# DELAYED HYPOXEMIA FOLLOWING TRAUMATIC BRAIN INJURY: A NEW TARGET FOR NEUROPROTECTIVE THERAPEUTICS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $333,594

## Abstract

ABSTRACT
 Despite advances in care, morbidity following traumatic brain injury (TBI) remains high. Notably, all
therapeutics for primary TBI that have shown promise in preclinical animal models have failed to demonstrate
efficacy in humans, a lost in translation phenomenon. Treatment of secondary insults to TBI patients while in
the intensive care setting provides a unique opportunity for therapeutic interventions. Specifically, patients with
TBI in the intensive care setting are at high risk for unavoidable hypoxemia and brain hypoxia due to
pulmonary contusions, aspiration, and as a result of required procedural interventions. To explicitly model the
contribution of secondary brain hypoxia, we have developed a clinically relevant murine model of TBI with
delayed hypoxemia. Our objective is to test therapeutics that may mitigate secondary injury from delayed
hypoxemia following TBI. We propose a rigorous preclinical trial funnel design including adequate sample
sizes, minimization of bias, validation/replication of results, clinically relevant long term outcomes, and testing
of sex and genotype factors, as recommended by NINDS and others, to establish a framework for efficient
testing of potential candidate therapeutics. Preliminary screening of several candidate therapeutics in our
translational model has identified three FDA approved agents with potential short term efficacy: epoetin alfa
(EPO), minocycline (MINO), and N-acetylcysteine (NAC). We hypothesize that targeting brain hypoxia after
TBI in the ICU setting will overcome many of the barriers of previous therapeutic failures, permit rapid
administration of neuroprotective agents with short temporal windows of efficacy, and improve outcomes. We
will first evaluate short term neuroprotective efficacy of three therapeutic candidates (EPO, MINO, and NAC)
following brain hypoxia after TBI. We will study 3 different doses and 2 treatment start times for each candidate
therapeutic in a randomized, placebo controlled fashion. To assess initial efficacy, we will determine lesion
volume and perform rigorous blinded quantification of immunohistochemistry for severity of axonal injury as
well as hippocampal neuronal protection using our novel high throughput automated image analysis. In Aim 2
we will evaluate long term neuroprotective efficacy of therapeutic candidates for brain hypoxia after TBI with
behavioral testing 6 months after initial injury. We will validate our findings by replicating drug candidate
dosing and timing studies in a second laboratory by investigators not involved in the initial studies. Finally in
Aim 3, to improve the likelihood of successful translation, we will determine sex-distinct responses to
therapeutics. Our approach with an enhanced animal model with a clinically relevant delayed secondary insult
and rigorous preclinical study design has excellent potential to yield a high probability of effective translation to
success in human studies and rapidly eliminate therape...

## Key facts

- **NIH application ID:** 10130634
- **Project number:** 5R01NS097721-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STUART H FRIESS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130634

## Citation

> US National Institutes of Health, RePORTER application 10130634, DELAYED HYPOXEMIA FOLLOWING TRAUMATIC BRAIN INJURY: A NEW TARGET FOR NEUROPROTECTIVE THERAPEUTICS (5R01NS097721-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130634. Licensed CC0.

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