# Nitric Oxide Metabolism in Acute Traumatic Brain Injury

> **NIH NIH R21** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $413,927

## Abstract

Cerebral contusion (CC), the most common form of traumatic brain injury (TBI), is often associated with blood-
brain barrier (BBB) disruption, vasogenic cerebral edema (VCE), increased intracranial pressure (ICP), and
intracranial hemorrhage (ICH) resulting in severe disability or death. Thrombin has been implicated in BBB
disruption and VCE following the injury, but its inhibition without considering the ICH is potentially risky as
thrombin inhibition can cause more bleeding. Recently, our laboratory reported novel findings of CC-induced
imbalance of endothelial nitric oxide (NO) redox metabolites (peroxynitrite/ONOOˉ > S-nitrosoglutathione/GSNO)
as a potential target to attenuate early events of thrombin-induced BBB disruption. In cultured brain endothelial
cells, thrombin-induced ONOOˉ synthesis led to RhoA-mediated endothelial barrier disruption. On the other hand,
GSNO treatment inhibited thrombin-induced endothelial barrier disruption via inhibiting RhoA-mediated
mechanisms. Based on these findings, the goal of this proposal is to evaluate drugs targeting imbalanced NO
redox metabolites (ONOOˉ > GSNO) for inhibition of non-hemostatic thrombin activity and associated vascular
pathology in TBI. ONOOˉ inhibits platelet activity for hemostatic blood coagulation. For this reason, scavenging
ONOOˉ by its scavenger FeTPPS might be also beneficial for control of bleeding as well as protection of BBB
disruption. Alternatively, systemic exogenous GSNO treatment might also be beneficial for BBB protection.
However, it is potentially risky, if the injury involves active ICH, because of its anti-platelet activity in the blood.
GSNO is synthesized intracellularly and is not readily diffusible across the cell membrane. In the cells, GSNO is
degraded by cytosolic enzyme GSNO reductase (GSNOR) and thus its inhibition primarily increases intracellular
GSNO levels while minimizing the elevation of GSNO in blood. Based on the above rationale, we hypothesize
that N6022 (inhibitor of GSNOR) will provide better outcomes than systemic GSNO treatment by increasing
the intracellular GSNO levels, thus inhibiting the endothelial cell signaling for BBB disruption, while minimizing
the elevation of blood GSNO levels, thus sparing the blood coagulation activity. We further hypothesize that
scavenging ONOOˉ by FeTTPs also provide additional efficacy by inhibiting the pathological role of ONOOˉ in
BBB disruption as well as blood coagulation. To test these hypotheses, the proposed specific aims are;
Aim 1: To evaluate the efficacy of NO-metabolomic drugs (GSNO, N6022, and FeTPPS) on primary vs.
 secondary injuries following the CC.
Aim 2: To investigate the role of NO-metabolomic drugs on hemostatic blood coagulation process
 and BBB disruption induced by non-hemostatic endothelial cell signaling pathway.
 The proposed studies are built upon our recent findings identifying NO metabolome as a novel target of
VCE. If successful, these studies will result in new insights into ...

## Key facts

- **NIH application ID:** 10055288
- **Project number:** 1R21NS114433-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Jeseong Won
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,927
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055288

## Citation

> US National Institutes of Health, RePORTER application 10055288, Nitric Oxide Metabolism in Acute Traumatic Brain Injury (1R21NS114433-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10055288. Licensed CC0.

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