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Original Article

Maternal metformin protects developing auditory brainstem function after neonatal hypoxia-ischemia in a neonatal rat model

Sei Eun Kim¹, Joo Young Kweon^2,3  , Yong Joo Ahn^2,3  , Jun Hee Kim^1,4 

¹Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
²Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Korea
³School of Convergence Science and Technology, Medical Science and Engineering Program, Pohang University of Science and Technology (POSTECH), Pohang, Korea
⁴Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA

Correspondence Jun Hee Kim ,Email: kimjunh@umich.edu

Received: May 24, 2026; Revised: July 3, 2026   Accepted: July 9, 2026.

Abstract

Background
Neonatal hypoxia-ischemia (HI) disrupts brain development and can impair sensory circuit maturation. However, how HI vulnerability is modified within developing auditory pathways remains poorly defined.
Purpose
Metformin is used during pregnancy in select cases and modulates cellular energy signaling. Here, we tested whether maternal metformin administration during gestation alters functional and cellular outcomes in offspring brain after neonatal HI.
Methods
Pregnant rat dams received metformin in drinking water, and offspring rat pups underwent HI during early postnatal life. Auditory pathway function was assessed in vivo using auditory brainstem responses (ABRs), and cellular pathology within the medial nucleus of the trapezoid body (MNTB) was evaluated by immunohistochemistry across postinjury developmental time points.
Results
HI significantly elevated click-evoked ABR thresholds and reduced wave II and III amplitudes, whereas maternal metformin exposure prevented the HI-induced click-threshold elevation and preserved wave II and III amplitudes without altering peripheral or central conduction times. Histologically, HI produced an age-dependent decline in MAP2-positive neuronal density in the MNTB, culminating in marked neuronal loss at later postnatal stages. Notably, maternal metformin partially rescued HI-associated reductions in MNTB neurons, with a parallel trend toward preservation of oligodendrocyte lineage cells.
Conclusion
Together, these findings indicate that maternal metformin administration during pregnancy enhances metabolic signaling and mitigates HI-related auditory brainstem dysfunction and cellular pathology in offspring, supporting maternal metabolic modulation as a determinant of neonatal sensory brain injury outcomes.

Keywords :Hypoxia-ischemia, Metformin, Auditory brainstem response, Neuroprotection