New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria

Abstract

: Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes, and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets, and summarize the promising therapeutic strategies targeting mitochondria for SAH.

2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats

“…Mitochondrial dysfunction leads to the overproduction oxygen radicals, the release of apoptogenic proteins and the generation of mitochondria-related inflammation, which are associated with brain injury after SAH [ 30 , 31 ]. Figure 7 shows SAH significantly induced a nearly four-fold increase in the production of ROS as compared to the sham group, whereas 2-PMAP reduced these elevated levels.…”

“…They not only can decrease brain edema, preserve BBB and protect neurons from damage, but also ensue scar formation, enhance the release of cytokines and limit axonal regeneration. Astrocyte activation is a possible consequence of microglia activation, which can cause neuro-inflammation [ 31 ]. In SAH patients, GFAP and S100B are elevated in both CSF and serum [ 77 , 78 ], in which high S100B levels in CSF is associated with poor one-year clinical outcomes [ 79 ].…”

ASK1 inhibitor NQDI‑1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

“…In steady-state cells, ROS are primarily byproducts of respiration produced by the mitochondrial electron respiratory chain and moderate levels of ROS repair damaged DNA and serve a physiological role in the promotion of cell survival ( 38 ). Upon SAH, due to the autoxidation of blood in the subarachnoid space, ROS catalysis by heme and intracellular mitochondrial dysfunction, electrons escape into the cytoplasm and the antioxidant system is insufficient to compensate, which results in accumulation of large amounts of ROS in neuronal cells ( 39 ), which leads to oxidative stress damage. Therefore, therapeutic strategies that target oxidative stress and apoptosis may be considered effective therapeutic directions following SAH.…”

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

“…Extracellular mitochondria in CSF may provide additional information on brain integrity and recovery after SAH. 46 , 47 Thus, mitochondrial dysfunction could be a potential therapeutic target for SAH management, 48 but further studies are needed to precisely evaluate the spatial variations and characterize the biological cascade.…”