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Updated: Jun 3, 2026
Acute Brain Trauma in Mice Followed By Longitudinal Two-photon Imaging
Published on: April 6, 2014
A novel strategy to activate cytoprotective genes in the injured brain
Jing Zhao1, John B Redell, Anthony N Moore
1Department of Neurobiology and Anatomy, The University of Texas Medical School, PO Box 20708, Houston, TX 77225, USA. Jing.Zhao@uth.tmc.edu
Abstract:
The transcription factor nuclear factor E2-related factor 2 (Nrf2) regulates the expression of multiple cytoprotective genes that have been shown to offer protection in response to a number of insults. The present study describes a novel strategy to increase expression of Nrf2-responsive genes in brain injured mice. Under normal conditions, the adapter protein Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2 and promotes its proteosomal degradation in the cytoplasm. The amino acid sequence DEETGE, located at amino acid 77-82 of Nrf2, is critical for Nrf2-Keap1 interaction, and synthetic peptides containing this sequence can be used to disrupt the complex in vitro. We observed that intracerebroventricular (i.c.v.) infusion of a peptide containing the DEETGE sequence along with the cell transduction domain of the HIV-TAT protein (TAT-DEETGE) into brain-injured mice did not increase the mRNA levels for Nrf2-driven genes. However, when a calpain cleavage sequence was introduced between the TAT sequence and the DEETGE sequence, the new peptide (TAT-CAL-DEETGE) increased the mRNA levels of these genes. Increased gene expression was not observed when the TAT-CAL-DEETGE peptide was injected into uninjured animals. Furthermore, injection of TAT-CAL-DEETGE peptides before or after brain injury reduced blood-brain barrier compromise, a prominent secondary pathology that negatively influences outcome. The present strategy to increase Nrf2-responsive gene expression can be adapted to treat other insults or diseases based on their underlying mechanism(s) of cellular damage.
Insights
A novel peptide strategy enhances cytoprotective gene expression in brain-injured mice by disrupting the Nrf2-Keap1 interaction. This approach shows promise for treating brain injuries and other conditions.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Nuclear factor E2-related factor 2 (Nrf2) controls cytoprotective genes, crucial for cellular defense against insults.
- Kelch-like ECH-associated protein 1 (Keap1) normally degrades Nrf2 in the cytoplasm.
- The DEETGE sequence in Nrf2 is key for Keap1 binding.
Purpose of the Study:
- To develop a novel strategy for increasing Nrf2-responsive gene expression in brain-injured mice.
- To investigate the efficacy of modified peptides in modulating Nrf2 activity post-brain injury.
Main Methods:
- Intracerebroventricular (i.c.v.) infusion of peptides designed to disrupt the Nrf2-Keap1 complex in brain-injured mice.
- Utilized peptides incorporating the DEETGE sequence, HIV-TAT transduction domain, and a calpain cleavage sequence (TAT-CAL-DEETGE).
- Assessed Nrf2-responsive gene mRNA levels and blood-brain barrier integrity.
Main Results:
- A TAT-CAL-DEETGE peptide significantly increased Nrf2-driven gene expression in injured mice, unlike a TAT-DEETGE peptide.
- No increase in gene expression was observed in uninjured animals treated with TAT-CAL-DEETGE.
- TAT-CAL-DEETGE peptide administration reduced blood-brain barrier compromise following brain injury.
Conclusions:
- A novel TAT-CAL-DEETGE peptide effectively enhances Nrf2-responsive gene expression in a brain injury model.
- This peptide-based strategy shows therapeutic potential for mitigating secondary damage after brain injury.
- The approach is adaptable for treating other insults or diseases involving cellular damage mechanisms.
