Berberine targets the STAT3 signaling pathway to improve cognitive impairment in chronic cerebral hypoperfusion rats.

Berberine (BBR) possesses varied pharmacological properties, including anti-apoptotic and potent neuroprotective effects, and can ameliorate cognitive impairments associated with diverse diseases. Despite the noted potential of BBR in mitigating cognitive deficits associated with chronic cerebral hypoperfusion (CCH), the precise mechanisms underlying its therapeutic effects remain inadequately defined. To explore these mechanisms, a CCH rat model was developed using a refined micro-spring method for bilateral common carotid artery stenosis (BCAS). For the experimental setup, rats were systematically divided into six groups: a Sham group (n = 15), a Sham + BBR group (n = 15), a BCAS group (n = 15), a BCAS + BBR group (n = 15), a BCAS + BBR + Colivelin group (with Colivelin serving as a STAT3 activator, n = 15), and a BCAS + AG490 group (AG490 acting as a JAK2 inhibitor, n = 15). Cognitive performance was evaluated through the Morris water maze and novel object recognition (NOR) tests. Additionally, neuronal integrity was assessed by Nissl and TUNEL staining within the hippocampal region. The study further examined the protein expressions of JAK2, STAT3, phosphorylated JAK2, phosphorylated STAT3, and cleaved caspase-3 using western blot analysis. Interaction targets of BBR were predicted through the STITCH database, and its binding affinity to STAT3 was confirmed using molecular docking and surface plasmon resonance (SPR) techniques. The findings indicated an increase in apoptosis and a decline in cognitive abilities among the hippocampal neurons of the BCAS model rats. These deleterious effects, however, were substantially alleviated following treatment with BBR. The study posits that BBR primarily exerts its neuroprotective effects through the inhibition of the JAK2/STAT3 pathway. Notably, while the activation of this pathway by Colivelin exacerbated neuronal damage and cognitive decline, its inhibition via AG490 markedly decreased apoptosis and improved cognitive outcomes. Therefore, this research suggests that BBR enhances cognitive functions in BCAS rats predominantly by reducing apoptosis in hippocampal neurons through the modulation of the JAK2/STAT3 pathway.