Temporal lobe epilepsy (TLE) is likely one of the commonest sorts of epilepsy worldwide. Though symptomatic drugs can be found, one-third of TLE sufferers stay unresponsive to present remedy, so new drug targets are critically wanted. A analysis crew co-led by a Metropolis College of Hong Kong (CityU) neuroscientist lately recognized and developed a brand new drug candidate that has the potential for successfully treating TLE by suppressing neuroinflammation.
Epilepsy is likely one of the most prevalent power mind problems and is characterised by recurrent and spontaneous seizures. Most anti-epileptic medicine which are presently accessible goal neurons and synapses within the mind. They’re efficient in altering neural circuits and synapses, however this remedy overlooks one other necessary pathology: neuroinflammation.
Neuroinflammation is brought on by the irregular functioning of reactive glial cells, corresponding to astrocytes and microglia, inflicting an immune response within the mind. Accumulating proof factors to a key position of connexin-based hole junctions and hemichannels in mind glial cells in TLE. A hemichannel is a channel or pathway shaped by the meeting of six proteins, which permits small molecules corresponding to glutamate to be launched from astrocytes and microglia to extracellular house. A niche junction is shaped when the hemichannels of two adjoining cells dock with one another, as proven in right here (Determine 1). However inhibiting each hole junctions and hemichannels can result in undesirable uncomfortable side effects as a result of the previous coordinate physiological features of cell assemblies. Due to this fact, scientists must discover a strategy to block solely connexin hemichannels to successfully cut back neuroinflammation with fewer uncomfortable side effects.
A analysis crew co-led by Dr Geoffrey Lau Chun-yue, Assistant Professor within the Division of Neuroscience, recognized a brand new, small natural molecule referred to as D4, which selectively blocks connexin hemichannels, however not hole junctions. The crew investigated its impact in treating TLE utilizing a mouse mannequin. The findings counsel that D4 strongly suppresses the TLE-induced neuroinflammation, curbs TLE seizures, and will increase the animal’s survival price.
The findings had been revealed within the worldwide scientific journal Proceedings of the Nationwide Academy of Sciences of the US of America (PNAS) below the title “Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy”.
New drug D4 suppresses neuroinflammation
“These are very thrilling and inspiring outcomes for translational analysis in epilepsy,” stated Dr Lau. “Now we have discovered a really promising new drug candidate for treating epilepsy that works by way of a brand new mechanism – blocking connexin hemichannels. Our findings additionally spotlight the necessary involvement of neuroinflammation in neurological problems corresponding to epilepsy.”
The brand new drug, D4, targets a brand new class of ion channels, the connexin hemichannels within the glial cells. Glial cells embrace astrocytes and microglia and are necessary for modulating neurotransmission. Extreme glutamate and different molecules can leak out from reactive glia through hemichannels to the extracellular setting, altering synapses, enhancing neuroinflammation and exacerbating seizures. By particularly blocking connexin hemichannels utilizing D4, Dr Lau’s crew can immediately goal neuroinflammation brought on by astrocytes and microglia.
The analysis adopted the pilocarpine mannequin of epilepsy in mice, a well known mannequin to provide phenotypes that resemble human TLE. Pilocarpine was injected into mice intraperitoneally to induce seizures. The administration of 1 dose of D4 orally earlier than inducing seizures successfully lowered neuroinflammation and altered synaptic inhibition, which elevated the animal’s survival price. For remedy after induced seizures, a single dose of D4 had a chronic impact on suppressing the activation of astrocytes and microglia. This means that D4 strongly alleviates neuroinflammation and has a long-term impact.
A single dose presents long-term advantages
Outcomes from each pre- and post-treatment point out that concentrating on connexion hemichannels by D4 is an efficient and promising technique for treating epilepsy wherein neuroinflammation performs a vital position. The drug might be taken orally to successfully get into the mouse mind to scale back the dangerous results of neuroinflammation. A single dose offers robust safety towards future seizures. “We hope that this may finally lead to new and higher remedy choices for epileptic sufferers,” stated Dr Lau. The crew will proceed to work on the astrocytic mechanisms of epilepsy and figuring out extra new therapeutic targets.
Reference: Guo A, Zhang H, Li H, et al. Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy. PNAS. 2022;119(45):e2213162119. doi: 10.1073/pnas.2213162119
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