Hu Wei-Fen, Lee Chien-Hui, Pang Cheng-Yoong, Huang Hsin-Yi, Tsai Sheng-Tzung, Wang Po-Kai, Shih Mu-Ting, Cheah Pei-Ying, Wu Yi-Feng, Tsai Andy Po-Yi, Tseng Kuan-Yin, Airavaara Mikko, Liew Hock-Kean
Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; PhD Program in Pharmacology and Toxicology, Tzu Chi University, Hualien 970, Taiwan.
Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; School of Medicine, Tzu Chi University, Hualien 970, Taiwan.
Exp Neurol. 2025 Mar;385:115098. doi: 10.1016/j.expneurol.2024.115098. Epub 2024 Dec 7.
Intracerebral hemorrhage (ICH) is associated with a large hematoma that causes compression, increased intracranial pressure (IICP), midline shift, and brain herniation, and may ultimately lead to death. Urgent surgical removal of the large hematoma can ameliorate these injuries, which would be life-saving, but has not improved clinical outcome. A suitable animal model that mimics the clinically relevant human severe ICH injury requiring surgical hematoma evacuation is urgently needed. Here, we established a novel model of severe ICH in rats allowing aspiration of the hematoma and studying the effects of mitochondrial dysfunction in ICH.
Severe ICH was induced by intra-striatal injection of 0.6 U of collagenase in 3 μL sterile saline over 15 min. Aspiration of approximately 75 % of the total hematoma was performed 6 h after induction of severe ICH. The effects of hematoma aspiration on hematoma volume, mortality, oxidative stress, ATP levels, mitochondrial dysfunction, and neurological function were measured in rats.
Severe ICH induction increased hematoma volume, neurological deficits, and mortality. Hematoma aspiration abolished mortality and significantly reduced hematoma volume, and neurological deficits. In addition, hematoma aspiration ameliorated the pronounced mitochondrial dysfunction responsible for the failure of energy production and excessive oxidative stress associated with severe hemorrhagic injury. Hematoma aspiration also modulated mitochondrial biogenesis and mitophagy, thereby promoting mitochondrial homeostasis. Markers of neuroinflammation, including iNOS, MMP9, and MPO, were elevated in severe ICH but attenuated by hematoma aspiration.
This study established an animal model of severe ICH and provides valuable insights into the complex pathogenesis of severe ICH. The results showed that hematoma aspiration effectively ameliorates mitochondrial dysfunction, oxidative stress, and neuroinflammation, highlighting its potential as a therapeutic intervention.
脑出血（ICH）与大血肿相关，该血肿会导致压迫、颅内压（IICP）升高、中线移位和脑疝形成，并最终可能导致死亡。紧急手术清除大血肿可改善这些损伤，这可能挽救生命，但尚未改善临床结局。迫切需要一种合适的动物模型，以模拟临床上需要手术清除血肿的严重ICH损伤。在此，我们建立了一种新型大鼠严重ICH模型，该模型允许抽吸血肿并研究ICH中线粒体功能障碍的影响。
通过在15分钟内将0.6 U胶原酶注射到3 μL无菌盐水中，经纹状体内注射诱导严重ICH。在诱导严重ICH 6小时后，抽吸约75%的总血肿。测量大鼠血肿抽吸对血肿体积、死亡率、氧化应激、ATP水平、线粒体功能障碍和神经功能的影响。
诱导严重ICH会增加血肿体积、神经功能缺损和死亡率。血肿抽吸消除了死亡率，并显著减少了血肿体积和神经功能缺损。此外，血肿抽吸改善了导致能量产生失败的明显线粒体功能障碍以及与严重出血性损伤相关的过度氧化应激。血肿抽吸还调节线粒体生物合成和线粒体自噬，从而促进线粒体稳态。包括诱导型一氧化氮合酶（iNOS）、基质金属蛋白酶9（MMP9）和髓过氧化物酶（MPO）在内的神经炎症标志物在严重ICH中升高，但通过血肿抽吸而减弱。
本研究建立了一种严重ICH动物模型，并为严重ICH的复杂发病机制提供了有价值的见解。结果表明，血肿抽吸可有效改善线粒体功能障碍、氧化应激和神经炎症，突出了其作为一种治疗干预措施的潜力。
