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, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing
brain injury. Our previous study showed that
CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic
reperfusion injury, and promoted the normalization of
tumor vasculature. Here, we evaluated the effects of
CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain.
RESULTS: In this study, we investigated the protective effects of
CU06-1004 against oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with
hydrogen peroxide (H2O2) to establish an oxidative stress-induced model of cellular injury. Compared with H2O2 treatment alone, pretreatment of HBMECs with
CU06-1004 considerably reduced oxidative stress-induced cytotoxicity,
reactive oxygen species generation, senescence-associated β-
galactosidase activity, senescence marker expression, and the expression levels of inflammatory
proteins. Based on the observed cytoprotective effects of
CU06-1004 in HBMECs, we examined whether
CU06-1004 displayed protective effects against cerebrovascular aging in 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 the extravasation of plasma
IgG by improving BBB integrity in the aged mouse brain, associated with reductions in neuronal injury. A series of behavioral tests also revealed improved motor and cognitive functions in aged mice that received long-term
CU06-1004 administration.
CONCLUSIONS: These findings suggest that
CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age.