Status epilepticus (SE) is a life-threatening neurological emergency characterized by persistent seizures, leading to brain damage that increases the risk of recurrent seizures due to abnormal electrical impulses produced by damaged neurons. However, the molecular mechanism by which convulsive SE leads to neuronal damage is not completely understood. Cathepsin S (Ctss), a lysosomal cysteine protease, has been implicated in secondary injury after traumatic brain injury. This study sought to explore whether Ctss is also involved in SE-induced neuronal damage in the hippocampus. Immunohistochemistry and Western blotting were utilized to detect the expression of Ctss in the hippocampal subregions of male C57BL/6J mice at various times following kainic acid (KA)-induced SE. The reactivity of microglia was assessed using immunohistochemistry, and Fluoro-Jade C (FJC) staining was employed to identify damaged neurons. We found that the mature form of Ctss is barely observed in naïve adult (12-week-old) mouse hippocampus, but its expression is significantly evident at 50 weeks of age. In adult mice, the expression of both pro-and mature forms of Ctss in the hippocampal CA3 region was increased as early as 16 h following KA-induced SE. The increased Ctss immunoreactivity was mainly found in microglia following KA-induced SE. The damaged neurons visualized by FJC staining were prominent in the CA3 region at 16 h following KA-induced SE. Ctss knockdown did not affect KA-induced behavioral seizures but significantly reduced SE-induced microglia activation and neuronal damage. An increase in chemokine CX3C motif ligand 1 (CX3CL1) immunoreactivity on microglia was observed following KA-induced SE, and CX3C motif chemokine receptor 1 (CX3CR1) antagonist AZD8797 treatment significantly attenuated SE-induced microglia activation and neuronal damage. Altogether, these results indicate a crucial role of Ctss in SE-induced neuronal damage, possibly through CXC3L1-mediated microglial activation, and provide a new perspective for preventing SE-induced neuronal damage.
Date:
2025-03-05
Relation:
Journal of Neurochemistry. 2025 Mar 05;169(3):Article number e70037.
