Translational Stroke Research最新文献

Disruption of the blood-brain barrier (BBB) is an important pathological hallmark of ischemic stroke. Blood-brain barrier disruption (BBBD) is a consequence of ischemia and may also exacerbate damage to brain parenchyma. Therefore, maintaining BBB integrity is critical for the central nervous system (CNS) homeostasis. This review offers a concise overview of BBB structure and function, along with the mechanisms underlying its impairment following a stroke. In addition, we review the recent imaging techniques employed to study blood-brain barrier permeability (BBBP) in the context of ischemic brain injury with the goal of providing imaging guidance for stroke diagnosis and treatment from the perspective of the BBBD. This knowledge is vital for developing strategies to safeguard the BBB during cerebral ischemia.

Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX^−/− mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day 5 to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. In SAH mice, 12/15-LOX was upregulated in brain vascular cells, and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4–5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.

The glymphatic system is crucial for clearing metabolic waste from the brain, maintaining neural health and cognitive function. This study explores the glymphatic system's role in Moyamoya disease (MMD), characterized by progressive cerebral artery stenosis and brain structural lesions. We assessed 33 MMD patients and 21 healthy controls using diffusion tensor imaging along the perivascular space (DTI-ALPS) and global cortical gray matter-cerebrospinal fluid (CSF) coupling indices (gBOLD-CSF), which are indirect measurements of the glymphatic system. Cerebral perfusion in patients was evaluated via computed tomography perfusion imaging. We also measured the peak width of skeletonized mean diffusivity (PSMD), white matter hyperintensity (WMH) burden, and cognitive function. MMD patients exhibited lower ALPS and gBOLD-CSF coupling indices compared to controls (P < 0.01), indicating disrupted glymphatic function. Significant cognitive impairment was also observed in MMD patients (P < 0.01). ALPS indices varied with cerebral perfusion stages, being higher in earlier ischemic stages (P < 0.05). Analysis of brain structure showed increased CSF volume, PSMD index, and higher WMH burden in MMD patients (P < 0.01). The ALPS index positively correlated with white matter volume and cognitive scores, and negatively correlated with CSF volume, PSMD, and WMH burden (P < 0.05). Mediation analysis revealed the number of periventricular WMH significantly mediated the relationship between glymphatic dysfunction and cognitive impairment. In summary, MMD patients exhibit significant glymphatic system impairments, associated with brain structural changes and cognitive deficits.

Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) have shown considerable promise as restorative stroke treatment. In a head-to-head comparison in mice exposed to transient proximal middle cerebral artery occlusion (MCAO), sEVs obtained from MSCs cultured under hypoxic conditions particularly potently enhanced long-term brain tissue survival, microvascular integrity, and angiogenesis. These observations suggest that hypoxic preconditioning might represent the strategy of choice for harvesting MSC-sEVs for clinical stroke trials. To test the efficacy of hypoxic MSCs in a second stroke model in an additional species, we now exposed 6-8-month-old Sprague-Dawley rats to permanent distal MCAO and intravenously administered vehicle, platelet sEVs, or sEVs obtained from hypoxic MSCs (1% O₂; 2 × 10⁶ or 2 × 10⁷ cell equivalents/kg) at 24 h, 3, 7, and 14 days post-MCAO. Over 28 days, motor-coordination recovery was evaluated by rotating pole and cylinder tests. Ischemic injury, brain inflammatory responses, and peri-infarct angiogenesis were assessed by infarct volumetry and immunohistochemistry. sEVs obtained from hypoxic MSCs did not influence infarct volume in this permanent MCAO model, but promoted motor-coordination recovery over 28 days at both sEV doses. Ischemic injury was associated with brain ED1⁺ macrophage infiltrates and Iba1⁺ microglia accumulation in the peri-infarct cortex of vehicle-treated rats. Hypoxic MSC-sEVs reduced brain macrophage infiltrates and microglia accumulation in the peri-infarct cortex. In vehicle-treated rats, CD31⁺/BrdU⁺ proliferating endothelial cells were found in the peri-infarct cortex. Hypoxic MSC-sEVs increased the number of CD31⁺/BrdU⁺ proliferating endothelial cells. Our results provide evidence that hypoxic MSC-derived sEVs potently enhance neurological recovery, reduce neuroinflammation. and increase angiogenesis in rat permanent distal MCAO.

The active hemorrhage surrounding the hematoma is caused by the infiltration of blood into the cerebral parenchyma through the ruptured vessel, including the compromised blood-brain barrier (BBB). This process is thought to be mainly driven by inflammation and serves as a significant pathological characteristic that contributes to the neurological deterioration observed in individuals with intracerebral hemorrhage (ICH). Heat shock protein 90 (HSP90) exhibits abnormally high expression levels in various diseases and is closely associated with the onset of inflammation. Here, we found that blocking HSP90 effectively alleviates the inflammatory damage to BBB and subsequent bleeding around the hematoma. We have observed increased HSP90 levels in the serum of patients with ICH and the perihematoma region in ICH rats. Treatment with anti-HSP90 drugs (Geldanamycin and radicicol) effectively reduced HSP90 levels, resulting in enhanced neurological outcomes, decreased hematoma volume, and prevented peripheral immune cells from adhering to the BBB and infiltrating the brain parenchyma surrounding the hematoma in ICH rats. Mechanistically, anti-HSP90 therapy alleviated BBB injury caused by ICH-induced inflammation by suppressing TLR4 signaling. The study highlights the potential of anti-HSP90 therapy in mitigating BBB disruption and hemorrhage surrounding the hematoma, providing new insights into the management of ICH by targeting HSP90.

The interdependence between arteriogenesis and angiogenesis is crucial for enhancing perfusion by synchronously improving leptomeningeal collaterals (LMCs) and microvascular networks after stroke. However, current approaches often focus on promoting arteriogenesis and angiogenesis separately, neglecting the potential synergistic benefits of targeting both processes simultaneously. Therefore, it is imperative to consider both arteriogenesis and angiogenesis as integral and complementary strategies for post-stroke revascularization. To gain a deeper understanding of their relationships after stroke and to facilitate the development of targeted revascularization strategies, we compared them based on their timescale, space, and pathophysiology. The temporal differences in the occurrence of arteriogenesis and angiogenesis allow them to restore blood flow at different stages after stroke. The spatial differences in the effects of arteriogenesis and angiogenesis enable them to specifically target the ischemic penumbra and core infarct region. Additionally, the endothelial cell, as the primary effector cell in their pathophysiological processes, is promising target for enhancing both. Therefore, we provide an overview of key signals that regulate endothelium-mediated arteriogenesis and angiogenesis. Finally, we summarize current therapeutic strategies that involve these signals to promote both processes after stroke, with the aim of inspiring future therapeutic advances in revascularization.

The 2023 International Subarachnoid Hemorrhage Conference identified a need to provide an up-to-date review on prevention methods for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage and highlight areas for future research. A PubMed search was conducted for key factors contributing to development of delayed cerebral ischemia: anesthetics, antithrombotics, cerebrospinal fluid (CSF) diversion, hemodynamic, endovascular, and medical management. It was found that there is still a need for prospective studies analyzing the best methods for anesthetics and antithrombotics, though inhaled anesthetics and antiplatelets were found to have some advantages. Lumbar drains should increasingly be considered the first line of CSF diversion when applicable. Finally, maintaining euvolemia before and during vasospasm is recommended as there is no evidence supporting prophylactic spasmolysis or angioplasty. There is accumulating observational evidence, however, that intra-arterial spasmolysis with refractory DCI might be beneficial in patients not responding to induced hypertension. Nimodipine remains the medical therapy with the most support for prevention.

Middle cerebral artery steno-occlusive disease (MCAD) has been recognized as a different clinical entity from moyamoya disease (MMD). Although MCAD can progress to MMD, the extent to which patients actually progress and the risk factors for this progression have not been fully elucidated. We retrospectively reviewed patients with MCAD who underwent RNF213 genotyping. Demographic features, RNF213 p.R4810K mutation, medical history, and longitudinal changes in angiography were analyzed. Sixty patients with 81 affected hemispheres were enrolled. During the follow-up period, 17 patients developed MMD, and the RNF213 p.R4810K mutation was the only factor significantly associated with progression to MMD (odds ratio, 16.1; 95% CI, 2.13-731; P = 0.001). The log-rank test demonstrated that patients with the mutation had a higher risk of progression to MMD (P = 0.007), stenosis progression (P = 0.010), and symptomatic cerebral infarction or hemorrhage (P = 0.026). In Cox regression analysis the p.R4810K mutation remained a significant factor after adjusting for age group (childhood or adult onset) at diagnosis (hazard ratio, 8.42; 95% CI, 1.10-64.4). Hemisphere-based analysis also showed that the mutation was associated with a higher risk of progression to the MMD hemisphere (P = 0.002), stenosis progression (P = 0.005), and cerebral infarction or hemorrhage (P = 0.012). The RNF213 p.R4810K mutation was identified as a risk factor for progression from MCAD to MMD. Genotyping for this mutation may contribute to risk stratification in MCAD.