Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Calpains are implicated in neurodegeneration, but specific isoform functions remain unclear.
• Calpain-1 and calpain-2 exhibit opposing roles in synaptic plasticity, learning, and neurodegeneration.
• Understanding these distinct roles is crucial for developing targeted neuroprotective therapies.

Purpose of the Study:

• To investigate the opposing roles of calpain-1 and calpain-2 in brain function.
• To develop selective calpain-2 inhibitors for potential therapeutic applications.
• To evaluate the neuroprotective and cognitive-enhancing effects of calpain-2 inhibitors.

Main Methods:

• Utilized calpain-1 knockout mice and forebrain-specific calpain-2 deletion models.
• Conducted medicinal chemistry campaigns to identify selective calpain-2 inhibitors.
• Assessed inhibitor efficacy in animal models of acute neurodegeneration and learning tasks.

Main Results:

• Calpain-1 activation is essential for synaptic plasticity, learning, and neuroprotection.
• Calpain-2 activation impairs synaptic plasticity, learning, and promotes neurodegeneration.
• Selective calpain-2 inhibitors facilitated learning and demonstrated neuroprotection in preclinical models.
• NA-184, a selective calpain-2 inhibitor, is advancing to clinical trials for traumatic brain injury.

Conclusions:

• Calpain-1 and calpain-2 possess distinct, opposing functions in the brain.
• Targeting calpain-2 with selective inhibitors represents a viable therapeutic strategy for neurodegenerative conditions.
• Further development of calpain-2 inhibitors, such as NA-184, holds significant potential for treating brain injuries and diseases.