{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T06:19:10Z","timestamp":1783491550672,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bronchopulmonary dysplasia (BPD) in preterm infants is frequently accompanied by neurodevelopmental impairment, yet the central neuropharmacological actions of dexamethasone (DEX), a commonly used therapy for severe or evolving BPD, remain incompletely understood. In particular, whether DEX exerts timing-dependent neuroprotection in the developing brain and the mechanisms underlying such effects are unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the neuroprotective effects of DEX in a neonatal rat double-hit model combining prenatal maternal lipopolysaccharide exposure with postnatal hyperoxia. A tapered DEX regimen was initiated on postnatal day (P)1, P3, or P8 to evaluate the therapeutic window. Lung pathology, survival, hippocampal injury, microglial reactivity, behavioral outcomes, resting-state functional magnetic resonance imaging (rs-fMRI), targeted metabolomics, and microglia-neuron coculture experiments were used to characterize pharmacological efficacy and mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among the tested regimens, DEX initiated at P3 produced the most consistent protective effects, improving alveolar structure, survival, hippocampal pathology, and microglial reactivity. P3-initiated DEX also improved recognition memory, exploratory\/anxiety-related behavior, spatial memory retention, and motor coordination, and was associated with partial restoration of hippocampal functional connectivity. At the molecular level, DEX partially restored hippocampal glutamate\/GABA balance, reduced Synapsin I phosphorylation, and normalized VGLUT1\/VGAT associated synaptic abnormalities. Mechanistically, microglia-derived IL-1\u03b2 promoted neuronal ERK\/Syn1 activation, whereas DEX interrupted this inflammatory signaling axis in a microglia-neuron coculture system. Targeted metabolomics and perturbation experiments further showed that DEX increased Acod1-dependent itaconate reprogramming under inflammatory priming, thereby suppressing microglial IL-1\u03b2 and downstream neuronal P-Syn1\/Syn1 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify a developmentally sensitive therapeutic window for DEX neuroprotection in neonatal BPD-associated brain injury and suggest that microglial Acod1-itaconate-dependent regulation of IL-1\u03b2\/ERK\/Syn1 signaling contributes to its central protective effects. This study expands the pharmacological interpretation of DEX beyond pulmonary benefit and supports an immunometabolic framework for understanding corticosteroid actions in the developing brain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1840628","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:58:40Z","timestamp":1783490320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Developmentally sensitive neuropharmacological effects of dexamethasone in neonatal bronchopulmonary dysplasia-associated brain injury via microglial Acod1-itaconate\/IL-1\u03b2 signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Wen","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Chongqing Maternal and Child Health Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingli","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5622","DOI":"10.1016\/j.csbj.2022.09.042","article-title":"Integrative analysis of macrophage ribo-Seq and RNA-seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes","volume":"20","author":"Ansari","year":"2022","journal-title":"Comput. 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