RESUMEN
Objective: We evaluated the extent to which frailty mediated the association between age, poor functional outcomes, and mortality after acute ischemic stroke when patients were treated with brain reperfusion (thrombolytic therapy and/or thrombectomy). Materials and methods: This retrospective cohort study included patients diagnosed with ischemic stroke who had undergone intravenous cerebral reperfusion therapy and/or mechanical thrombectomy. We created a mediation model by analyzing the direct natural effect of an mRS score > 2 and death on age-mediated frailty according to the Frailty Index. Results: We enrolled 292 patients with acute ischemic stroke who underwent brain reperfusion. Their mean age was 67.7 ± 13.1 years. Ninety days after the stroke ictus, 54 (18.5%) participants died, and 83 (28.4%) lived with moderate to severe disability (2 < mRS < 6). In the mediation analysis of the composite outcome of disability (mRS score > 2) or death, frailty accounted for 28% of the total effect of age. The models used to test for the interaction between age and frailty did not show statistically significant interactions for either outcome, and the addition of the interaction did not significantly change the direct or indirect effects, nor did it improve model fit. Conclusion: Frailty mediated almost one-third of the effect of age on the composite outcome of disability or death after acute ischemic stroke.
RESUMEN
Ischemic stroke is a leading cause of mortality and chronic disability worldwide, underscoring the need for reliable and accurate animal models to study this disease's pathology, molecular mechanisms of injury, and treatment approaches. As most clinical strokes occur in regions supplied by the middle cerebral artery (MCA), several experimental models have been developed to simulate an MCA occlusion (MCAO), including transcranial MCAO, micro- or macro-sphere embolism, thromboembolisation, photothrombosis, Endothelin-1 injection, and - the most common method for ischemic stroke induction in murine models - intraluminal MCAO. In the intraluminal MCAO model, the external carotid artery (ECA) is permanently ligated, after which a partially-coated monofilament is inserted and advanced proximally to the common carotid artery (CCA) bifurcation, before being introduced into the internal carotid artery (ICA). The coated tip of the monofilament is then advanced to the origin of the MCA and secured for the duration of occlusion. With respect to other MCAO models, this model offers enhanced reproducibility regarding infarct volume and cognitive/functional deficits, and does not require a craniotomy. Here, we provide a detailed protocol for the surgical induction of unilateral transient ischemic stroke in mice, using the intraluminal MCAO model. Graphic abstract: Overview of the intraluminal monofilament method for transient middle cerebral artery occlusion (MCAO) in mouse.
RESUMEN
Cerebral ischemia-reperfusion (IR) injury is associated with mitochondrial damage. Macrophage-stimulating 1 (MST1) reportedly stimulates mitochondrial apoptosis by suppressing BCL-2. We investigated whether MST1 promotes the progression of cerebral IR injury by inducing mitochondrial dysfunction in vivo and in vitro. Western blot analysis, quantitative polymerase chain reaction, immunofluorescence, and mitochondrial function assays were conducted in cells from wild-type and Mst1-knockout mice subjected to cerebral IR injury. MST1 expression in wild-type glial cells increased following cerebral IR injury. Cerebral IR injury reduced the mitochondrial membrane potential and mitochondrial metabolism in glial cells, while it enhanced mitochondrial reactive oxygen species generation and mitochondrial calcium levels in these cells. The deletion of Mst1 attenuated cerebral IR injury by improving mitochondrial function and reducing mitochondrial damage. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was suppressed in wild-type glial cell upon cerebral IR injury but was reactivated in Mst1-knockout glial cell. Accordingly, blocking the MAPK/ERK pathway abolished the beneficial effects of Mst1 deletion during cerebral IR injury by inducing mitochondrial damage in glial cells. Our results suggest that cerebral IR injury is associated with MST1 upregulation in the brain, while the genetic ablation of Mst1 can attenuate mitochondrial damage and sustain brain function following cerebral IR injury.