Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy worldwide. Although symptomatic drugs are available, one-third of TLE patients continue to fail to respond to current treatment, so new drug targets are urgently needed. A research team led by a neuroscientist from the City University of Hong Kong (CityU) recently identified and developed a new drug candidate that has the potential to effectively treat TLE by suppressing neuroinflammation.
Epilepsy is one of the most common chronic brain disorders and is characterized by recurrent and spontaneous seizures. Most antiepileptic drugs currently available target neurons and synapses in the brain. They are effective at altering neural circuits and synapses, but this treatment overlooks another important pathology: neuroinflammation.
Neuroinflammation is caused by the abnormal functioning of reactive glial cells, such as astrocytes and microglia, which trigger an immune response in the brain. Mounting evidence points to a key role of connexin-based gap junctions and hemichannels in brain glial cells in TLE. A hemichannel is a channel or pathway formed by the assembly of six proteins, allowing the release of small molecules such as glutamate from astrocytes and microglia into the extracellular space. A gap junction is formed when the hemichannels of two adjacent cells dock with each other, as shown here (Figure 1). But inhibiting both gap junctions and hemichannels can lead to unwanted side effects because the former coordinate physiological functions of cell assemblies. Therefore, scientists need to find a way to block only connexin hemichannels to effectively reduce neuroinflammation with fewer side effects.
A research team led by Dr. Geoffrey Lau Chun-yue, assistant professor in the Department of Neuroscience, identified a new, small organic molecule called D4, which selectively blocks connexin hemichannels, but not gap junctions. The team investigated its effect in the treatment of TLE using a mouse model. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, inhibits TLE attacks and increases the animal’s survival rate.
The findings were published in the international scientific journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) under the title “Inhibition of Connexin Hemichannels Alleviates Neuroinflammation and Hyperexcitability in Temporal Lobe Epilepsy”.
New drug D4 suppresses neuroinflammation
“These are very exciting and encouraging results for translational epilepsy research,” said Dr. Lau. “We have found a promising new drug candidate for the treatment of epilepsy that works through a novel mechanism: blocking connexin hemichannels. Our findings also highlight the important involvement of neuroinflammation in neurological disorders such as epilepsy.”
The new drug, D4, targets a new class of ion channels, the connexin hemichannels in the glial cells. Glial cells include astrocytes and microglia and are important for modulating neurotransmission. Excess glutamate and other molecules can leak from reactive glia through hemichannels into the extracellular environment, altering synapses, enhancing neuroinflammation and exacerbating epileptic seizures. By specifically blocking connexin hemichannels using D4, Dr. Lau directly target neuroinflammation caused by astrocytes and microglia.
The research adopted the pilocarpine model of epilepsy in mice, a known model to produce phenotypes similar to human TLE. Pilocarpine was injected intraperitoneally into mice to induce seizures. The oral administration of one dose of D4 before epileptic seizures effectively reduced neuroinflammation and altered synaptic inhibition, increasing the animal’s survival rate. For treatment after induced seizures, a single dose of D4 had a long-lasting effect of suppressing astrocyte and microglia activation. This suggests that D4 strongly alleviates neuroinflammation and has a long-lasting effect.
A single dose provides long-term benefits
Both pre- and post-treatment results indicate that targeting connexin hemichannels by D4 is an effective and promising strategy for the treatment of epilepsy in which neuroinflammation plays a critical role. The drug can be taken orally to effectively enter the mouse brain to reduce the harmful effects of neuroinflammation. A single dose provides strong protection against future attacks. “We hope that this will ultimately result in new and better treatment options for epileptic patients,” said Dr. Lau. The team will continue to work on the astrocytic mechanisms of epilepsy and identify more novel therapeutic targets.
The paper’s first author is Dr. Guo Anni, a CityU graduate and a postdoctoral researcher in Dr. Lau’s lab. Corresponding co-authors are Dr. Lau and Professor Juan C Saez, from the University of Valparaíso, in Chile. Dr. Lau’s doctoral student, Zhang Huiqi, and research assistant, Li Huanhuan, also participated in the study. The research was funded by CityU, the Hong Kong Research Grants Council, InnoHK and the Shenzhen General Basic Research Program.