Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy worldwide. Although symptomatic medications are available, one-third of TLE patients remain unresponsive to current treatment, so new drug targets are critically needed. A research team co-led by a City University of Hong Kong (CityU) neuroscientist has recently identified and developed a new drug candidate with the potential for effectively treating TLE by suppressing neuroinflammation.
Epilepsy is one of the most prevalent chronic brain disorders and is characterized by recurrent and spontaneous seizures. Most anti-epileptic drugs that are currently available target neurons and synapses in the brain. They are effective in changing 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, causing an immune reaction in the brain. Accumulating 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, which permits small molecules such as glutamate to be released from astrocytes and microglia to extracellular space. A gap junction is formed when the hemichannels of two adjacent cells dock with each other.
But inhibiting both gap junctions and hemichannels can lead to undesirable 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 co-led by Dr. Geoffrey Lau Chun-yue, Assistant Professor in the CityU 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 treating TLE using a mouse model. The findings suggest that D4 strongly suppresses the TLE-induced neuroinflammation, curbs TLE seizures, and increases the animal’s survival rate.
The findings were published in the international scientific journal Proceedings of the National Academy of Sciences (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 research in epilepsy,” said Dr. Lau. “We have found a very promising new drug candidate for treating epilepsy that works through a new 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. Excessive glutamate and other molecules can leak out from reactive glia via hemichannels to the extracellular environment, altering synapses, enhancing neuroinflammation and exacerbating seizures. By specifically blocking connexin hemichannels using D4, Dr. Lau’s team can directly target neuroinflammation caused by astrocytes and microglia.
The research adopted the pilocarpine model of epilepsy in mice, a well-known model to produce phenotypes that resemble human TLE. Pilocarpine was injected into mice intraperitoneally to induce seizures. The administration of one dose of D4 orally before inducing seizures effectively reduced neuroinflammation and altered…
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