Unlocking Propofol’s Potential in Epilepsy Treatment
Article Summary
- Miller School researcher Dr. Xiaoan Wu co-led a study on a drug that may treat pain and seizures for epilepsy patients.
- Dr Wu and collaborator Dr. H. Peter Larsson investigated how propofol binds to the HCN1 channel.
- They learned that the drug restores the function of epilepsy-associated mutant channels.
With approximately 50 million people worldwide living with epilepsy, enhancing therapies for this condition is crucial. Xiaoan Wu, Ph.D., from the Department of Physiology and Biophysics at the University of Miami Miller School of Medicine, collaborated with H. Peter Larsson, Ph.D., to co-lead a study that may identify potential epilepsy therapies.
The research, recently published in Nature Journal, explores the therapeutic effects of the anesthetic drug propofol.
This study, conducted in collaboration with researchers from Weill Cornell Medicine, investigates the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. These channels play a key role in regulating heart rhythms and nerve signals. The research suggests that drugs targeting a specific type of HCN channel, known as HCN1, could help treat nerve pain and epileptic seizures.
“This is fantastic news, as we found propofol, a commonly used intravenous anesthetic, actually restores the function of epilepsy-associated mutant channels to normal,” Dr. Wu said. “This collaborative project aims to reveal how propofol binds to the HCN channel and modulates its function. Identifying a unique binding site for an HCN inhibitor is crucial for developing guidelines to create selective drugs and improve the design of anti-epileptic medications.”
Inhibiting HCN1 Channels
Certain genetic mutations in HCN channels, such as M305L and D401H, have been linked to various types of epilepsy, including a severe form called early infantile epileptic encephalopathy (EIEE). Although only a few cases of EIEE have been documented, recent studies suggest that these mutations might be more common than currently believed. As a result, drugs that inhibit HCN1 channels could potentially treat EIEE and nerve pain.
Current treatments largely focus on blocking the pores of HCN channels. While propofol selectively inhibits HCN1 over other HCN channels, the exact mechanism behind this inhibition was not fully understood.
“Identifying the binding site for allosteric inhibitors like propofol is crucial for developing drugs that can selectively target HCN channels,” Dr. Wu said. “This could lead to better treatments for various medical conditions, including neuropathic pain and epilepsy. Our research could pave the way for new, targeted drug therapies.”
The Propofol Effect
To understand how propofol works, the labs studied the movement of a part of the channel that senses voltage changes. Researchers found that propofol’s blocking effect doesn’t depend on changes in this voltage sensor.
Instead, changes at two specific positions, one in the S5 helix and another in the S6 helix, hinder the channel from closing without affecting the voltage sensor’s movement. This finding suggests that stabilizing these positions is key to closing the channel.
Advanced imaging and electrical testing techniques revealed that propofol’s blockage is effective even in the presence of two epilepsy-related mutations, M305L and D401H, which typically make it difficult for the channel to close.
“In our future research, we aim to understand how propofol binds to other HCN channels, HCN2 to HCN4, and why it is more effective at inhibiting HCN1 compared to the others,” Dr. Wu said. “Additionally, we will focus on designing and discovering new drugs similar to propofol that have improved and more selective effects on HCN-related epilepsy mutations.”
Tags: Department of Physiology & Biophysics, Dr. Xiaoan Wu, epilepsy, H. Peter Larsson