# Erythropoietin and Melatonin Combination Therapy for Perinatal Opioid-Induced Brain Injury

> **NIH NIH U18** · JOHNS HOPKINS UNIVERSITY · 2020 · $245,625

## Abstract

SUMMARY
The prevalence of Neonatal Opioid Withdrawal Syndrome (NOWS) has risen 5-fold in the past decade, and is a
well-recognized consequence of perinatal opioid exposure (POE). By contrast, the long-term damage to the
developing brain from opioid medications is just beginning to be recognized as a serious concern. No study has
directly addressed repair of the developing brain secondary to opioid-induced neural injury. Thus, in response to
this immense gap in knowledge and significant need for therapeutic strategies that improve brain health and
function in vulnerable infants with opioid exposure, we propose to test a clinically-viable therapeutic regimen of
the pleiotropic, endogenous neuroreparative molecules, erythropoietin (EPO) plus melatonin (MLT), for the
treatment of perinatal opioid-induced brain injury. EPO and MLT are both endogenous developmentally-
regulated neurorestorative agents with pluripotent mechanisms, including established anti-inflammatory
properties. Our published data suggest that opioid exposure commencing in utero negatively affects the
maturation of the neural-immune system, and trajectory of central nervous system (CNS) development.
Specifically, methadone induces peripheral immune hyper-reactivity (SPIHR), lasting structural and
microstructural brain injury, and significant deficits in executive function and cognitive control in adult animals
following in utero exposure. Our central hypothesis is that a neonatal combination therapy with EPO plus MLT
will mitigate cognitive and executive function deficits, structural and functional connectivity abnormalities, and
neural-immune dysregulation in a validated preclinical model of perinatal methadone exposure. To investigate
this hypothesis we will: 1) test that neonatal combined EPO+MLT therapy attenuates deficits of cognitive control
and executive function in adult animals following perinatal methadone exposure; 2) test whether combined
EPO+MLT therapy mitigates structural and functional brain injury in adulthood following perinatal methadone
exposure; and 3) test that combined EPO+MLT therapy diminishes a sustained systemic pro-inflammatory
microenvironment propagated by perinatal methadone exposure. Using state-of-the-art preclinical magnetic
resonance imaging (MRI), including diffusion tensor (DTI) and functional connectivity (FcMRI), in concert with
translational touchscreen cognitive assessment, we will rigorously test structure-function relationships secondary
to perinatal opioid exposure and potential repair/recovery with EPO+MLT treatment. We will focus on neural
networks and major white matter tracts essential to cognition and executive function. A clinical biomarker
platform, multiplex electrochemiluminescent immunoassay (MECI), will be used to assay proinflammatory
cytokines and chemokines over the lifespan and in response to EPO+MLT treatment. These investigations will
be the first to examine a clinically-viable, mechanistically-targeted intervention for the...

## Key facts

- **NIH application ID:** 10105779
- **Project number:** 1U18DA052402-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** LAUREN Leigh Cooney JANTZIE
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,625
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105779

## Citation

> US National Institutes of Health, RePORTER application 10105779, Erythropoietin and Melatonin Combination Therapy for Perinatal Opioid-Induced Brain Injury (1U18DA052402-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105779. Licensed CC0.

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