# Metabolic origin of oxidative stress injury in brain ischemia/reperfusion

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $254,250

## Abstract

Summary:
 The annual worldwide mortality from perinatal hypoxic-ischemic (HI) insult is ~1.2 million.
In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy and life-
long neurological disability. The lifetime cost for patients with cerebral palsy is estimated to be
$11.5 billion per affected individual. This dictates a need for therapeutic strategies based on a
better understanding of the mechanisms of HI injury.
 HI-reperfusion-associated disruption in glycolysis, the Krebs cycle, mitochondrial energy
production, nitrogen metabolism, and oxidative stress negatively affect the survival of cerebral
brain cells. These are the major factors contributing to brain tissue damage in HI. However,
neither the exact mechanisms of the so-called secondary energy failure nor the origin of
oxidative stress in ischemia/reperfusion are known. We propose that brain oxygen deprivation
leads to degradation of amino acids and purine nucleotides resulting in the accumulation of
ammonia (NH4+). This, in turn, activates reactive oxygen species (ROS) production by the
mitochondrial enzyme -ketoglutarate dehydrogenase during reperfusion causing oxidative
injury. Our preliminary data identify the presence of this metabolic cascade in the HI brain
prompting further study.
 In the proposed study, we will pursue the novel hypothesis that increased ROS generation
and mitochondrial bioenergetics failure correlated with ischemic NH4+ accumulation. This is
consistent with all experimental data observed in HI and stroke models. This is a new, insofar
unrecognized, and unexplored mechanism of injury, which explains the published experimental
data showing the transient burst of ROS during brain ischemia/reperfusion. The data obtained in
this study will significantly alter the current paradigm of the origin of neuronal
ischemia/reperfusion damage. We aim to define the major role of NH4+ in stimulation of
mitochondria ROS production during bioenergetics failure in neonatal HI. The preclinical impact
of this project is to provide a rationale for further clinical studies aimed at the reduction of post-
HI brain injury.

## Key facts

- **NIH application ID:** 10354477
- **Project number:** 1R21NS125466-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alexander Galkin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2022-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354477

## Citation

> US National Institutes of Health, RePORTER application 10354477, Metabolic origin of oxidative stress injury in brain ischemia/reperfusion (1R21NS125466-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10354477. Licensed CC0.

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