# A novel BDNF potentiator for the treatment of neonatal brain injury

> **NIH NIH R21** · BROWN UNIVERSITY · 2024 · $268,020

## Abstract

Perinatal brain injury resulting in intellectual impairment and cerebral palsy affects more than 10,000 infants
each year in the United States (1 to 3 per 1000 births). There is no therapy other than supportive care to
prevent brain damage in hypoxic-ischemic (HI) encephalopathy (HIE) in premature infants. Due to the
complex nature of the pathophysiological events, single-mechanism drug interventions in clinical studies
have failed, and there remains an unmet medical need for therapeutics that prevent secondary neuronal
damage. Brain-derived neurotrophic factor (BDNF) through activation of its high affinity receptor, TrkB, is a
key player in promoting learning, and therapeutic strategies to enhance BDNF signaling protect against HI-
induced injury. Treatment with systemic BDNF is limited by its short plasma half-life and poor brain
penetration. Our research has circumvented these limitations through the development of cyclized-peptides
targeting PSD-95, a TrkB associated synaptic scaffolding protein required for BDNF-induced signaling. We
developed a macrocyclic compound, Syn3, that specifically binds the PDZ3 domain of PSD-95. Syn3
increases the recruitment of PSD-95 to TrkB to augment prosurvival signaling. Attached to the macrocycle
is a cell–penetrating C-R(7) moiety that further mediates neuroprotection by reducing mitochondrial
membrane hyperpolarization and the generation of reactive oxygen species. In a series of preclinical
studies in a HI rodent model we found that Syn3 rapidly penetrates the CNS to reduce the degree of injury.
The overall goal is to investigate the efficacy of our newly defined neuroprotective and immunomodulatory
peptidomimetic, Syn3, to attenuate HI-related brain damage in the neonate. We hypothesize that
administration of the optimal dose of Syn3 during the therapeutic time window will reduce brain injury,
decrease neuronal and glial cell death, decrease apoptosis, free radical exposure and improve short and
long-term behavioral outcomes. In Aim 1 we will determine the optimal dose and therapeutic time window
for neuroprotection with Syn3 after HI related brain injury in the neonate. Aim 2 will assess the short and
long-term neuroprotective efficacy of Syn3 administration after HI related brain injury on molecular (Aim
2.1) and behavioral (Aim 2.2) outcomes.

## Key facts

- **NIH application ID:** 10887723
- **Project number:** 1R21NS133544-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Xiaodi Felix Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $268,020
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887723

## Citation

> US National Institutes of Health, RePORTER application 10887723, A novel BDNF potentiator for the treatment of neonatal brain injury (1R21NS133544-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10887723. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*