Abstract
Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.
Highlights
Intracerebral hemorrhage (ICH) is an acute cerebrovascular event with a high mortality and disability rate [1, 2]
Our results suggest that acrolein, an unsaturated aldehyde, is a critical pathogenic factor in secondary brain injury (SBI) after intracranial hemorrhage (ICH)
We found that acrolein induced mitochondrial fragmentation accompanied by loss of mitochondrial membrane potential, the generation of reactive oxidative species, and the release of mitochondrial cytochrome c
Summary
Intracerebral hemorrhage (ICH) is an acute cerebrovascular event with a high mortality and disability rate [1, 2]. Pathological processes after ICH include primary brain injury, and secondary brain injury (SBI) [3, 4]. Primary brain injury refers to the physical disruption of the cellular architecture induced by the initial hematoma. The hematoma leads to SBI, which includes oxidative damage, the inflammatory response, glutamate toxicity, neural death, and blood-brain barrier disruption [5,6,7]. Multiple treatments have emerged in clinical practice, the outcomes of ICH remain unsatisfactory [8]. These considerations impelled us to explore whether there are critical pathological factors that have not been focused on in previous treatments
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