Mechanism of DKK3 protecting brain tissues in ischemic stroke by regulating LGI1 expression and activity

Objective: To investigate the mechanism of Dickkopf-3 (DKK3) in protecting brain tissues in ischemic stroke (IS) by regulating LGI1 expression and activity.

Methods: 220 patients with acute ischemic stroke (AIS) were enrolled to measure the serum DKK3 levels and analyze the predictive ability of serum DKK3 for early neurological deterioration (END) in AIS patients. A murine model of permanent middle cerebral artery occlusion (pMCAO) was established. Neurological function recovery in mice was assessed using neurological function scores and behavioral experiments, and the volume of cerebral infarction in mice was measured. The histopathological morphology of the cortex in mice was observed by hematoxylin‒eosin staining; apoptotic neurons were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. DKK3 and leucine-rich glioma-inactivated protein 1 (LGI1) expression levels were measured by immunofluorescence, RT-qPCR, or Western blot, and their interaction was verified by bioinformatics analysis and Co-IP. A cellular model of oxygen-glucose deprivation (OGD) injury was established using HT22 murine neurons for in vitro investigation.

Results: DKK3 was downregulated in IS and shows potential as a biomarker for predicting END in AIS patients. DKK3 overexpression contributed to neurological recovery and attenuated brain injury in pMCAO mice. DKK3 co-localized and interacted with LGI1. LGI1 downregulation weakened the protective effect of DKK3 against pMCAO-induced brain damage and OGD-induced neuronal injury.

Conclusion: DKK3 protects against ischemic injury in permanent cerebral ischemia by regulating LGI1 expression and activity.

DKK3; HT22; Ischemic stroke; LGI1.