# Targeting mitochondrial PARP1 in neuronal ischemia-reperfusion injury

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $51,036

## Abstract

PROJECT SUMMARY
Cardiac arrest (CA) remains one of the most prevalent causes of disability and death in the United States with
more than 550,000 in- and out-of-hospital CA in the past year. Only 12% of out-of-hospital CA patients survive
to discharge and 85% experience mild to severe neurocognitive deficits. Ischemia-reperfusion (I/R)-induced
neuronal death occurs hours to days post-CA and is the likely cause of its high morbidity and mortality.
Unfortunately, I/R has proven resistant to most therapeutic approaches, an exception is targeted temperature
management. There are currently no effective pharmacologic-based interventions to treat brain I/R. Identifying
druggable targets for intervention has proven difficult. One ever promising source of targets is the
mitochondria, as mitochondrial dysfunction is a hallmark of reperfusion injury. I/R induces hyperactivation of
mitochondrial poly(ADP-ribose)polymerase 1 (mt-PARP1), exacerbating ATP depletion and cell death.
Interestingly, mt-PARP1 activity and corresponding mitochondrial dysfunction can be observed hours before
detection of classic nuclear PARP1 activity. This makes sense given oxidatively damaged DNA is a key trigger
for PARP activation and injured mitochondria are a key source of oxidants. Unlike the pro-DNA repair activity
of nuclear PARP1, PARP1-/- animals have increased mtDNA integrity and mitochondrial function. Therefore,
we hypothesize that selective inhibition of mt-PARP1 will increase neuronal survival by reducing energetic
depletion and improving mitochondrial function post-CA – all while sparing beneficial activity of nuclear PARP1.
In this proposal, we aim to test this hypothesis. We have conceptualized and synthesized a novel
mitochondria-specific PARP1 inhibitor (mt-veliparib). We will verify the mitochondrial targeting specificity of mt-
veliparib (Aim 1.1), determine its preliminary pharmacokinetic and toxicity profile (Aim 1.2, 1.3), confirm its
efficacy in vitro (Aim 2.1) and verify the hypothesized mechanisms of action (Aim 2.2). Early experiments have
shown mt-veliparib significantly (both in effect size and statistically) reduces oxygen-glucose deprivation and
glutamate excitotoxity-induced neuronal death. Follow-up in vivo experiments will measure the efficacy of mt-
veliparib in a murine model of CA, assessing its effects on survival and functional outcome (Aim 3). These
experiments will not only determine the role of mt-PARP1 in I/R, but they will also demonstrate the feasibility of
our generalizable hemigramicidin-mediated mitochondria targeting strategy. Most importantly, mt-PARP1
inhibition offers a chance to elucidate an effective druggable target for neuronal I/R and other mitochondrial
disorders where none currently exists.

## Key facts

- **NIH application ID:** 10140412
- **Project number:** 5F30HL142130-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Andrew Michael Lamade
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-04-30 → 2023-04-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140412

## Citation

> US National Institutes of Health, RePORTER application 10140412, Targeting mitochondrial PARP1 in neuronal ischemia-reperfusion injury (5F30HL142130-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140412. Licensed CC0.

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