Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases

Frontiers in Molecular Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Янв. 14, 2025

Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria lysosomes, independent of mitophagy the lysosomal degradation mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk these cell compartments, regulation organelle networks, substance exchanges. Emerging evidence suggests that abnormalities mitochondria-lysosome (MLCSs) contribute to diseases, including Parkinson’s disease, Charcot–Marie-Tooth (CMT) storage epilepsy. This article reviews recent research advances regarding tethering processes, regulation, function MLCSs role

Язык: Английский

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Targeting Kv7 Potassium Channels for Epilepsy

CNS Drugs, Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 play a critical role in modulating susceptibility to seizures, mutations genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation has long been considered an attractive target search for novel antiseizure medications. Ezogabine (retigabine), first Kv7.2/3 activator introduced 2011 treatment focal was withdrawn from market 2017 due declining use after discovery its association with pigmentation changes retina, skin, mucosae. A formulation ezogabine pediatric (XEN496) recently investigated children KCNQ2-related developmental epileptic encephalopathy, but trial terminated prematurely reasons unrelated safety. Among openers clinical development, azetukalner shown dose-dependent efficacy against drug-resistant seizures good tolerability profile no evidence pigmentation-related adverse effects early studies, it is now under investigation phase III trials generalized tonic-clonic major depressive disorder. Another activator, BHV-7000, completed I studies healthy subjects, excellent at plasma drug concentrations exceed median effective preclinical model anticonvulsant activity, data patients are available date. other activators development as potential medications, pynegabine CB-003 have safety pharmacokinetic results not yet reported. Overall, interest targeting indications remains strong. Future breakthroughs area could come exploitation mechanistic differences action activators, molecules combine mechanisms action.

Язык: Английский

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A Novel Compound QO‐83 Alleviates Acute and Chronic Epileptic Seizures in Rodents by Modulating K_V7 Channel Activity

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(3)

Опубликована: Март 1, 2025

KV7 channels are promising targets for antiepileptic therapy. However, the classic channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel opener, QO-83, with good chemical stability and blood-brain barrier penetration, sought evaluate its KV7-opening activity, effects, mechanisms of action. used patch-clamp electrophysiology, electroencephalogram recordings, dynamic simulations, various epilepsy models investigate activity QO-83. Compound QO-83 exhibits greater potency at KV7.2/7.3 compared KV7.4 or KV7.5 channels. It shows superior efficacy KV7.2 voltage-dependent opening than retigabine, W236 identified as key binding site channel. significantly inhibited epileptiform discharge influenced hippocampal sEPSC sIPSC amplitudes. more effective dose 1 mg/kg in acute chronic smaller that (10 mg/kg). The higher may be attributed pocket retigabine. newly Kv7.2 advantages stable properties, strong affinity, high is expected become new drug.

Язык: Английский

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Design, synthesis, and structure-activity relationship of 5,7- dimethylbenzo[d]thiazoles as novel Kv7.2/7.3 activators with antiepileptic effects

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117660 - 117660

Опубликована: Апрель 1, 2025

Язык: Английский

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Visualizing Kv7 channels in living cells using a novel fluorescent probe

Bioorganic Chemistry, Год журнала: 2025, Номер 162, С. 108574 - 108574

Опубликована: Май 15, 2025

Язык: Английский

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