Mannosamine preserves blood brain barrier integrity and promotes angiogenesis in a stroke model

Cerebral ischemia remains a major global health challenge, contributing significantly to long-term disability and mortality, with limited therapeutic options currently available. This study explores the therapeutic potential of Mannosamine (ManN), an hexosamine previously shown to be a mitogen for endothelial cells (ECs), in the context of cerebral ischemic injury. Using a transient middle cerebral artery occlusion (tMCAO) mouse model, we assessed the effects of ManN administration on ischemic brain damage. Mice receiving ManN exhibited significantly smaller infarct volumes, as measured by magnetic resonance imaging (MRI), and reduced blood–brain barrier (BBB) permeability compared to controls. ManN treatment enhanced pericyte coverage, improved EC survival, and increased vascular density in the ischemic brain regions. Our analyses revealed attenuation of ischemia-induced structural abnormalities, including reduced vacuolation, cellular shrinkage, and nuclear condensation. To elucidate the underlying mechanisms, in vitro experiments with brain endothelial cells (bEND.3) demonstrated that ManN treatment promoted GSK3β phosphorylation and facilitated nuclear accumulation of β-catenin. This activation of the Wnt/β-catenin pathway led to upregulation of key target genes such as LEF1 , TCF7 , AXIN2 , and APCDD1 . Enhanced interaction of β-catenin with LEF1/TCF7 was associated with increased expression of tight junction proteins and transcytosis inhibitors, contributing to BBB stabilization and angiogenic support. Collectively, these findings highlight the ability of ManN to activate endothelial Wnt/β-catenin signaling, thereby preserving BBB integrity and promoting angiogenesis, suggesting its promise as a novel therapeutic strategy for cerebral ischemia.