Complementing Subarachnoid Hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) can lead to poor functional outcome and cognitive impairment. The most important determinant of poor functional outcome after aneurysmal SAH is early brain injury, which is directly related to the initial bleeding. Other major determinants of poor functional outcome are rebleeding of the aneurysm, and delayed cerebral ischemia (DCI), which can occur 4-14 days after the initial bleeding5. In patients with cognitive impairment, many domains can be affected, such as memory, attention, executive function, and language. Upon SAH, there is an overwhelming immune response. The immune response is supposed to limit the damage inflicted by the SAH. However, it probably also causes additional brain injury, which can contribute to functional outcome and cognitive impairment. We aimed to characterize the complement and glial responses after SAH, and identify their impact on the brain. In chapter 1, we systematically reviewed the literature on the glial response after SAH until July 2015 (an update is presented in the text below). We also gave insights into the potential functional consequences and clinical implications of this glial response. We discussed how immune activated glial cells may affect brain functions after aneurysmal SAH. Furthermore, we focused on their contribution to early brain injury, DCI, and cognitive impairment. In chapter 2, we studied the role of the complement system in the development of brain injury after SAH. We found an increase in the presence of complement components C1q and C3 in the brain of SAH patients. Furthermore, we found an association between a single nucleotide polymorphisms in the complement gene C5 and poor functional outcome in patients. Patients with this risk allele had lower plasma C5a levels, although the plasma levels did not correlate with poor functional outcome. Moreover, we found that complement component C5a levels in cerebrospinal fluid were highly increased 1 day after SAH. In mice lacking the C5a receptor, we found a reduced microglia response and reduced neural cell death after experimentally induced SAH. Moreover, the microglia response and neural cell death were also reduced in wildtype mice which were given injections with an antibody that prevents the cleavage of C5 into C5a and C5b, after experimentally induced SAH. In chapter 3, we investigated the glial response in the frontal cortex of SAH patients. The results suggested an activated state of both astrocytes and microglia in humans after SAH. We focused on the glial response and cognitive changes in an SAH mouse model and found that mice with SAH have memory impairment. Furthermore, there was an increased complement/ glial response in the hippocampus of mice with SAH, which correlated with memory impairment. In chapter 4, we investigated whether the glial response can be beneficial, by having regenerative properties to repair brain tissue after SAH. We did not find a difference in the amount of proliferative neurogenic astrocytes within the neurogenic niches of the mouse brain. However, we observed a potential self-repair mechanism that led to induction of newborn neurons near highly damaged brain areas.