[Peptide drug cortexin inhibits brain caspase-8]

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Cortexin, a hydrolyzed brain peptide preparation, is clinically used, but its neuroprotective mechanisms are not fully understood.
• Existing research has not elucidated the specific molecular targets responsible for Cortexin's therapeutic effects.

Purpose of the Study:

• To investigate the hypothesis that Cortexin's neuroprotective action is mediated by the inhibition of brain proteases.
• To identify the specific proteases inhibited by Cortexin and their role in neuronal protection.

Main Methods:

• Assayed Cortexin's inhibitory activity against various brain proteases including caspases, cathepsin B, and calpain.
• Isolated a peptide fraction from Cortexin to assess its inhibitory capacity.
• Evaluated the neuroprotective effects of Cortexin and its fraction in a glutamate-induced neuronal cell death model.

Main Results:

• Cortexin demonstrated significant inhibition of brain caspase-8.
• Inhibitory effects on other proteases like caspase-1, -3, -9, cathepsin B, and calpain were minimal or absent.
• A simplified peptide fraction of Cortexin retained the full inhibitory activity.
• Both Cortexin and its fraction conferred neuroprotection against glutamate-induced cell death in neuronal cultures.

Conclusions:

• The neuroprotective effects of Cortexin may be attributed to its ability to inhibit the initiator caspase-8 in the brain.
• Targeting caspase-8 represents a potential therapeutic strategy for neuroprotection.