Catalpol Confers Neuroprotection against Cerebral Ischemic Injury by Regulating the Phosphatidylinositol 3-kinase/Protein Kinase B/Glycogen Synthase Kinase 3 Beta/β-catenin Signaling Pathway

Abstract Background: Ischemic stroke is a leading cause of long-term neurological disability worldwide. Within minutes of its onset, blood flow to the brain’s ischemic core drops dramatically, resulting in irreversible damage and eventual neuronal death in the affected area. Currently, effective clinical therapies to reduce brain injury caused by ischemic stroke are still limited. Catalpol, a bioactive compound extracted from the traditional Chinese medicine herb Rehmannia glutinosa , has shown neuroprotective effects in various neurological disorders. Emerging evidence suggests that catalpol exerts therapeutic benefits in ischemic stroke; however, its effect on neuronal apoptosis following cerebral ischemia (CI) and the underlying pharmacological mechanisms remain incompletely understood. Objective: This study aimed to gain deeper insights into the effects of catalpol on neuronal apoptosis following ischemic stroke. Materials and Methods: To evaluate the effects of catalpol both in vivo and in vitro , a rat model of middle cerebral artery occlusion/reperfusion and an oxygen–glucose deprivation/reperfusion (OGD/R) cell model were established. Behavioral assessments were performed to determine the impact of catalpol on neurological function in ischemic rats. In addition, cerebral infarction size, brain index, cerebral blood flow, and histological analyses, including 2,3,5-triphenyltetrazolium chloride and hematoxylin-eosin staining, were used to assess the therapeutic potential of catalpol. Neuronal apoptosis in ischemic rats was evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The protective effects of catalpol against OGD/R-induced injury in SH-SY5Y cells were assessed using cell counting kit-8 and lactate dehydrogenase assays. Hoechst 33342 and TUNEL staining were also employed to examine apoptosis in OGD/R-exposed neurons following catalpol treatment. Furthermore, immunofluorescence staining and Western blot analysis were conducted to detect the expression of key signaling proteins. Results: In vivo , catalpol alleviated neurological deficits and improved both neurological function and brain tissue integrity in ischemic rats. It enhanced neuronal morphology and reduced apoptosis following CI. In vitro , catalpol protected against OGD/R-induced cellular injury. Findings from both animal and cell-based experiments confirmed that catalpol mitigates oxidative stress damage and inflammation while inhibiting neuronal apoptosis after CI. These neuroprotective effects are likely mediated through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3 beta (GSK3β)/β-catenin signaling pathway. Conclusions: The present study suggests that catalpol protects neurons and inhibits apoptosis by activating the PI3K/Akt/GSK3β/β-catenin signaling cascade, highlighting its potential as a therapeutic intervention for ischemic stroke.