The nonsteroidal anti-inflammatory drug meclofenamate mitigates kainic acid–induced seizures via TRPM4 inhibition

Transient receptor potential melastatin 4 (TRPM4) is a Ca²⁺-activated non-selective cation channel that regulates various physiological functions of excitable cells. In accordance with our previous findings, TRPM4 is known to be present and to be functionally active in hilar mossy cells where it controls seizure susceptibility. With the help of <i>in vivo</i> and <i>in vitro</i> electrophysiological and histological experiments, we investigated the effect of TRPM4 channel inhibition upon kainic acid-induced seizures. In this study, we present that <i>in vivo</i> administration of meclofenamate a novel blocker of TRPM4 before kainic acid injection reduces both seizure frequency and duration in mice. Furthermore, our findings reveal that meclofenamate treatment prior to kainic acid injection selectively reduced mossy cell loss in the ventral hippocampus. Interestingly, we observed elevated expression of TRPM4 in mossy cells of the ventral hippocampus highlighting the heterogenity of these neurons in the hippocampus. In addition, patch clamp recordings revealed that meclofenamate modulates both the spontaneous activity and the action potential dynamics of mossy cells. Lastly, we revealed the presence of <i>TRPM4</i> transcript in human mossy cells. Altogether, these findings suggest that pharmacological inhibition of TRPM4 may reduce seizure frequency thus possibly protect mossy cells.