# Oxidative Stress and Pathological Glutamate Release in Stroke

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2022 · $364,450

## Abstract

SUMMARY
Stroke is the fifth leading cause of death and the leading cause of adult long-term disability in the U.S. and other
industrialized nations. Yet only one therapeutic agent (the clot-dissolving drug tPA) is approved for acute
treatment. Among the critical injurious factors in stroke, oxidative stress is thought to contribute to the terminal
steps of tissue damage. Antioxidants and free radical scavengers are highly protective in animal stroke models.
Yet, for poorly understood reasons, they have shown limited or no benefits in clinical trials. In the prior NIH-
sponsored project, we collected strong data which may help to revise our understanding of the mechanisms
contributing to oxidative injury in ischemia: (1) In a rat model of stroke, we found that the superoxide dismutase
(SOD) mimetic tempol was more protective than clinically used antioxidants. (2) Potent protection by tempol
correlated with reduction of redox-sensitive glutamate release in the ischemic penumbra. (3) Glutamate release
was mediated by at least two redox-sensitive mechanisms: volume-regulated anion channels (VRAC) and Ca2+-
dependent changes in membrane permeability. (4) The glutamate-permeable VRAC was composed of proteins
from the leucine-rich repeat-containing family 8 (LRRC8). We have assembled a synergistic team of investi-
gators and propose to use highly innovative molecular and animal tools to test the HYPOTHESIS that reactive
oxygen species (ROS, particularly superoxide anions) propagate and amplify stroke injury via stimulation
of redox-sensitive glutamate release in the clinically relevant penumbra. In the planned studies we will
address the following critical questions: (1) Is the LRRC8A-containing VRAC a viable target for neuroprotection
in stroke? (2) Is glutamate release via the heteromeric LRRC8 channels responsible for tissue injury? (3) What
is the chemical nature of the tempol-targeted ROS and the cellular site of their production? (4) Does glutamate
release via VRAC drive disruption at the neurovascular interface (changes in blood flow and BBB integrity)? The
immediate goal of the proposed work is to identify new molecular mechanisms that govern oxidative brain
injury and determine the protective actions of antioxidants. Our long-term objective is to provide a blueprint
for the development of new effective stroke therapies based on SOD mimetics and/or VRAC blockers.

## Key facts

- **NIH application ID:** 10335287
- **Project number:** 5R01NS111943-04
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** Alexander A Mongin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,450
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335287

## Citation

> US National Institutes of Health, RePORTER application 10335287, Oxidative Stress and Pathological Glutamate Release in Stroke (5R01NS111943-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10335287. Licensed CC0.

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