Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461.
Proc Natl Acad Sci U S A. 2021 Sep 7;118(36). doi: 10.1073/pnas.2103084118.
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.
脑室内出血（IVH）可导致早产儿脑室周围炎症、白质髓鞘形成不良和脑积水。目前尚无有效的治疗方法来预防这些疾病。过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂可减轻炎症、缓解自由基生成，并增强小胶质细胞吞噬作用，促进碎片和红细胞的清除。我们假设激活 PPAR-γ 会增强髓鞘形成、减少脑积水，并促进 IVH 新生儿的神经恢复。这些假设在 IVH 的早产兔模型中进行了测试，并分析了伴有和不伴有 IVH 的早产儿尸检脑样本。我们发现，IVH 可增强早产儿人类和兔仔小胶质细胞中的 PPAR-γ 表达。PPAR-γ 激动剂治疗或腺病毒递送过表达 PPAR-γ 可进一步提高小胶质细胞中的 PPAR-γ 水平，减少促炎细胞因子，增加小胶质细胞吞噬作用，并改善 IVH 兔仔的少突胶质前体细胞（OPC）成熟。对 OPC 的转录组分析确定了以前未被识别的 PPAR-γ 诱导的嘌呤能信号、环磷酸腺苷生成和抗氧化剂产生基因，这将使这些祖细胞重新编程以促进髓鞘形成。小胶质细胞的 RNA-seq 分析显示，PPAR-γ 触发了几个促炎基因和参与帕金森病和肌萎缩性侧索硬化症的转录本的下调，有助于 IVH 兔仔的神经恢复。因此，PPAR-γ 激活增强了 IVH 兔仔的髓鞘形成和神经功能。这也增强了小胶质细胞对红细胞的吞噬作用，但并未减少脑积水。PPAR-γ 激动剂的治疗可能会增强伴有 IVH 的早产儿的髓鞘形成和神经恢复。
