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Advanced Neurology Aging blood-brain barrier in stroke

greater loss of tight junctions following ischemia in contribute to the age-dependent changes within the BBB
the aging population . Therefore, endothelial barrier that influence the degree of ischemic insult and clinical
[37]
degradation following ischemia clearly varies with age outcome. The key molecular players in stroke-induced
and appears to occur to a greater extent in the elderly and BBB degradation are MMPs, inflammatory cytokines,
to an even greater extent in the presence of pre-existing and ROS. Comparable to cellular changes, the molecular
conditions. mechanisms described below differ in their characteristics
Ischemia in adults also activates resident microglia and the degree to which they contribute to BBB degradation
immune cells and increases the degree of infiltrating after stroke.
leukocytes, including macrophages, which contribute As reviewed by Lakhan et al., MMPs, specifically
to greater destructive inflammatory responses in MMP-2 and MMP-9 secreted by resident and infiltrating
the brain, including BBB degradation and resulting inflammatory cells, are largely thought to regulate BBB
hemorrhagic transformation . While aging is similarly integrity after stroke by degrading tight junction and
[40]
[45]
associated with an elevated immune response after basal lamina proteins . MMP-induced BBB degradation
ischemia that further disrupts BBB integrity and in turn contributes to further leukocyte infiltration, edema, and
worsens clinical outcome , the cellular profile of this hemorrhage. MMP-2 and MMP-9 were both elevated
[9]
inflammatory response is quite distinct from the young in adult ischemic stroke patients on admission . MMP
[46]
adult response. In mice subjected to MCAO injury, older elevation is correlated with both injury severity and
mice express more CD68 cells in the peri-infarct region prognosis [46,47] . MMP-9 expression in response to stroke is
+
up to 14 days post-ischemia than younger mice, indicating two-fold greater in elderly patients than that in younger
[41]
greater macrophage and microglia activation . The adults . MMP-2 further contributes to ischemia-induced
[38]
disproportionately large microglial response is thought BBB breakdown, and the activities of both MMP-9 and
to be a key contributing factor to exacerbated ischemic MMP-2 were aggravated in aged-related comorbidities.
BBB injury in aged models . In addition to an intensified Patients with diabetes exhibit significantly greater and
[41]
resident immune response, aged mice demonstrate a earlier MMP-2 activity and a seven-fold increase in
strong neutrophilic response to ischemia that appears to MMP-9 activity after stroke, as compared with those
be one of the more differentiating features of ischemic without diabetes [33,34,48] . The observed elevation in MMP-9
events in this age group, as younger adults are subject to a activity after stroke in the context of diabetes is thought to
stronger monocytic response . The neutrophilic response be the result of both a greater neutrophilic response, which
[41]
to ischemic stroke in the aging population correlates with is already elevated in older patients, and reductions in
more severe ischemic injury outcomes and hemorrhagic MMP-9 inhibition [34,43] . In addition, AD-associated CAA
transformation, according to both animal and human was also associated with significant elevations in MMP-2
data . In addition, recent evidence suggests that a and MMP-9 expression, with a significant 2.4-fold increase
[41]
[37]
disproportionately elevated level of neutrophils correlates in MMP-9 activity compared with controls . Therefore,
with greater cognitive impairment post-stroke, affecting while MMPs play a role in both adult and elderly BBB
both memory and visuospatial abilities up to 3 months post- degradation, the timing and degree to which they do
injury . Subjects with diabetes also experience this strong so vary across age groups with and without additional
[42]
neutrophilic reaction, which may be compounded by age, medical conditions.
demonstrating earlier, and larger neutrophil infiltration Certain pro-inflammatory cytokines, namely, tumor
in cortical and subcortical regions of the ipsilateral necrosis factor alpha (TNF-α), interleukin (IL)-6, and
hemisphere 4 and 24 h post-stroke, which is strongly IL-1b, are thought to contribute to ischemic injury by
associated with greater infarct volume [34,43] . Although it is degrading the BBB and are associated with poorer clinical
yet to be elucidated, AD patients may also be at a further outcomes [49-51] . After stroke, microglial, endothelial, and
disadvantage because of their natural predisposition for infiltrating immune cells release such cytokines, which
greater neutrophil reactivity . However, the role this wreak havoc on the integrity of the BBB, beginning hours
[44]
plays in ischemia and the consequences on the BBB remain after injury and lasting days post-stroke [50,51] . Patients
to be explored. with higher TNF-α and IL-6 levels had significantly
lower neurological scores, both acutely and 30 days
3.3. Molecular mechanisms of BBB damage
after stroke , which correlated to significantly elevated
[49]
Activation of the cellular mechanisms of BBB degradation BBB permeability through reductions in claudin-5,
is accompanied by the release of numerous molecular occludin, and ZO-1 expression as a consequence of these
factors that can disassemble tight junction complexes and inflammatory cytokines . Aging is associated with
[52]
increase BBB permeability. These molecular mechanisms elevated inflammatory responses to ischemia, correlating

Volume 1 Issue 2 (2022) 5 https://doi.org/10.36922/an.v1i2.1