The anesthetic propofol could be significant in creating new treatment methods for epilepsy and other neurological conditions, suggests a recent study.
A recent study led by researchers from Weill Cornell Medicine and Linköping University in Sweden indicates that the general anesthetic propofol may be pivotal in developing innovative treatment approaches for epilepsy and various neurological disorders.
Published on July 31 in Nature, the study details how researchers uncovered the intricate structural mechanics of how propofol inhibits the action of HCN1, an ion channel protein prevalent in various neuronal types. Inhibiting HCN1 is viewed as a promising strategy for addressing neurological issues like epilepsy and chronic pain. Unexpectedly, the researchers found that propofol binds to HCN1 in a way that can restore its functionality, particularly when the channel has one of two mutations linked to epilepsy.
“We might harness propofol’s distinctive binding mode to HCN1 for treating drug-resistant epilepsies and other disorders related to HCN1, whether by repurposing propofol itself or developing new, more targeted medications with a similar mechanism,” stated Dr. Crina Nimigean, one of the study’s co-senior authors and a professor at Weill Cornell Medicine.
Dr. Peter Larsson, a professor in the biomedical and clinical sciences department at Linköping University, served as the other co-senior author.
The primary author of the study was Dr. Elizabeth Kim, a postdoctoral research associate in Dr. Nimigean’s lab at Weill Cornell Medicine’s Department of Anesthesiology. Dr. Xiaoan Wu, also a postdoctoral research associate but in Dr. Larsson’s lab, was a co-first author. Contributions to this research were also made by Dr. Alessio Accardi and Dr. Peter Goldstein from Weill Cornell Medicine.
Humans have four types of HCN ion channels—HCN1 to HCN4—primarily located in heart and nervous system cells. These channels function as switches regulating electrical voltage across cell membranes. They open to allow positively charged potassium and sodium ions to flow in—essentially depolarizing the cell—once the voltage hits a specific threshold. This crucial role explains why HCN channels are referred to as pacemaker channels, as they help control the rhythmic activities of brain and heart cells.
Through techniques like cryo-electron microscopy, the researchers examined how propofol selectively reduces activity in HCN1 compared to other HCN channels. They discovered that propofol binds in a specific groove of the channel protein’s central pore structure, making it difficult for the pore to open.
While examining propofol’s interaction with HCN1, the researchers also looked at how the drug influences known mutants of the channel, including variants that are excessively open and linked to challenging epilepsy conditions like early infantile epileptic encephalopathy (EIEE). They were surprised to find that propofol could restore the function of two different EIEE-related HCN1 mutations to normal or nearly normal levels.
From their studies, a model emerged where mutations disrupt HCN1’s ability to sense voltage and open the pore. However, propofol successfully reconnects these mechanisms, reinstating membrane voltage’s control over ion flow.
These findings open up at least two potential therapeutic pathways. One involves using propofol, an existing and approved medication, to treat epilepsies associated with HCN1 mutations, as well as potentially other HCN1-related disorders. Though propofol is a powerful anesthetic requiring careful medical oversight, it might be possible to utilize it at lower doses that do not induce general anesthesia.
The other avenue, according to researchers, would be to utilize the new structural insights about propofol’s binding to engineer altered, non-anesthetic derivatives of propofol, or even entirely different compounds, that interact with HCN1 in a similar manner while avoiding effects on other channels to minimize side effects.
“For that, we will need a better understanding of how propofol inhibits HCN1 more effectively than other HCN channels,” Dr. Kim mentioned.
This research was partially funded by the National Institute of General Medical Sciences and the National Institute of Neurological Disorders and Stroke, both part of the National Institutes of Health, through grants GM124451, GM139164, GM128420, R42NS129370, NS137561, and GM145091. Additional support came from the Hartwell Foundation.
