Cerebral Inhibition of the H3K9 Methylation Could Ameliorate Blood-Brain Barrier Dysfunction and Neural Damage in Vascular Dementia

Dementia encompasses a broad category of brain diseases characterized by various degenerative or vascular components that lead to a long-term and often gradual decline in cognitive abilities, significantly affecting daily functioning. Literature indicates that the G9a/GLP enzyme, through the upregulation of histone 3 lysine 9 dimethylation (H3K9me2), plays a pivotal role in vascular dementia (VD). The increase in H3K9 methylation by G9a/GLP during VD inhibits the expression of neuroprotective proteins and diminishes the expression of proteins crucial for maintaining blood-brain barrier (BBB) integrity. Using a model of permanent common carotid artery (CCA) occlusion, we investigated the effects of a G9a/GLP inhibitor (BIX01294) on VD. Following CCA occlusion, BIX01294 (22.5 µg/kg) was administered intraperitoneally three times a week for one month. We assessed neuronal damage using Nissl staining, BBB permeability via the Evans blue test, and measured brain water content. Western blot analysis was employed to evaluate the hippocampal levels of Bax and Bcl2 proteins. Treatment with BIX01294 enhanced BBB stability (P < 0.05) and subsequently reduced brain edema compared to the VD group (P < 0.05 for both measures). Neuronal injury in the CA1 region of the hippocampus significantly decreased following BIX01294 administration compared to the VD group (P < 0.05). Furthermore, the Bax/Bcl2 ratio markedly decreased in the treatment group (P < 0.0001). In summary, our research demonstrates that inhibiting H3K9 methylation can prevent the progression of vascular dementia by reducing cerebral edema and neuronal apoptosis in the hippocampus following ischemic stroke.