The potential benefits of quercetin on brain ischemic injury in rats

Cerebral ischemia/reperfusion (I/R) injury is a leading cause of neuronal damage, contributing to neurodegenerative diseases. This study explored the neuroprotective effects of quercetin (QCT), a natural flavonoid, in a rat I/R model. In Silico analysis was conducted using online databases to identify potential QCT targets related to brain ischemia. Forty male albino rats (220–250 g) were distributed into four groups as follows: the first group (Gp1): Sham group, Gp2: I/R untreated group, Gp3 and Gp4: I/R groups pretreated with QCT at 25 and 50 mg/kg b.wt, respectively for seven days before middle cerebral artery occlusion, followed by reperfusion for 24 hours. Brain injury and protection were evaluated via biochemical, histopathological, and ultrastructural assessments. Intersection analysis revealed 46 shared targets between QCT and cerebral ischemia, with epidermal growth factor receptor (EGFR), protein kinase B (AKT), proto-oncogene tyrosine-protein kinase Src (c-Src), glycogen synthase kinase 3 beta (GSK3β), and matrix metalloproteinase-9 (MMP9). Docking studies showed strong QCT binding to these proteins. I/R elevated Src and MMP9 levels, while reducing phosphorylated EGFR, AKT, and GSK3β levels, contributing to neuronal damage, mitochondrial swelling, endoplasmic reticulum (ER) stress, synaptic loss, and blood-brain barrier (BBB) disruption. QCT pretreatment, particularly at 50 mg/kg, prevents these effects by reducing Src and MMP9 levels, restoring EGFR/AKT/GSK3β phosphorylation, and preserving mitochondrial, ER, neuronal, and BBB integrity. QCT provides dose-dependent neuroprotection by modulating key proteins and preserving cortical neuron and BBB structure after I/R injury.