Gasotransmitters are a relatively untapped therapeutic target in epilepsy. The carbonic anhydrase inhibitor, acetazolamide, is an approved antiseizure drug, and low levels of CO₂ have been linked with asynchronous neuronal firing and higher seizure propensity. Nitric oxide is another critical signaling molecule that has undergone a high degree of scrutiny in epilepsy and other neurological diseases. However, other gasotransmitters are less well characterized. Our recent collaboration with the Totah lab in UW Medicinal Chemistry sought to address this knowledge gap by studying the seizure and epilepsy-induced changes in H₂S expression in the mouse brain.

H₂S is an important signaling molecule involved in various biological processes, including cytoprotection, anti-inflammation, oxygen sensing, neuromodulation, and neuroprotection. The antioxidant function of H₂S has been extensively studied, demonstrating that this gasotransmitter has a diversity of biological roles.   However, it has been relatively challenging to quantify the precise levels of this gasotransmitter until the recent advances in LC-MS/MS methodology developed by the Totah lab have allowed for the capability to accurately measure H₂S and its methylated metabolite (MeSH).

This collaboration started as an undergraduate research project for Ms. Stephanie Mizuno to train in rodent seizure and epilepsy models. The project ultimately blossomed into a large-scale study to assess the dynamic changes in H₂S and MeSH following acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the early phases of the corneally kindled mouse model of chronic seizures.

One of the more interesting aspects of this project is the demonstration of rapid changes in H₂S levels within the plasma following an acute seizure.  Exogenous application of H₂S itself has been shown to have acute anticonvulsant potential. A 1956 case report of a patient whose seizures with olfactory auras could be controlled by exposure to strong and unpleasant odors, including H₂S, offers an interesting opportunity for acute seizure suppression that warrants further scrutiny. The nasal epithelium is one of the most direct routes of CNS penetrance, therefore it is plausible that rapid inhalation of H₂S could be a way to stop acute seizures.

This study highlights an understudied area for epilepsy in particular and demonstrates the power of team-science based approaches to therapeutic discovery. The Totah lab has predominately focused on cardiovascular function and cytochrome P450s. Our group works in epilepsy drug discovery. We’ve merged two research areas to offer a new and interesting look at the role of gasotransmitters in neurological disease.

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