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Advanced Neurology Aging blood-brain barrier in stroke

with severe BBB disruption and subsequent injury. relevant in older patients who are already at a greater
Aging is naturally associated with elevated inflammatory risk of hemorrhage after treatment . Along these lines,
[31]
mediators, such as IL-6 and TNF-α, resulting in a natural the elderly BBB undergoes greater damage following tPA
leakiness of the BBB via the loss of tight junctions . This treatment, which is correlated to the greater likelihood of
[30]
is more exacerbated during ischemic events in the elderly hematoma formation compared with the young brain
[31]
compared to younger adults. Compared with 2-month- and can limit the potential benefits of tPA treatment. tPA-
old adult mice, aged (12-month-old) mice that started to induced damage to the BBB and the corresponding risk
experience senescence had significantly higher IL-1b of hematoma and death are suspected to be linked to the
[53]
and IL-6 expression after ischemia, correlating to more neutrophilic response that the elderly brain experiences
severe and longer-lasting behavioral deficits and infarction during ischemia [41,54] . The elderly neutrophilic response
due to greater BBB leakage . Thus, similar to MMPs, is associated with increased MMP-9, which is a predictor
[38]
inflammatory cytokines play a greater role in vulnerable of hemorrhagic transformation and death following
elderly brains (with greater damage inflicted on the BBB tPA administration . Furthermore, the efficacy of
[55]
post-stroke) than in the brains of younger adults. tPA treatment may be reduced in elderly patients with
Finally, oxidative stress caused by ROS and other free comorbid health conditions. For example, diabetes
radicals released by reactive and infiltrating immune cells significantly reduces tPA efficacy in infarction reduction,
plays an important role in ischemic injury progression. which is associated with increased hemispheric swelling
[56]
It contributes to the loss of tight junctions and promotes and hemorrhage due to greater BBB degradation ,
MMP-9 degradation of the BBB, ultimately leading to a conceivably through even greater microglial proliferation
loss of barrier integrity . Microglia and neutrophils have and increased MMP-9 activity.
[50]
been shown to produce more ROS in response to ischemia Appreciating the different timelines of BBB disruption
in elderly compared to younger adult brains . This may following ischemic injury is critical for the development
[41]
be further observed under age-associated comorbid and administration of new potential neuroprotective drugs
conditions, such as hyperglycemia, which is associated in both adult and elderly populations . Most research
[57]
with greater oxidative stress, superoxide production, BBB is conducted using adult rodent models, even though,
degradation, and increased MMP-9 activity after stroke . as discussed, BBB opening can occur to a greater extent
[48]
and at a much earlier time in elderly patients compared
4. The BBB in ischemic treatment and the with young and middle-aged adults. Thus, unlike with
influence of age younger patients, for elderly patients (with a higher level
Not only can the BBB influence the timing of of BBB permeability), it may be useful to develop potential
administration and effectiveness of ischemic stroke neuroprotectants with a longer time frame for delivery
treatments and strategies but also it is itself considered to and larger composition. To this end, understanding the
be an increasingly attractive target for future therapeutic timing, extent, and mechanisms of BBB degradation in
development. As outlined throughout the current review, vulnerable patients with and without comorbid conditions
the degree of ischemic injury and later recovery depend could facilitate the development of new and more effective
on the degradation of the BBB. Thus, maintaining the BBB treatment options that take advantage of the timelines of
after stroke may be the key for achieving better long-term BBB permeability in different age groups.
clinical outcomes. However, due to the above-mentioned
age-dependent mechanisms of BBB degradation after 4.2. Targeting the BBB in ischemic stroke treatment
stroke, considering these cellular and molecular variations BBB degradation is associated with more severe ischemic
is crucial for developing new potential therapeutics. injury, subsequent edema, and hemorrhage, and therefore
protecting the BBB from further damage following
4.1. Drug delivery and efficacy ischemia has been a goal to improve clinical prognosis for
The time frame for drug delivery and treatment efficacy are all age groups [58,59] . Such treatments are largely suggested
largely dictated by post-ischemia BBB dynamics and age- to target the inflammatory cytokine and MMP proteolytic
specific BBB characteristics and comorbidities. At present, mechanisms underlying BBB degradation, as discussed in
tissue plasminogen activator (tPA) is the only therapy the current review. In addition, targeting the BBB may allow
for ischemic stroke in the mature brain approved by the effective treatment to be delivered during a more clinically
U.S. Food and Drug Administration. However, tPA has relevant time frame and may widen the time frame for
a short time frame of delivery of <3 h, largely due to the delivery of current therapeutics [60,61] . However, the above-
increased risk of hemorrhagic transformation because of mentioned age-specific characteristics of the BBB under
delayed tPA-induced BBB degradation. This is especially ischemic conditions must be taken into consideration.

Volume 1 Issue 2 (2022) 6 https://doi.org/10.36922/an.v1i2.1