Chrysin and Gallic Acid Protect the Hippocampal Neurons and Mitigate Blood-Brain Barrier Disruption in a Mouse Model of Global Cerebral Ischemia

Background: Cerebral ischemia activates harmful biochemical pathways that result in blood-brain barrier (BBB) breakdown and neuronal damage. Natural compounds such as chrysin and gallic acid (GA), known for their antioxidant and anti-inflammatory properties, may protect the BBB and reduce neuronal injury. Objectives: This study aimed to examine the effects of combining chrysin and GA on hippocampal neuronal damage, cognitive function, BBB integrity, and claudin-5 expression in a mouse model of cerebral ischemia. Methods: Cerebral ischemia was induced through bilateral common carotid artery occlusion (BCCAO) for 30 minutes, followed by 48 hours of reperfusion. Chrysin (30 mg/kg, intraperitoneally), GA (50 mg/kg, intraperitoneally), and their combination were administered at the start of reperfusion and subsequently at 30 minutes and 1 hour. Hippocampal neuronal damage, spatial memory, Evans blue (EB) leakage, and claudin-5 expression were evaluated 48 hours after reperfusion. Results: Administration of chrysin, GA, and their combination significantly enhanced neuronal survival in the CA1, CA3, and dentate gyrus (DG) regions (P < 0.001). The combination diminished neurological deficit scores (1.5 ± 0.22 vs. control 3.5 ± 0.56, P < 0.05) and escape latency time (12.8 ± 4.5 vs. control 40 ± 4.82 seconds, P < 0.01). Likewise, these interventions significantly reduced EB leakage (3.46 ± 0.62 vs. control 11.28 ± 0.98 μg/g of brain tissue) and upregulated claudin-5 expression (38% ± 1.29 vs. control 10.75% ± 1.65, P < 0.001). Conclusions: This study demonstrated that the combined treatment of chrysin and GA synergistically promoted hippocampal neuron survival, improved neurological function, and maintained BBB integrity by upregulating claudin-5 expression. We suggest that this therapeutic approach may offer potential benefits for stroke patients, though further experimental and clinical investigation is required to confirm its efficacy.