Buyang Tongluo Decoction Mitigates Acute Ischemic Stroke by Suppressing NLRP3/Caspase-1/GSDMD Pathway-Induced Pyroptotic Cell Death

Abstract

Background: Acute ischemic stroke (AIS) is associated with neuroinflammation and pyroptotic cell death. The NLRP3/Caspase-1/GSDMD signaling pathway plays an important role in ischemia-induced inflammatory injury. Buyang Tongluo Decoction (BTD), a modified traditional Chinese medicine formulation derived from Buyang Huanwu Decoction (BHD), may exert neuroprotective effects in AIS. Objectives: This study investigated the neuroprotective effects of BTD in AIS and their association with inhibition of pyroptosis pathways involving NLRP3, Caspase-1, and GSDMD. Methods: A focal cerebral ischemia–reperfusion model was established using a modified filament occlusion technique. Experimental animals were assigned to four groups: sham controls, untreated model animals, BTD-treated animals, and a positive comparator group receiving BHD. Post-intervention evaluations included neurological assessment using Longa scores, cerebral perfusion analysis by laser speckle imaging, and quantification of ischemic lesions by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histological examination of brain tissue and neuronal architecture was performed using Nissl and hematoxylin and eosin (H&E) staining, and cellular ultrastructure was assessed using transmission electron microscopy. Protein expression levels of NLRP3, Caspase-1, GSDMD, and HIF-1α were analyzed by Western blotting, and inflammatory cytokine concentrations were determined by enzyme-linked immunosorbent assay. The primary outcomes were neurological score and cerebral infarct volume. Secondary outcomes included cerebral blood flow, histological changes, ultrastructural findings, pyroptosis-related protein expression, and inflammatory cytokine levels. Results: Compared with the untreated model group, neurological impairment scores were significantly reduced in both the BTD and BHD groups, with BTD showing a greater trend toward neurological recovery. Cerebral perfusion was reduced and infarct volume was increased in untreated model animals, whereas these pathological changes were alleviated by BTD and BHD. BTD treatment was associated with marginally smaller infarct volumes than BHD. Histopathological examination of untreated specimens revealed substantial neuronal injury and disruption of tissue architecture, accompanied by characteristic pyroptotic changes at the ultrastructural level. Both interventions restored morphological and ultrastructural features. In addition, untreated model animals showed increased expression of pyroptosis-related proteins and elevated inflammatory markers, which were significantly suppressed after BTD and BHD administration. Comparative analysis indicated that BTD showed a stronger trend toward modulation of these molecular pathways. Conclusions: Buyang Tongluo Decoction exerted neuroprotective effects by alleviating neurological dysfunction and reducing cerebral tissue injury. These effects were associated with the suppression of NLRP3/Caspase-1/GSDMD pathway-mediated pyroptosis and inflammatory responses.