PPAR-γ activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage

Sunil Krishna, Bokun Cheng, Deep R. Sharma, Sunita Yadav, Erin S. Stempinski, Sahil Mamtani, Elisa Shah, Anjali Deo, Trishna Acherjee, Teena Thomas, Xusheng Zhang, Jinghang Zhang, Dumitru A. Iacobas, Praveen Ballabh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Intraventricular hemorrhage (IVH) results in periventricular inflammation, hypomyelination of the white matter, and hydrocephalus in premature infants. No effective therapy exists to prevent these disorders. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists reduce inflammation, alleviate free radical generation, and enhance microglial phagocytosis, promoting clearance of debris and red blood cells. We hypothesized that activation of PPAR-γ would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPAR-γ expression in microglia of both preterm human infants and rabbit kits. The treatment with PPAR-γ agonist or PPAR-γ overexpression by adenovirus delivery further elevated PPAR-γ levels in microglia, reduced proinflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPAR-γ–induced genes for purinergic signaling, cyclic adenosine monophosphate generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-sequencing analyses of microglia revealed PPAR-γ–triggered down-regulation of several proinflammatory genes and transcripts having roles in Parkinson’s disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPAR-γ activation enhanced myelination and neurological function in kits with IVH. This also enhanced microglial phagocytosis of red blood cells but did not reduce hydrocephalus. Treatment with PPAR-γ agonist might enhance myelination and neurological recovery in premature infants with IVH.

Original languageEnglish (US)
Article numbere2103084118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number36
DOIs
StatePublished - Sep 7 2021

Keywords

  • Microglia
  • Myelin
  • Oligodendrocyte
  • PPAR-γ

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'PPAR-γ activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage'. Together they form a unique fingerprint.

Cite this