Mitigating mitochondrial dysfunction and neuroinflammation by hematoma aspiration in a new surgical model for severe intracerebral hemorrhage.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.