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
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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.
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