Caspase-1-mediated pyroptosis drives secondary thalamic neurodegeneration after focal cerebral infarction

Secondary neurodegeneration in brain regions remote from the primary infarct contributes substantially to long-term neurological dysfunction after ischemic stroke. Although pyroptosis has been implicated in acute ischemic injury, its contribution to delayed secondary thalamic degeneration remains poorly understood. This study investigated whether canonical inflammasome-mediated pyroptosis contributes to secondary thalamic injury following focal cerebral infarction.

A permanent distal middle cerebral artery electrocoagulation model was established in male C57BL/6 mice. Adeno-associated virus-mediated short hairpin RNA targeting caspase-1 was stereotactically delivered into the ipsilateral thalamus two weeks before ischemic injury. Behavioral assessments, histological analyses, immunofluorescence, and Western blotting were performed at predefined time points after infarction. Focal cortical ischemia induced marked activation of caspase-1 and downstream pyroptotic signaling within the ipsilateral thalamus, accompanied by progressive neuronal loss, astrocytic activation, and microglial polarization toward a pro-inflammatory phenotype. Targeted caspase-1 knockdown significantly improved sensory and cognitive performance, preserved thalamic neurons, reduced astrocyte proliferation, suppressed the expression of gasdermin D, interleukin-1β, and interleukin-18, and promoted polarization of Iba-1-positive cells toward an anti-inflammatory M2-like phenotype.

Canonical inflammasome-mediated pyroptosis plays an important role in secondary thalamic neurodegeneration after focal cerebral infarction. Targeted inhibition of caspase-1 attenuated remote neuroinflammation and neurodegeneration, supporting canonical inflammasome signaling as a promising therapeutic target for limiting delayed brain injury following ischemic stroke.