Long-term Administration of CU06-1004 Ameliorates Cerebrovascular Aging and BBB Injury in Aging Mouse Model: A Randomized Control Trial

Abstract

Abstract Background: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption and vascular dementia are emerging as potential risks for many neurodegenerative diseases. Therefore, endothelial cells that constitute the cerebrovasculature play a key role in preventing brain injury. Our previous study showed that CU06-1004, endothelial cell dysfunction blocker, prevented vascular leakage and enhanced vascular integrity in ischemic reperfusion injury and normalization of tumor vasculature. Here, we evaluate the effects of CU06-1004 on age-related decline in cerebrovascular function of aged mice brain. Results: In this study, we investigated the protective effects of CU06-1004 on reducing oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress-induced cellular injury model. Pretreatment with CU06-1004 considerably reduced oxidative stress-induced cytotoxicity, ROS generation, senescence-associated β-galactosidase activity, and senescence markers in HBMECs. Additionally, pretreatment with CU06-1004 decreased the expression levels of inflammatory proteins, compared to H2O2 treatment alone. Based on the cytoprotective effect of CU06-1004 in HBMECs, we further examined the vascular protective effects of CU06-1004 on cerebrovascular aging in aged mice. Long-term administration of CU06-1004 alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in the aged mouse brain. CU06-1004 supplementation also reduced extravasation of plasma IgG by improving BBB integrity in the aged mouse brain. This improvement in BBB integrity was associated with reduced neuronal injury and cognition memory dysfunction in aged mice. A series of behavioral tests revealed improved motor and cognitive function in aged mice that received CU06-1004. Conclusion: These findings suggest CU06-1004 has promise as a therapeutic for delaying age-related cerebrovascular impairment and improving cognitive function in old age.