Leptomeningeal Glial Modulation of Ischemic Stroke Reperfusion to Avoid Futile Recanalization

Background

Ischemic Stroke is caused by the sudden blockage of cerebral arteries, leading to millions of disabilities and deaths globally each year. The current treatment for ischemic stroke primarily involves intravenous thrombolysis or mechanical thrombectomy, or a combination of both to restore blood flow. However, despite timely and successful revascularization of the blocked vessels, many patients do not show significant clinical improvement, a phenomenon known as “Futile Recanalization.” Effective vascular recanalization is fundamental for restoring cerebral blood flow, but multiple processes, including distal thrombus fragmentation, pericyte contraction, or neutrophil capillary plugging, can impede reperfusion in the ischemic brain area, leading to “futile recanalization.”

Leptomeningeal Collaterals (LMCs) are anastomotic vessels connecting the terminal branches of the middle cerebral artery (MCA) with the terminal branches of the anterior cerebral artery (ACA) and posterior cerebral artery (PCA). Studies have shown that under healthy physiological conditions, the blood flow in LMCs is minimal, but when the major supplying artery is blocked, the blood flow in LMCs is mobilized to provide partial cerebral perfusion. In stroke patients, extensive LMCs are associated with better thrombolysis and mechanical thrombectomy outcomes, but how LMCs influence reperfusion post-recanalization remains to be explored.

Source of Research

This study was conducted by Nadine Felizitas Binder, Mohamad El Amki, Chaim Glück, and others from the Department of Neurology at the University Hospital Zurich and the University of Zurich in Switzerland. The results were published on May 1, 2024, in the journal Neuron.

Research Process

Study Design and Procedure

The study utilized three strains of mice with significantly different quantities of LMCs: C57BL/6 mice (abundant LMCs), Rabep2-/- mice (moderate to sparse LMCs), and Balb-c mice (sparse LMCs). Using brain clarification and immunostaining techniques, the researchers employed laser sheet microscopy to image alpha-smooth muscle actin-positive cells within the mouse brain, defining the quantity of LMCs (average of 10 per hemisphere, 2-3, and nearly none).

To study the impact of LMCs on thrombosis and thrombolysis processes, researchers induced stroke in the three mouse strains using a thrombin model and intervened with thrombolytic therapy. They observed cerebral blood flow changes during reperfusion using laser speckle contrast imaging (LSCI), ultra-fast ultrasound imaging, and two-photon microscopy. In vivo whole-brain imaging and in vitro blood flow simulation were utilized to analyze the redistribution effect of LMCs on blood flow.

Experimental Results

In the control mice, vascular occlusion persisted for 2 hours post-thrombin injection, while in the rt-PA (thrombolytic enzyme) infusion model starting 30 minutes post-stroke, the recanalization rate showed no significant differences across strains. This indicates that LMCs do not directly influence the thrombolysis process.

The study found that C57BL/6 mice with abundant LMCs had the smallest infarct volume and highest sensorimotor function seven days post-stroke, whereas Balb-c mice with sparse LMCs showed the opposite. Two-photon microscopy revealed that post-stroke, blood flow in LMCs redistributed from ACA to MCA and gradually returned to baseline levels after MCA recanalization.

Blood flow simulation demonstrated that with abundant LMCs, blood flow redistributed from ACA to MCA side, reaching maximal levels (100% LMCs resulted in a 714% increase in flow saturation within a 250μm range compared to no LMCs).

Laser speckle imaging showed that in C57BL/6 mice with rich LMCs, reperfusion in the ischemic area was slower but more stable, whereas LMC-deficient mice showed rapid and uncontrolled reperfusion, leading to hemorrhagic complications and worse prognosis.

Validation in Clinical Data

Clinically, researchers collected data from 96 patients treated for acute ischemic stroke at the University Hospital Zurich. Analysis revealed that patients with sparse LMCs exhibited a similar rapid reperfusion pattern post-recanalization, accompanied by higher hemorrhagic transformation rates and poor recovery trends.

Conclusion

Through meticulous animal experiments and clinical data analysis, the study confirms the crucial role of LMCs in ischemic stroke reperfusion. In mice with abundant LMCs, reperfusion is gradual and stable, maintaining better tissue integrity and clinical outcomes. Conversely, LMC-deficient mice and patients may experience rapid and excessive reperfusion, increasing tissue damage and hemorrhage risk.

Future stroke treatments should focus on enhancing LMC function to ensure favorable reperfusion following thrombolysis and mechanical thrombectomy. This study reveals the potential of LMCs as a new target for stroke therapy and offers a new perspective for related treatment strategies.

Research Highlights

1. The study for the first time reveals the critical role of LMCs in stroke treatment, enriching the understanding of cerebral reperfusion mechanisms.
2. Utilized multiple advanced imaging techniques to precisely monitor blood flow changes, proving the protective role of LMCs in reperfusion.
3. Clinical data validated the animal experiment results, indicating that the quantity of LMCs is closely related to clinical outcomes, providing important evidence for stroke treatment strategies.

Through this research, the medical community is expected to develop more targeted stroke treatments in the future, reduce the phenomenon of futile recanalization, and improve patient recovery rates and quality of life.