Neuroserpin and Extracellular Vesicles in Ischemic Stroke

TY - JOUR

T1 - Neuroserpin and Extracellular Vesicles in Ischemic Stroke

T2 - Partners in Neuroprotection?

AU - Brenna, Santra

AU - Glatzel, Markus

AU - Magnus, Tim

AU - Puig, Berta

AU - Galliciotti, Giovanna

PY - 2024/10/1

Y1 - 2024/10/1

N2 - Ischemic stroke represents a significant global health challenge, often resulting in death or long-term disability, particularly among the elderly, where advancing age stands as the most unmodifiable risk factor. Arising from the blockage of a brain-feeding artery, the only therapies available to date aim at removing the blood clot to restore cerebral blood flow and rescue neuronal cells from death. The prevailing treatment approach involves thrombolysis by administration of recombinant tissue plasminogen activator (tPA), albeit with a critical time constraint. Timely intervention is imperative, given that delayed thrombolysis increases tPA leakage into the brain parenchyma, causing harmful effects. Strategies to preserve tPA's vascular benefits while shielding brain cells from its toxicity have been explored. Notably, administering neuroserpin (Ns), a brain-specific tPA inhibitor, represents one such approach. Following ischemic stroke, Ns levels rise and correlate with favorable post-stroke outcomes. Studies in rodent models of focal cerebral ischemia have demonstrated the beneficial effects of Ns administration. Ns treatment maintains blood-brain barrier (BBB) integrity, reducing stroke volume. Conversely, Ns-deficient animals exhibit larger stroke injury, increased BBB permeability and enhanced microglia activation. Furthermore, Ns administration extends the therapeutic window for tPA intervention, underscoring its potential in stroke management. Remarkably, our investigation reveals the presence of Ns within extracellular vesicles (EVs), small membrane-surrounded particles released by all cells and critical for intercellular communication. EVs influence disease outcome following stroke through cargo transfer between cells. Clarifying the role of EVs containing NS could open up urgently needed novel therapeutic approaches to improve post-ischemic stroke outcome.

AB - Ischemic stroke represents a significant global health challenge, often resulting in death or long-term disability, particularly among the elderly, where advancing age stands as the most unmodifiable risk factor. Arising from the blockage of a brain-feeding artery, the only therapies available to date aim at removing the blood clot to restore cerebral blood flow and rescue neuronal cells from death. The prevailing treatment approach involves thrombolysis by administration of recombinant tissue plasminogen activator (tPA), albeit with a critical time constraint. Timely intervention is imperative, given that delayed thrombolysis increases tPA leakage into the brain parenchyma, causing harmful effects. Strategies to preserve tPA's vascular benefits while shielding brain cells from its toxicity have been explored. Notably, administering neuroserpin (Ns), a brain-specific tPA inhibitor, represents one such approach. Following ischemic stroke, Ns levels rise and correlate with favorable post-stroke outcomes. Studies in rodent models of focal cerebral ischemia have demonstrated the beneficial effects of Ns administration. Ns treatment maintains blood-brain barrier (BBB) integrity, reducing stroke volume. Conversely, Ns-deficient animals exhibit larger stroke injury, increased BBB permeability and enhanced microglia activation. Furthermore, Ns administration extends the therapeutic window for tPA intervention, underscoring its potential in stroke management. Remarkably, our investigation reveals the presence of Ns within extracellular vesicles (EVs), small membrane-surrounded particles released by all cells and critical for intercellular communication. EVs influence disease outcome following stroke through cargo transfer between cells. Clarifying the role of EVs containing NS could open up urgently needed novel therapeutic approaches to improve post-ischemic stroke outcome.

KW - Extracellular Vesicles/metabolism

KW - Ischemic Stroke/metabolism

KW - Animals

KW - Neuroserpin

KW - Humans

KW - Serpins/metabolism

KW - Neuropeptides/metabolism

KW - Blood-Brain Barrier/metabolism

KW - Neuroprotection/drug effects

KW - Neuroprotective Agents/therapeutic use

KW - Tissue Plasminogen Activator/metabolism

U2 - 10.14336/AD.2024.0518

DO - 10.14336/AD.2024.0518

M3 - SCORING: Review article

C2 - 39191396

VL - 15

SP - 2191

EP - 2204

JO - AGING DIS

JF - AGING DIS

SN - 2152-5250

IS - 5

ER -