Hemoglobin induces oxidative stress and mitochondrial dysfunction in oligodendrocyte progenitor cells

Chirayu D. Pandya, Hemendra Vekaria, Binoy Joseph, Stacey A. Slone, John C. Gensel, Patrick G. Sullivan, Brandon A. Miller

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative stress that occurs in many forms of brain injury. One common cause of infant brain injury is neonatal intraventricular hemorrhage (IVH), which releases blood into the CSF and brain parenchyma of preterm infants. Although blood contains the powerful oxidant hemoglobin, the direct effects of hemoglobin on OPCs have not been studied. We utilized a cell culture system to test if hemoglobin induced free radical production and mitochondrial dysfunction in OPCs. We also tested if phenelzine (PLZ), an FDA-approved antioxidant drug, could protect OPCs from hemoglobin-induced oxidative stress. OPCs were isolated from Sprague Dawley rat pups and exposed to hemoglobin with and without PLZ. Outcomes assessed included intracellular reactive oxygen species levels using 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent dye, oxygen consumption using the XFe96 Seahorse assay, and proliferation measured by BrdU incorporation assay. Hemoglobin induced oxidative stress and impaired mitochondrial function in OPCs. PLZ treatment reduced hemoglobin-induced oxidative stress and improved OPC mitochondrial bioenergetics. The effects of hemoglobin and PLZ on OPC proliferation were not statistically significant, but showed trends towards hemoglobin reducing OPC proliferation and PLZ increasing OPC proliferation (P=0.06 for both effects). Collectively, our results indicate that hemoglobin induces mitochondrial dysfunction in OPCs and that antioxidant therapy reduces these effects. Therefore, antioxidant therapy may hold promise for white matter diseases in which hemoglobin plays a role, such as neonatal IVH.

Original languageEnglish
Pages (from-to)13-23
Number of pages11
JournalTranslational Research
Volume231
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
This publication is based upon work supported in part by a Hydrocephalus Association Innovator Award to BAM, NIH/NINDS K08 NS112580 to BAM, University of Kentucky CCTS KL2 Fellowship to BAM, University of Kentucky CCTS Pilot Award to BAM and JCG UL1TR001998 and a University of Kentucky Research Alliance Award to BAM. We are thankful to Thomas Dolan and Matthew Hazzard, medical illustrators at University of Kentucky, for assistance with figures. All authors have read the journal's policy on conflicts of interest. Also, all authors have read the journal's authorship agreement.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Free radicals
  • Intraventricular hemorrhage
  • Seahorse
  • White matter

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Physiology (medical)
  • Biochemistry, medical

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