Background: Temporal lobe epilepsy (TLE) is a common form of epilepsy, characterized by recurrent seizures, hippocampal tissue cell loss, and cognitive impairment. This study aimed to investigate the role of aspartyl-tRNA synthetase 2 (DARS2) in regulating the pathophysiological characteristics and apoptosis of hippocampal tissue in a rat model of TLE.

Methods: TLE was induced in rats using pilocarpine. Gene and protein expression levels in hippocampal tissues were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Spatial memory was evaluated using the Morris water maze test, and histopathological changes were analyzed by hematoxylin and eosin (HE) staining. The levels of inflammatory cytokines and antioxidant-related factors were determined by enzyme-linked immunosorbent assay (ELISA).

Results: DARS2 expression was significantly reduced in hippocampal tissues of TLE rats (p < 0.05). Upregulation of DARS2 improved spatial memory, alleviated histopathological damage, decreased cell apoptosis and inflammation, enhanced antioxidant capacity, increased expression of heme oxygenase-1 (HO-1) and B-cell lymphoma 2 (Bcl-2), and reduced cleaved caspase-3 levels (p < 0.05). Mechanistically, DARS2 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in rat hippocampal tissues, and silencing Nrf2 reversed the protective effects of DARS2 overexpression (p < 0.05).

Conclusion: DARS2 exerts neuroprotective effects in TLE by mitigating rat hippocampal pathophysiological damage, suppressing apoptosis, and enhancing antioxidant defenses through activation of the Nrf2 signaling pathway. These findings suggest that DARS2 may serve as a promising therapeutic target for the treatment of TLE and related cognitive deficits.