Bovis calculus sativus improves cognitive function after ischemic stroke by regulating PKA/CREB/Sirt1/eIF2α signaling...

Bovis calculus sativus (BCS) is a traditional medicinal agent known for its pharmacological properties, which include heat-clearing, mental faculty revitalization, liver-cooling, and anticonvulsant effects. It is widely used application in the treatment of ischemic stroke accompanied by cognitive impairment; however, further research is necessary to clarify its effects and underlying mechanisms.

This study examined the therapeutic potential of BCS in mitigating ischemic stroke-induced cognitive impairment induced by ischemic stroke, focusing on its mechanism of action in enhancing synaptic plasticity via the PKA/CREB/Sirt1/eIF2α signaling pathway.

ICR mice were randomly allocated into six groups: sham-operated, model, edaravone (EDA), and BCS at dosages of 5, 10, and 15 mg/kg. The global cerebral ischemia/reperfusion (GCI/R) model was established using double-vessel occlusion combined with hypotension. Cognitive function was assessed through eight-arm maze and novel object recognition tests. Histological alterations in the hippocampal CA1 region were assessed via hematoxylin-eosin (HE) staining, while neuronal morphology was analyzed using Golgi staining. The expression levels of Synapsin1 (SYN1), postsynaptic density-95 (PSD95), phosphorylated protein kinase A (p-PKA), phosphorylated cAMP response element-binding protein (p-CREB), silent mating type information regulation 2 homolog-1 (Sirt1), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), and phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK) were quantified through Western blot analysis. In vitro, PC12 cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R) were treated with BCS and the Sirt1 inhibitor EX527 was employed to elucidate the mechanism of action.

BCS (10 and 15 mg/kg) significantly improved cognitive performance, reduced memory errors (P < 0.05), and increased dendritic branching and spine density (P < 0.001). Histological analysis revealed a significant loss of neurons in the model group, while BCS treatment significantly preserved neuronal integrity (P < 0.001). BCS increased p-PKA levels, thereby activating CREB transcriptional activity and upregulating Sirt1 expression. Moreover, BCS suppressed the PERK/eIF2α pathway, elevating PSD95 and SYN1 expression. This promoted synaptic remodeling and restored cognitive function after ischaemic injury. In the OGD/R model, BCS restored PSD95, SYN1, and Sirt1 expression (P < 0.001), whereas EX527 markedly reduced their expression (P < 0.01). In contrast, p-eIF2α expression was significantly higher in the model group (P < 0.001) but decreased after BCS treatment. EX527 raised the p-eIF2α levels again (P < 0.05).

BCS appears to enhance hippocampal synaptic plasticity, possibly via the PKA/CREB/Sirt1/eIF2α pathway, which may promote neuronal survival and partially improve cognitive function in ischemic stroke models. These findings suggest that BCS could be a potential therapeutic agent for stroke-induced cognitive impairment.