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.