regulator of the inflammatory cascade. Collectively, our results elucidate the essential role of Hv1 channels in microglial functions and also demonstrate that their pharmacological inhibition and activation during inflammatory conditions are neuroprotective or neurotoxic, respectively.
Keywords: Microglia, Hv1 channels, Neuroinflammation, activator, inhibitor, Signalling pathway
Received: 07 May 2025; Accepted: 01 Jul 2025.
Copyright: © 2025 Sharma, Kale, Yadav, Yadav, Ranawat, Shinde and Kshatri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Aravind Singh Kshatri, Central drug research institute, Lucknow, India
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