Bifendate inhibits cell PARthanatos by activating the MEK/ERK pathway

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• PARthanatos is a programmed cell death pathway involved in neurodegenerative diseases and ischemic stroke.
• Conventional PARP-1 inhibitors can halt PARthanatos but may lead to genomic instability with prolonged use.

Purpose of the Study:

• To identify a novel suppressor of PARthanatos from an NMPA-approved compound library.
• To investigate the mechanism of action of Bifendate (DDB) in inhibiting PARthanatos.
• To evaluate DDB as a potential therapeutic agent for neurological disorders.

Main Methods:

• Screening of an NMPA-approved compound library to identify PARthanatos suppressors.
• Cell viability assays in HeLa and SH-SY5Y cells treated with MNNG and DDB.
• Western blotting to assess protein levels of PARP-1, AIF, and MIF.
• Mitochondrial assays to evaluate membrane potential and AIF translocation.
• ERK signaling pathway analysis (MEK, ERK activation, Bad phosphorylation).

Main Results:

• Bifendate (DDB) was identified as an effective PARthanatos suppressor.
• DDB increased cell viability by approximately 30% in HeLa and 70% in SH-SY5Y cells.
• DDB blocked AIF translocation from mitochondria without altering PARP-1, AIF, or MIF protein levels.
• DDB activated the MEK/ERK pathway, leading to Bad phosphorylation, maintaining mitochondrial integrity, and preventing AIF release.
• DDB inhibited PARthanatos downstream of PARP-1 activation without affecting PARP-1 enzymatic activity.

Conclusions:

• DDB is a promising therapeutic candidate for neurological disorders due to its ability to inhibit PARthanatos.
• DDB offers a neuroprotective strategy by modulating ERK signaling and preventing AIF-mediated cell death.
• DDB represents a safer alternative to traditional PARP-1 inhibitors, avoiding risks of genomic instability.