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Advanced Neurology Aging blood-brain barrier in stroke

As discussed, older patients experience significantly damaging response of the hyperinflammatory neutrophils
increased MMP-9 activity following ischemic stroke in systemic circulation before entry into the brain. This
compared with younger patients. Because MMP-9 would reduce MMP, ROS, and inflammatory cytokine
activity plays a crucial role in BBB degradation (which loads, while still allowing anti-inflammatory subsets to
leads to poorer clinical outcomes), it is pertinent that permeate the BBB. Thus, leveraging the heterogeneity of the
future therapies aim to reduce this proteolytic activity. nucleophilic response and avoiding global suppression of
The mechanisms of MMP-9 inhibition in the context of critical immune function may effectively support ischemic
ischemic stroke treatment are reviewed by Chaturvedi and injury recovery and suppress inflammatory destruction of
Kaczmarek . Altogether, MMP-9 inhibition seems to be a the BBB.
[59]
viable target for adult and especially elderly stroke patients, Additional therapeutic avenues that maintain BBB
given their comparably robust MMP-9 response to integrity and can be delivered in conjunction with current
ischemia. However, MMP-9 has also been linked to critical treatment options to improve clinical outcomes are also
angiogenic mechanisms and neurological recovery in under investigation. Adjuvant therapeutics in conjunction
[62]
the late stages of stroke . Thus, targeting MMP-9 activity
[63]
would require a highly controlled mechanism and time with tPA treatment that stabilize the BBB not only reduce
frame of inhibitory action because a long-term therapeutic injury severity and risk of hemorrhagic transformation
strategy to reduce MMP-9 activity may interfere with the but also increase the time frame for treatment in elderly
beneficial actions and effects of this enzyme during the patients. Delivery of tPA outside the recommended 3-h
later recovery stages after stroke. time frame after initial injury may increase the likelihood
of hemorrhagic transformation because of tPA-induced
Inhibition of inflammatory processes successfully MMP-9 activation . Because, as previously discussed,
[55]
mitigates injury severity in older patients. Older stroke elderly patients are at a greater risk of hemorrhagic
patients are subject to greater inflammatory BBB damage transformation after tPA treatment, providing an MMP-9
after stroke, and thus drugs that restrict stroke-induced inhibitor in conjunction with tPA may improve clinical
inflammation seem to be a viable avenue to use in this outcomes in this population. Treatment with minocycline
cohort of patients. Inhibiting inflammation in the aged (an MMP inhibitor) in combination with tPA significantly
brain significantly diminishes stroke volume and improves reduces 24-h infarct size and ameliorates hemorrhagic
neurological function by reducing TNF-α- and MMP-9- transformation, allowing tPA treatment to successfully
mediated BBB degradation and corresponding inhibition delay ensuing ischemic injury as a direct consequence of
of neutrophil infiltration . Because the aging population MMP-9 inhibition . However, how MMP-9 inhibition
[64]
[66]
experiences a strong neutrophilic response to ischemia, affects later stages of recovery and angiogenic events still
which largely contributes to BBB degradation and poor needs to be elucidated.
clinical outcomes, a drug that could inhibit neutrophil
infiltration and reduce systemic neutrophil levels would Neural stem cell transplantation in conjunction with
[42]
be ideal for improving acute and chronic stroke outcomes tPA treatment has also been shown to reduce infarct
in aging patients. volume in the aged brain after stroke through reduction
of pro-inflammatory cytokines (e.g., TNF-α and IL-6) and
In fact, the discrepancy in the cellular profile of the MMP-9, thereby reducing BBB damage and maintaining
immune response after ischemia between adult and elderly tight junctions, while allowing a longer time frame of
brains may provide key insight into the optimal treatment successful tPA treatment (6 h) . Stem cell administration
[67]
of post-stroke patients by taking into consideration age- in animal models of ischemic stroke has further been
dependent disease characteristics. The strong neutrophilic associated with improved neurological function as a result
response in elderly stroke patients, as reviewed, contributes of reductions in post-stroke ischemic injury [68,69] .
to both greater ischemic injury in terms of infarct volumes
as well as secondary injury due to BBB damage, and has Neutrophil activity inhibits the efficacy of tPA treatment
further been linked to worsened cognitive impairment through tPA-induced formation of neutrophil extracellular
months after injury [42,65] . Interestingly, this inflammatory traps, which largely contributes to an increased risk of
event may be one of the easier targets to address, as it begins hemorrhage . Thus, efforts should be made to identify
[70]
systemically rather than beyond the BBB. Furthermore, the means to selectively inhibit inflammatory neutrophil
extensive knowledge has accumulated regarding the subsets activity in conjunction with tPA treatment. Knecht et al.
of neutrophils that respond to injury, essentially classifying further outline specific pharmacological and non-drug
the helpful from the harmful based on extracellular interventions that target molecules contributing to BBB
proteins . Using this knowledge, efforts should be made degradation in ischemic stroke; these may represent
[65]
to identify clinically relevant methods that may disarm the potential adjuvant therapies to tPA, increase the time frame

Volume 1 Issue 2 (2022) 7 https://doi.org/10.36922/an.v1i2.1