Structure-based discovery of CZL80, a caspase-1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
06
10
2019
revised:
08
04
2020
accepted:
09
04
2020
pubmed:
30
4
2020
medline:
22
6
2021
entrez:
30
4
2020
Statut:
ppublish
Résumé
Febrile seizures (FS), the most common seizures in childhood and often accompanied by later epileptogenesis, are not well controlled. Inflammatory processes have been implicated in the pathophysiology of epilepsy. However, whether caspase-1 is involved in FS generation and could be a target for the treatment of FS is still unclear. By using pharmacological and gene intervention methods in C57BL/6J mice, we assessed the role of caspase-1 in FS generation. We used structural virtual screening against the active site of caspase-1, to screen compounds for druggable and safe low MW inhibitors of caspase-1 in vitro. One compound was chosen to test in vivo for therapeutic potential, using FS models in neonatal mice and epileptogenesis in adult mice. In mice, levels of cleaved caspase-1 increased prior to FS onset. Caspase-1 Caspase-1 is essential for FS generation. CZL80 is a promising low MW inhibitor of FS and later enhanced epileptogenic susceptibility.
Sections du résumé
BACKGROUND AND PURPOSE
Febrile seizures (FS), the most common seizures in childhood and often accompanied by later epileptogenesis, are not well controlled. Inflammatory processes have been implicated in the pathophysiology of epilepsy. However, whether caspase-1 is involved in FS generation and could be a target for the treatment of FS is still unclear.
EXPERIMENTAL APPROACH
By using pharmacological and gene intervention methods in C57BL/6J mice, we assessed the role of caspase-1 in FS generation. We used structural virtual screening against the active site of caspase-1, to screen compounds for druggable and safe low MW inhibitors of caspase-1 in vitro. One compound was chosen to test in vivo for therapeutic potential, using FS models in neonatal mice and epileptogenesis in adult mice.
KEY RESULTS
In mice, levels of cleaved caspase-1 increased prior to FS onset. Caspase-1
CONCLUSION AND IMPLICATIONS
Caspase-1 is essential for FS generation. CZL80 is a promising low MW inhibitor of FS and later enhanced epileptogenic susceptibility.
Identifiants
pubmed: 32346861
doi: 10.1111/bph.15076
pmc: PMC7348094
doi:
Substances chimiques
Serpins
0
Viral Proteins
0
interleukin-1beta-converting enzyme inhibitor
96282-35-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3519-3534Subventions
Organisme : National Natural Science Foundation of China
ID : 81630098
Organisme : National Natural Science Foundation of China
ID : 81521062
Organisme : Young Elite Scientist Sponsorship Program by CAST
ID : 2018QNRC001
Informations de copyright
© 2020 The British Pharmacological Society.
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