Synergistic Strategies for Ischemic Stroke Revascularization: Unraveling the Role of the Tryptophan-Indole-NETs Axis in Acupuncture and rt-PA Thrombolysis

Ischemic stroke remains a leading cause of disability and mortality worldwide, with timely revascularization being critical to successful outcomes. While recombinant tissue plasminogen activator (rt-PA) remains the gold standard for thrombolytic therapy, its efficacy is often limited by delayed administration, reperfusion injury, and systemic side effects. Recent research has highlighted the potential of integrative approaches such as acupuncture to enhance the effectiveness and safety of rt-PA therapy. This study investigates the synergistic effects of acupuncture and rt-PA thrombolysis in ischemic stroke treatment, focusing on the regulatory role of the tryptophan-indole-neutrophil extracellular traps (NETs) axis in promoting neurovascular recovery. Using a controlled experimental model, we observed that acupuncture modulates gut microbiota-derived indole metabolites from tryptophan, which in turn downregulate NETs formation—a key mediator of inflammation and thrombosis. The combined treatment not only improved cerebral blood flow and infarct resolution but also reduced neuronal apoptosis and inflammatory markers, suggesting a neuroprotective mechanism. These findings suggest that the tryptophan-indole-NETs axis serves as a critical biological bridge through which acupuncture potentiates rt-PA’s thrombolytic and neurovascular effects. This study offers novel insights into how metabolic and immunological pathways intersect with traditional therapies to improve clinical outcomes in ischemic stroke management and opens new avenues for integrated, precision-based interventions.