A team of City University of Hong Kong (CityU) neuroscientists recently identified and developed a new drug candidate for treating temporal lobe epilepsy (TLE) by suppressing neuroinflammation called D4. The study and its promising results were published in Proceedings of the National Academy of Sciences. TLE is one of the most common types of epilepsy and about one-third of TLE patients have a drug resistant form of the disorder, so drug discovery for this patient population is critical.
The CityU research team adopted the pilocarpine model of epilepsy in mice in order to produce phenotypes that resemble human TLE. Pilocarpine was injected into mice to induce seizures. One oral dose of D4 before inducing seizures effectively reduced neuroinflammation. It also altered synaptic inhibition, which increased the animal’s survival rate. A single dose of D4 after an induced seizure also effectively limited the activation of astrocytes and microglia. This finding suggests D4 strongly alleviates neuroinflammation and has a long-term effect.
Most anti-epileptic drugs that are currently available target neurons and synapses in the brain, but this treatment does not always address the pathology of neuroinflammation. Abnormal functioning of reactive glial cells results in neuroinflammation known as astrocytes and microglia. The study suggested that D4 significantly suppresses the TLE-induced neuroinflammation, curbs seizures, and increases survival rate by blocking connexin hemichannels. 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, the researchers can specifically target neuroinflammation caused by astrocytes and microglia.