# Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $592,096

## Abstract

Quality survival after brain injury is currently the greatest challenge for critically ill or injured infants and
children. A universal contributor limiting quality survivorship is the devastating impact of hypoxic-ischemic
encephalopathy (HIE), either as a primary consequence in cases of cardiac arrest, stroke, or intracranial
hemorrhage or as secondary sequelae in cases of status epilepticus, circulatory or septic shock,
neuroinflammation, or traumatic brain injury (TBI); with the principal cause of HIE spanning from infancy
through adolescence a consequence of cardiac arrest. As to-date a cure for HIE has not been discovered, a
paradigm-shifting strategy is likely necessary to improve neurological outcome for victims of HIE.
 Accordingly, we have developed a new class of therapeutics to treat HIE via preservation of critical
cellular energy stores by selectively targeting poly(ADP-ribose) polymerase (PARP) in mitochondria (mtPARP),
linking the mitochondria-targeting moieties hemi-gramicidin S (XJB) or triphenylphosphonium (TPP) to PARP
inhibitors used clinically. Ischemia-induced PARP overactivation triggered by DNA damage consumes NAD+,
generating branch chain poly(ADP-ribose) polymers (PARylation) resulting in ATP depletion, energy failure,
and cell death by necrosis and/or apoptosis-inducing factor (AIF)-mediated parthanatos. As mitochondria are
the major source of ATP and NAD+ in aerobic organisms, preservation of mitochondrial energy stores
represents a logical “druggable” target for mitigation of HIE. We recently reported that the mitochondria-
targeting PARP1 inhibitor XJB-veliparib preserves NAD+ stores and prevents neuronal death after oxygen-
glucose deprivation (OGD) in vitro at nanomolar concentrations. Importantly, XJB-veliparib selectively targets
mitochondria and thereby does not impede nuclear DNA repair in vitro. We present provocative pilot data
suggesting that XJB-veliparib and the readily translatable mitochondria-targeting compound TPP-veliparib may
be efficacious after cardiac arrest in post-natal day (PND) 17 rats, a developmental age equivalent to a young
child and a time associated with peak cerebral metabolism. This new class of therapeutics has the advantage
of preventing PARP-mediated energy failure and cell death by selectively targeting mtPARP while sparing
PARP1-facilitated nuclear DNA repair and provide a tool to definitively establish (or refute) a role for mtPARP
in the pathogenesis of HIE.
 If proven effective, mtPARP1 inhibitors would represent novel, safe (in terms of nuclear DNA repair),
and translatable therapies to mitigate HIE, with special potential in the highly vulnerable, developing brain
where metabolic rate is at its peak.

## Key facts

- **NIH application ID:** 9993658
- **Project number:** 1R01NS117000-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Hülya Bayir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $592,096
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993658

## Citation

> US National Institutes of Health, RePORTER application 9993658, Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia (1R01NS117000-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993658. Licensed CC0.

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