Epilepsy is one of the most prevalent chronic brain disorders and is characterised by recurrent and spontaneous seizures. Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy worldwide. 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.
New drug suppresses neuroinflammation and stop seizures
A research team co-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 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. 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 synaptic inhibition, which increased the animal’s survival rate.
For treatment after induced seizures, a single dose of D4 had a prolonged effect on suppressing the activation of astrocytes and microglia. This suggests that D4 strongly alleviates neuroinflammation and has a long-term effect.
Long-term benefits after a single dose
Results from both pre- and post-treatment indicate that targeting connexin hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role. The drug can be taken orally to effectively get into the mouse brain to reduce the harmful effects of neuroinflammation. A single dose provides strong protection against future seizures.
Anni Guo, Huiqi Zhang, Huanhuan Li, Arthur Chiu, Claudia García-Rodríguez, Carlos F. Lagos, Juan C. Sáez, Chunyue Geoffrey Lau. Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy. Proceedings of the National Academy of Sciences, 2022; 119 (45) DOI: 10.1073/pnas.2213162119