Raloxifene Prevents Chemically-Induced Ferroptotic Neuronal Death In Vitro and In Vivo

Area of Science:

• Cell Death and Survival
• Neurobiology
• Drug Discovery

Background:

• Ferroptosis is iron-dependent cell death involving lipid peroxidation.
• Protein disulfide isomerase (PDI) mediates chemically induced ferroptosis.
• Raloxifene (RAL) is known for neuroprotective effects.

Purpose of the Study:

• To investigate raloxifene's (RAL) effect on protein disulfide isomerase (PDI) and ferroptosis.
• To elucidate the mechanism of RAL's neuroprotection.
• To evaluate RAL's efficacy in vitro and in vivo.

Main Methods:

• In vitro and in situ binding assays of RAL to PDI.
• Biochemical analysis of PDI catalytic activity and His256 mutation.
• Assessment of nitric oxide synthase dimerization and nitric oxide accumulation.
• In vivo kainic acid-induced memory deficit and hippocampal damage models in mice.

Main Results:

• RAL directly binds to and inhibits PDI's catalytic activity.
• RAL's inhibition of PDI reduces nitric oxide synthase dimerization and nitric oxide accumulation.
• RAL protects HT22 neuronal cells from chemically induced ferroptosis.
• RAL treatment prevents memory deficits and hippocampal damage in mice.

Conclusions:

• Raloxifene (RAL) is a potent inhibitor of protein disulfide isomerase (PDI).
• RAL effectively prevents ferroptosis in hippocampal neurons via PDI inhibition.
• This study reveals an estrogen receptor-independent neuroprotective mechanism for RAL.