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

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-gamma (PPAR-gamma) 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-gamma 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-gamma expression in microglia of both preterm human infants and rabbit kits. The treatment with PPAR-gamma agonist or PPAR-gamma overexpression by adenovirus delivery further elevated PPAR1 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-gamma-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-gamma-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-gamma 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-gamma agonist might enhance myelination and neurological recovery in premature infants with IVH.

Automated summary

Activation of PPAR-γ enhances myelination and neurological function in preterm rabbits with IVH, but does not reduce hydrocephalus. Treatment with PPAR-γ agonist may enhance myelination and neurological recovery in premature infants with IVH.