# Nrf2-Antioxidant Response Element Neuroprotection in TBI

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $329,219

## Abstract

ABSTRACT
 Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our most
validated secondary injury mechanisms, and thus remains a highly rational neuroprotective target that
continues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs.
In addition to chemically scavenging free radicals, there is increasing interest in the possibility of
pharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as a
neuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclear
factor E2-related factor) which interacts with the antioxidant response element (ARE) of various
cytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurological
injury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuse
weight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specific
elements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male and
female mice. This will be followed by a systematic dose-response evaluation of the comparative potency
and efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards to
its ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective
dose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damage,
preserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-induced,
calpain-mediated neuronal cytoskeletal damage, all surrogate markers of secondary brain injury. After
completion of those experiments, the ability of repeated administration of the best dose of carnosic acid
will be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor and
cognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies will
test the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBI
models can be acutely neuroprotective and form the basis for the discovery of more effective and fast-
acting Nrf2 inducing compounds for acute and chronic neurodegeneration.

## Key facts

- **NIH application ID:** 9930664
- **Project number:** 5R01NS100093-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** EDWARD D. HALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,219
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930664

## Citation

> US National Institutes of Health, RePORTER application 9930664, Nrf2-Antioxidant Response Element Neuroprotection in TBI (5R01NS100093-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9930664. Licensed CC0.

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