SPP1 / OPN Alleviates Post‐Intracerebral Hemorrhage Depression and Cognitive Impairment via Nrf2 / BDNF Signaling Activation in Mice

作者：Pengpeng Li, Yangyang Gao, Shaojun Du, Zhanglei Mu, Zhenxing Tao, Xu‐Qi Zhang, Xudong Zhao · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1002/cns.70680 · 被引用次数：3 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Genomics, phytochemicals, and oxidative stress、Nerve injury and regeneration

BACKGROUND: Post-stroke depression represents a prevalent neuropsychiatric complication following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain less understood compared to ischemic stroke. METHODS: This translational investigation employed a multi-omics approach, combining bioinformatics analysis of depression-related (GSE214921) and ICH-related (GSE18193) datasets from the GEO database with experimental validation. Using a collagenase-induced striatal ICH murine model, we evaluated the effects of intranasal administration of osteopontin (OPN, encoded by SPP1) through neurobehavioral tests, histopathological evaluation, and molecular biology techniques. RESULTS: Integrated bioinformatics analysis identified the SPP1 signaling pathway as a potential key regulator in post-ICH depression pathogenesis. In vivo, OPN treatment produced sustained neurobehavioral improvements at 28 days post-ICH, significantly ameliorating neurological deficits, mitigating anxiety-depressive behaviors, and enhancing spatial learning-memory performance. Histopathological evaluation revealed OPN's multifaceted neuroprotective effects, including attenuated hippocampal neuroinflammation, preserved Nissl body integrity, and restored dendritic arborization complexity. Mechanistically, OPN exerted its therapeutic effects through activation of the Nrf2/BDNF signaling axis, as pharmacological inhibition of Nrf2 with ML385 completely abrogated both neuroprotection and BDNF upregulation. ...