Celowanie w budowę HMGB1 nowatorskim antagonistą: innowacyjna strategia terapeutyczna do hamowania zapalenia nerwowego inicjowanego przez HMGB1 w epilepsji
Targeting HMGB1 Conformation with a Novel Antagonist: An Innovative Therapeutic Strategy to Inhibit HMGB1-Initiated Neuroinflammation in Epilepsy
W skrócie
[Preprint - wstępne wyniki] Badacze testują nowy lek o nazwie GP10, który zmienia strukturę białka HMGB1 odpowiedzialnego za zapalenie mózgu u pacjentów z epilepsją. W eksperymentach na myszach lek zmniejszył napady padaczkowe poprzez redukcję strat neuronów i zapalenia, co sugeruje obiecujący kierunek do opracowania nowych leków przeciwpadaczkowych działających na przyczynę, a nie tylko objawy choroby.
Oryginalny abstract (angielski)
Abstract Epilepsy is a cerebral dysfunction disorder caused by aberrant hyperexcitability of neurons, and novel therapeutics targeting core epileptogenic mechanisms are urgently needed. Sustained neuroinflammation accumulates post-seizure in epileptic foci, which further drives recurrent seizures. High-mobility group box 1 (HMGB1), a vital damage-associated molecular pattern (DAMP), mediates the initiation and progression of epileptogenic inflammation. Therefore, we propose a novel anti-epileptic strategy: modulating the spatial conformation of HMGB1 to block the pro-inflammatory function and alleviate secondary inflammatory injury to epileptic lesions. To validate this strategy, GP10, a tetrahydroprotoberberine (THPB) derivative selectively suppressing HMGB1 pro-inflammatory activity, was utilized as a tool compound to interfere with HMGB1-triggered neuroinflammation. Mechanistically, GP10 specifically bound to phenylalanine 89 and induced conformational changes in HMGB1, which underpinned the selective suppression by GP10 of HMGB1-triggered inflammatory cascades at the cellular level. In the pilocarpine-induced mouse epilepsy model, GP10 markedly attenuated neuronal loss and neuroinflammation triggered by neuronal hyperexcitability, thereby alleviating secondary recurrent seizures. Collectively, this study demonstrated that targeting HMGB1-initiated inflammatory signaling is an effective strategy to ameliorate and retard epileptic seizures, providing novel mechanistic insights for discovering natural anti-epileptic drugs.