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

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.

Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats

“… 65 – 68 Treatments that reduce inflammation can enhance myelination and neurological recovery after intraventricular hemorrhage. 69 Multiple inflammatory chemokines and mediators such as Ccl2 , Ccl4 , Ccl6 , Tlr5 , Mmp8 , and Spp1 were upregulated 72 hours after GMH, likely reflecting the activation of microglia. Also, at this time point immune responses and inflammation were the most enriched processes, and pathways involved in the production of inflammatory mediators were predicted to be upregulated.…”

“…Accordingly, CSF2, a cytokine secreted by macrophages, was predicted to be one of the upstream regulators possibly involved in the inflammatory response. Macrophages and microglia play a pivotal role in hematoma clearance after GMH, 66 , 69 but the pathophysiological role of B-cells after intracerebral hemorrhage has not been well studied. In contrast to our findings, B-cells have been shown to have a low infiltration rate at 1 day and 5 days after insult in an adult mouse model of intracerebral hemorrhage.…”

Theory and Applications of the (Cardio) Genomic Fabric Approach to Post-Ischemic and Hypoxia-Induced Heart Failure

“…Although still limited to the change in the expression level, WIR not only considers all genes but weights their contribution according to the total absolute change of their expression level and the statistical confidence in their regulation. This measure was previously used to quantify the transcriptomic alterations in the left ventricle of a mouse model of Chagasic cardiomyopathy [ 32 ], in the cortical oligodendrocytes and microglia of a rabbit model of intra-ventricular hemorrhage [ 46 ], and in the hypothalamic arcuate node of a rat model of infantile spasms [ 35 ].…”

Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia

“…Two previous studies have investigated the use of RGZ in premature rabbits: Richter et al investigated the antenatal administration of RGZ, showing that RGZ (3 mg/kg) delivered through an intramuscular injection to the mothers 24 and 48 h prior to delivery attenuated the hyperoxic lung injury at PND 7 [ 17 ]. Recently, Krishna et al demonstrated that twice-daily administration of 0.1 mg/kg of RGZ improved myelination and neurological recovery in premature rabbit pups with intraventricular hemorrhage [ 40 ]. No issues were raised regarding RGZ-associated dyslipidemia in these studies.…”