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Berberine targets the STAT3 signaling pathway to improve cognitive impairment in chronic cerebral hypoperfusion rats
1Department of Rheumatology and Immunology, The Third Affiliated Hospital of Jinzhou Medical University, No.2, Section 5, Heping Road, Linghe District, Jinzhou 121000, Liaoning Province, China.
Insights
Berberine (BBR) protects against cognitive decline in chronic cerebral hypoperfusion (CCH) by reducing hippocampal neuron apoptosis via the JAK2/STAT3 pathway. This neuroprotective effect improves cognitive function in CCH models.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Berberine (BBR) shows neuroprotective potential against cognitive impairments.
- Mechanisms of BBR's therapeutic effects in chronic cerebral hypoperfusion (CCH) are not fully understood.
- CCH is linked to apoptosis and cognitive deficits.
Purpose of the Study:
- To elucidate the neuroprotective mechanisms of Berberine (BBR) in a rat model of chronic cerebral hypoperfusion (CCH).
- To investigate the role of the JAK2/STAT3 signaling pathway in BBR's therapeutic effects.
- To assess BBR's impact on cognitive function and hippocampal neuronal integrity.
Main Methods:
- A chronic cerebral hypoperfusion (CCH) rat model was established using bilateral common carotid artery stenosis (BCAS).
- Rats were treated with Berberine (BBR), a STAT3 activator (Colivelin), or a JAK2 inhibitor (AG490).
- Cognitive function was assessed using Morris water maze and novel object recognition tests; neuronal apoptosis was evaluated by TUNEL and Nissl staining; protein expression (JAK2, STAT3, cleaved caspase-3) was analyzed via Western blot; BBR targets were predicted using STITCH and validated by molecular docking and SPR.
Main Results:
- BCAS rats exhibited impaired cognitive function and increased hippocampal neuronal apoptosis.
- Berberine (BBR) treatment significantly alleviated cognitive deficits and reduced apoptosis in BCAS rats.
- BBR treatment modulated the JAK2/STAT3 pathway, decreasing apoptosis and improving cognitive outcomes, an effect mimicked by JAK2 inhibition (AG490) and reversed by STAT3 activation (Colivelin).
Conclusions:
- Berberine (BBR) demonstrates significant neuroprotective effects in chronic cerebral hypoperfusion (CCH) by reducing hippocampal apoptosis.
- The primary mechanism involves the modulation of the JAK2/STAT3 signaling pathway.
- BBR holds therapeutic potential for cognitive impairments associated with chronic cerebral hypoperfusion (CCH).
Abstract:
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.
