# Neuroprotection after TBI

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2021 · —

## Abstract

Traumatic brain injury (TBI) is one of the leading causes of disability in service personnel and veterans. The
effects of TBI in surviving veterans can often be seen for decades after the initial injury. Oxidative stress and
endoplasmic reticulum (ER) stress that starts within hours and continues for days are known promoters of
neuronal death that lead to long-term neurological deficits after TBI. Importantly oxidative stress and ER stress
potentiate each other and act synergistically. Hence, the goal of this proposal is to test if controlling oxidative
stress and ER stress is beneficial after TBI. Oxidative stress is induced mainly by the reactive oxygen species
(ROS). Hence, we will test a combo therapy that minimizes generation of ROS (by inhibiting NADPH oxidase
NOX2) and concomitantly potentiates disposal of ROS (by inducing the antioxidant transcription factor Nrf2)
decreases brain damage and promotes better motor and cognitive recovery following TBI. We will use a combo
of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 inducer) in both males and females at different ages subjected to
TBI. Furthermore, disruption of ER function after TBI leads to accumulation of unfolded proteins that start ER
stress and also induce ROS generation. A major ER stress pathway is mediated by PERK and its downstream
apoptotic genes. Hence, we will test if combining the antioxidant combo therapy with salubrinal (inhibitor of
PERK pathway) provides a better efficacy to protect brain and promote functional recovery after TBI. We will
also test the long-term consequences and the mechanisms of protection of the combo therapy in both males
and females subjected to TBI. As a long-term complication of TBI is the development of Parkinson's disease
(PD), we will test if the combo therapy during acute phase minimizes PD propensity during the chronic phase
after TBI.
We will test the hypothesis that an antioxidant combination therapy protects the brain and promotes long-term
functional gains in both sexes at different ages after TBI. We further hypothesize that preventing oxidative
stress and ER stress together is more efficacious to protect the brain and to promote neurological recovery
after TBI. We also hypothesize that controlling oxidative stress decreases the propensity of Parkinson's
disease (PD) pathology after TBI.
• Aim 1 will test the minimal efficacious dose, window of opportunity, effect of age and sex for the antioxidant
 combo (apocynin + TBHQ) therapy after TBI.
• Aim 2 will test if adding salubrinal increases the efficacy of antioxidant combo to protect brain and promotes
 better functional recovery after TBI.
• Aim 3 will test the long-term outcomes including motor function, cognitive function, neuropsychiatric
 function, gray and white matter damage and putative mechanisms of protection for the best combo therapy
 after TBI. This aim will further test if the combo therapy decreases the sensitivity of onset of PD-like
 pathology at a chronic stage after TBI.
Ov...

## Key facts

- **NIH application ID:** 10158429
- **Project number:** 5I01BX004344-03
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Raghu VEMUGANTI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158429

## Citation

> US National Institutes of Health, RePORTER application 10158429, Neuroprotection after TBI (5I01BX004344-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158429. Licensed CC0.

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