The anticonvulsive Phenhydan^® suppresses extrinsic cell death

Area of Science:

• Cell Biology
• Pharmacology
• Immunology

Background:

• Regulated cell death, including apoptosis and necroptosis, plays a role in various diseases like myocardial infarction and multiple sclerosis.
• Receptor-interacting serine/threonine protein kinase 1 (RIPK1) activity is critical for controlling cell fate in inflammation and cell death.
• Currently, no drugs targeting RIPK1-mediated cell death are approved for clinical use.

Purpose of the Study:

• To screen existing clinical compounds for their ability to inhibit RIPK1-mediated cell death.
• To identify potential therapeutic agents for diseases involving aberrant cell death pathways.

Main Methods:

• A small-scale screen of clinical compounds was performed.
• The compounds' ability to modulate RIPK1-mediated cell death was assessed.
• Phenhydan® was identified as a potent inhibitor.

Main Results:

• Phenhydan® effectively inhibited death receptor-induced necroptosis and apoptosis.
• The drug blocked necrosome formation/activation and death receptor-induced NF-κB signaling.
• Phenhydan® influenced cell membrane functions, including lipid raft formation.

Conclusions:

• Phenhydan®, an anti-epilepsy drug, is a potent inhibitor of RIPK1-mediated cell death.
• By targeting death receptor signaling and influencing membrane function, Phenhydan® may offer new therapeutic avenues.
• This FDA-approved drug presents a potential strategy for treating inflammation-driven diseases characterized by abnormal cell death.