399 - Erythropoietin and Melatonin Treatment Ameliorates Structural and Functional Brain Injury in Adult Animals Following Prenatal Opioid Exposure

Poster Number: 399
Publication Number: 399.236

Nethra Madurai, Johns Hopkins Hospital, Lutherville-Timonium, MD, United States; Yuma Kitase, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Eric M. Chin, Kennedy Krieger Institute, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins University, Baltimore, MD, United States; Lauren L. Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Background: The effects of prenatal opioid exposure (POE) extend beyond withdrawal symptoms in the first weeks of life. Previously, we have shown that POE adversely affects the maturation of the neuroimmune system in the developing central nervous system. Limited clinical data have shown smaller brain volumes, decreased white matter (WM) integrity and abnormal functional connectivity (FC) in infants with POE highlighting the need for more rigorous examination of underlying pathways to help develop treatments.

Objective: To examine the effects of POE on adult brain structural connectivity and functional activation and the potential for repair with erythropoietin (EPO) and melatonin (MLT) treatment. We hypothesized that POE would lead to WM microstructure abnormalities and aberrant FC that would be ameliorated with EPO+MLT.

Design/Methods: Osmotic mini pumps were implanted in pregnant Sprague Dawley rat dams for 28 days of continuous methadone (12mg/kg, 0.25μL/h) or saline infusion. A cohort of methadone-exposed pups received EPO from postnatal day 1 (P1)-P5 at 2500U/kg/dose and MLT from P1-P10 at 20mg/kg. Resting state functional MRI (fMRI) and diffusion tensor imaging (DTI) were evaluated at P60 in adulthood. 0.01-0.08Hz fMRI power was assessed for each rat within atlas-defined brain regions and normalized to whole brain fMRI power (mALFF-mean amplitude of low-frequency fluctuation). mALFF was compared between groups using a non-parametric ranksum test for equal medians with Holm-Bonferroni multiple comparisons correction and normalized effect size (Cohen’s d). Additional statistical differences were established using a two-way ANOVA with Bonferroni post-hoc correction with p< 0.05 considered significant (n=10-15/group).

Results: DTI revealed profound WM injury and decreased microstructural integrity in adult rats with POE as indicated by lower fractional anisotropy in the corpus callosum (p < 0.001) and external capsule (p < 0.001). This deficit was ameliorated with EPO+MLT in both the corpus callosum (p < 0.05) and external capsule (p < 0.01). Adult rats with POE showed decreased mALFF in the striatum (p < 0.05) and increased mALFF in the amygdala (p < 0.05) compared to controls that normalized with EPO+ MLT.Conclusion(s): POE results in profound structural and functional brain injury that persists in adulthood. Neonatal treatment with EPO+ MLT mitigates abnormalities in structural connectivity and functional activation suggesting potential for future therapies and imaging biomarkers. Further studies into  mechanisms of injury and timing of treatment are warranted to guide management for these vulnerable infants.