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Spatial Measurement and Inhibition of Calpain Activity in Traumatic Brain Injury with an Activity-Based
Marianne I Madias1, Lilyane N Stessman1, Sophia J Warlof1
1Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States.
ACS Nano
|September 5, 2024
Summary
Researchers developed an activity-based nanotheranostic (ABNT) to sense and inhibit calpain activity following traumatic brain injury (TBI). This ABNT targets specific brain cells and regions, aiding in understanding TBI progression and informing new drug designs.
Area of Science:
- Neuroscience and Pharmacology
- Biomaterials and Nanotechnology
Background:
- Traumatic brain injury (TBI) causes significant neurological damage due to sustained calpain protease activation.
- Calpain inhibition is a key therapeutic strategy for TBI, requiring precise measurement of its activity in injured brain tissue.
Purpose of the Study:
- To design and evaluate an activity-based nanotheranostic (ABNT) capable of both sensing and inhibiting calpain activity in TBI.
- To assess the ABNT's ability to target specific brain regions and cell types affected by TBI.
Main Methods:
- Designed an ABNT by scaffolding calpain-sensing (fluorophore/quencher peptide substrate) and inhibiting (calpastatin peptide) components onto a polymeric nanoscaffold.
- Tested ABNT's efficacy in vitro with recombinant calpain and in a mouse model of TBI, analyzing its distribution and effects on calpain activity in different brain structures and cell types (neurons, endothelial cells, microglia).
Main Results:
- The ABNT successfully sensed and inhibited calpain activity in vitro.
- Systemically administered ABNT reached perilesional brain tissue in TBI mice, inhibiting calpain activity in the cortex and hippocampus.
- ABNT demonstrated cell-specific inhibition in cortical neurons, endothelial cells, and microglia, with greater efficacy in cortical versus hippocampal neurons, and showed structure-dependent effects on apoptosis.
Conclusions:
- The developed ABNT platform provides a tool for precise, regional, and cell-specific monitoring and inhibition of calpain activity in TBI.
- This theranostic approach can advance the understanding of TBI pathophysiology and guide the development of targeted therapeutics for TBI.
