Targeting revascularization via tryptophan-indole-NETs axis: the synergistic power of acupuncture and rt-PA thrombolysis in ischemic stroke.

BACKGROUND: The Xingnao kaiqiao (XNKQ) method, meaning "awakening the mind," is an acupuncture technique developed by Academician Xuemin Shi. It has shown promise in ischemic stroke management. This study aims to explore the synergistic power and underlying mechanisms of XNKQ method and recombinant tissue plasminogen activator (rt-PA). METHODS: A rat embolic stroke model was utilized to replicate the pathological processes of ischemic stroke. The effects on cerebral perfusion and vascular leakage were assessed in vivo and in vitro. Both non-targeted and tryptophan-targeted metabolomic analyses were conducted to identify differential metabolites. Additionally, neutrophil extracellular traps (NETs) markers and vascular leakage were detected to elucidate the crosstalk. RESULTS: The combination of acupuncture and rt-PA has been shown to significantly ameliorate middle cerebral artery occlusion (MCAO)-induced cerebral infarction, blood flow obstruction, neurological deficits, and histopathological damage in rat models. Acupuncture may also reduce hemorrhagic transformation and cerebral edema linked to ultra-time window rt-PA thrombolysis. Metabolomic studies suggest acupuncture enhances the efficacy and safety of rt-PA via the tryptophan-indole metabolic pathway, facilitating the degradation of NETs proteases and reducing inflammation. Furthermore, NETs accumulation is linked to increased brain vascular permeability as evidenced by NETs regulators (LPS or DNase I). Acupuncture and NETs inhibitors both offer similar vascular protection during ultra-time window rt-PA thrombolysis, with acupuncture being more effective in reducing cerebral infarction. CONCLUSION: The degradation of NETs via the tryptophan-indole pathway may facilitate the restoration of vascular structure and function following ischemic stroke. Acupuncture has the potential to modulate this pathway, thereby possibly extending the therapeutic window for rt-PA thrombolysis.