Apoptotic mechanism in human brain microvascular endothelial cells triggered by 4'-iodo-α-pyrrolidinononanophenone:...

Area of Science:

• Medicinal Chemistry
• Cell Biology
• Toxicology

Background:

• α-pyrrolidinononanophenone (α-PNP) derivatives are investigated for their biological activities.
• Understanding structure-activity relationships is crucial for developing new therapeutic agents.
• The blood-brain barrier model using brain microvascular endothelial (HBME) cells is vital for neurovascular research.

Purpose of the Study:

• To synthesize and analyze the structure-cytotoxicity relationship of novel α-PNP derivatives.
• To elucidate the apoptotic mechanism of the most potent derivative, 4'-iodo-α-PNP (I-α-PNP), in HBME cells.
• To investigate the role of oxidative stress and proteasome activity in I-α-PNP-induced apoptosis.

Main Methods:

• Synthesis of four α-PNP derivatives, including 4'-halogenated compounds and α-pyrrolidinodecanophenone (α-PDP).
• Structure-cytotoxicity relationship analysis.
• Assessment of apoptotic events (caspase-3 activation, phosphatidylserine externalization, DNA fragmentation) in HBME cells.
• Measurement of reactive oxygen species (ROS) production, antioxidant levels, and proteasome activity.

Main Results:

• Cytotoxicity ranking: α-PNP < α-PDP < 4'-fluoro-α-PNP < 4'-chloro-α-PNP < 4'-bromo-α-PNP < I-α-PNP.
• I-α-PNP induced apoptosis in HBME cells, characterized by caspase-3 activation, phosphatidylserine externalization, and DNA fragmentation.
• Apoptosis was mediated by enhanced mitochondrial ROS production, evidenced by increased hydroxyl radical.
• I-α-PNP treatment decreased reduced glutathione and 26S proteasome activity, leading to aggresome formation.

Conclusions:

• 4'-halogenated α-PNP derivatives exhibit significantly higher cytotoxicity than α-PDP.
• I-α-PNP induces apoptosis in HBME cells through a ROS-dependent mechanism involving mitochondrial dysfunction.
• Impaired antioxidant capacity and proteasome activity contribute to I-α-PNP-induced apoptosis, highlighting its potential as a neurotoxic agent.