Abstract
Cerebral ischemia, or stroke, is widespread leading cause of death and disability. Surgical and pharmacological interventions that recover blood flow are the most effective treatment strategies for stroke patients. However, restoring the blood supply is accompanied by severe reperfusion injury, with edema and astrocyte end-feet disruption. Here, we report that the oral administration of CU06-1004 (previously Sac-1004), immediately after onset of ischemia/reperfusion (I/R), ameliorated cerebral damage. CU06-1004 stabilized blood‑brain barrier by inhibiting the disruption of the tight junction-related protein zona occludens-1 and the cortical actin ring in endothelial cells (ECs) after I/R. Interestingly, CU06-1004 significantly suppressed astrocyte end-feet swelling following I/R, by reducing aquaporin 4 and connexin 43 levels, which mediates swelling. Furthermore, the degradation of β1-integrin and β-dystroglycan, which anchors to the cortical actin ring in ECs, was inhibited by CU06-1004 administration after I/R. Consistently, CU06-1004 administration following I/R also suppressed the loss of laminin and collagen type IV, which bind to the cortical actin ring anchoring proteins. Unlike the protective effects of CU06-1004 in ECs, astrocyte viability and proliferation were not directly affected. Taken together, our observations suggest that CU06-1004 inhibits I/R-induced cerebral edema and astrocyte end-feet swelling by maintaining EC junction stability.Key messages• CU06-1004 ameliorates I/R-induced cerebral injury.• EC junction integrity was stabilized by CU06-1004 treatment after I/R.• CU06-1004 reduces astrocyte end-feet swelling following I/R.• EC junction stability affects astrocyte end-feet structure maintenance after I/R.
Highlights
Cerebral ischemia, or stroke, has become a leading cause of death and disability, worldwide [1]
Because the mechanism of astrocyte end-feet disruption after I/R injury and whether the breakdown of endothelial cells (ECs) junctions is closely involved in astrocyte end-feet disruption both remain elusive, here, we investigated the effects of CU06-1004 on edema and astrocyte end-feet swelling during I/R injury
To identify whether similar effects could be observed through other routes, we examined the oral administration of CU061004
Summary
Stroke, has become a leading cause of death and disability, worldwide [1]. Ischemia/reperfusion (I/R) injury is a feature of stroke that occurs when the blood supply is restored after ischemia. Reperfusion can be achieved either through thrombolysis using thrombolytic reagents or the surgical removal of thrombi [2]. Reperfusion causes detrimental effects, including edema, blood‐brain barrier (BBB) breakdown, and astrocyte endfeet swelling in stroke patients [2,3,4]. The underlying mechanisms associated with reperfusion damage remain poorly understood. Methods to protect against stroke need to be developed to inhibit reperfusion-induced damage
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