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Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis
Li-Gang Huang1, Jing Zou1, Qin-Chi Lu1
1Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Temporal lobe epilepsy (TLE) is a chronic neurological disease characterized by recurrent spontaneous seizures. MicroRNAs are dysregulated in various pathological conditions including epilepsy. Therefore, we hypothesized that the dysregulation of these microRNAs might also be associated with the pathogenesis of TLE. In this study, we found that a microRNA, hsa-miR-155-5p, was upregulated in patients with TLE post-surgery, and hence associated with clinical and pathological manifestations and seizure outcomes. We then used a rat model of experimental epilepsy induced by pilocarpine and revealed that the rat homologue was upregulated as well. Importantly, injection of an antagomiR of rno-miR-155-5p in vivo resulted in a reduction of the pathophysiological features associated with the status epilepticus, which was accompanied by decrease of apoptosis in the hippocampus. This effect was correlated with an increase in rat Sestrin-3 expression, which was a gene known to counteract oxidative stress. This rescue was also observed after injection of a lentivirus carrying the small interfering RNA of rat Sestrin-3 gene in the hippocampus. In addition, rno-miR-155-5p as well as rat Sestrin-3 mRNA and protein expression were partly dependent on oxidative stress induced by H2O2 in PC12 cells. Taken together, our data suggest that rno-miR-155-5p is a potent post-transcriptional regulator of rat Sestrin-3 and it may be one of the molecular links between brain damage and increased risk for seizures during damage by oxidative stress.
Insights
MicroRNA-155-5p is elevated in temporal lobe epilepsy (TLE) patients and rat models. Inhibiting this microRNA reduces seizures and brain damage by increasing Sestrin-3, a gene that combats oxidative stress.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Temporal lobe epilepsy (TLE) is a chronic neurological disorder marked by recurring seizures.
- MicroRNAs (miRNAs) are known to be dysregulated in various diseases, including epilepsy.
- The specific role of miRNAs in TLE pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the role of microRNA-155-5p (miR-155-5p) in the pathogenesis of temporal lobe epilepsy (TLE).
- To explore the relationship between miR-155-5p, Sestrin-3 expression, and oxidative stress in TLE.
- To assess the therapeutic potential of targeting miR-155-5p in experimental epilepsy.
Main Methods:
- Analysis of hsa-miR-155-5p levels in post-surgery TLE patients.
- Induction of experimental epilepsy in rats using pilocarpine to model TLE.
- Administration of antagomiR against rno-miR-155-5p and lentivirus carrying Sestrin-3 siRNA in rats.
- Assessment of apoptosis, oxidative stress markers, and Sestrin-3 expression in the hippocampus.
- Investigation of miR-155-5p and Sestrin-3 regulation by hydrogen peroxide (H2O2) in PC12 cells.
Main Results:
- hsa-miR-155-5p was upregulated in TLE patients and its rat homologue (rno-miR-155-5p) was upregulated in a rat epilepsy model.
- Inhibition of rno-miR-155-5p reduced seizure-associated pathophysiological features and hippocampal apoptosis.
- This inhibition correlated with increased rat Sestrin-3 expression, a known antioxidant.
- Silencing Sestrin-3 partially reversed the protective effects.
- miR-155-5p and Sestrin-3 expression were partly dependent on oxidative stress.
Conclusions:
- miR-155-5p is upregulated in TLE and associated with disease manifestations and outcomes.
- rno-miR-155-5p acts as a post-transcriptional regulator of rat Sestrin-3.
- The miR-155-5p/Sestrin-3 axis may represent a molecular link between oxidative stress-induced brain damage and epilepsy.
- Targeting miR-155-5p may offer a therapeutic strategy for TLE.
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