Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

Abstract

BackgroundBlood–brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring.ResultsHere, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-κB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation.ConclusionsTaken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0897-3) contains supplementary material, which is available to authorized users.

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…Another promising pharmacological approach targeting BBB breakdown is Sac-1004, a pseudo-sugar derivative of cholesterol, which enhances endothelial barrier by stabilizing the cortical actin ring. Sac-1004 suppressed IL-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cell loss of tight junctions, and expression of adhesion molecules and activation of NF-κΒ (Zhang et al, 2017). In a rat model of acute transient cerebral ischemia, Sac-1004 reduced BBB leakage and loss of tight junction proteins, inhibited glial activation, and ameliorated neurological deficits and ischemic damage (Zhang et al, 2017).…”

Early IV-injected human dermis-derived mesenchymal stem cells after transient global cerebral ischemia do not pass through damaged blood-brain barrier

“…However, Borlongan et al () demonstrated that, in a rat model of MCAO for 1 hr, intravenously injected hMSCs (human umbilical cord blood cells), which were injected with BBB permeabilizer (mannitol) during the occlusion of MCA, were not found in the damaged brain parenchyma at 3 days after ischemia (Borlongan et al, ). Regarding the degree of damage of ischemic areas after ischemic insults, it has been reported that 1 hr of transient focal cerebral ischemia did not induce coagulation necrosis in the ischemic area at immediate phase after ischemia (Garcia, Yoshida, Chen, et al, ), but, severe infarction is shown 1–4 days after 1 h of transient focal ischemia (Zhang, Park, Maharjan, et al, ). Furthermore, early BBB leakage is differently detected depending on molecular weight of used tracers, namely, plasma IgG (~150 kDa) is detected within 3 hr and fluorescein isothiocyanate‐dextran (2,000 kDa) within 1 day after focal ischemia (Shi, Zhang, Pu, et al, ), indicating that a larger molecular weight of tracer could be extravasated after severe infarction.…”

SALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175

“…I/R was induced by middle cerebral artery occlusion on the left side as previously described in Zhang et al . (24). Briefly, the left common carotid artery (CCA) was exposed and separated from the vagus nerve.…”

“…(24) with slight modification. Briefly, after 16 h reperfusion, EB (2% in 0.9% saline, 4 ml/kg) was injected into the tail vein.…”

“…A heating pad (JD-OT-03106; Jeung-Do Bio and Plant, Seoul, South Korea) was used to maintain a body temperature of 37°C during surgery. I/R was induced by middle cerebral artery occlusion on the left side as previously described in Zhang et al (24). Briefly, the left common carotid artery (CCA) was exposed and separated from the vagus nerve.…”