Dose-dependent neuroprotective effects of liraglutide in penicillin-induced epileptic neurotoxicity in rats

Introduction

Epileptic seizures are associated not only with abnormal neuronal discharges but also with long-term neuronal damage mediated by oxidative stress, apoptosis, and impaired neurotrophic signalling. Experimental studies have demonstrated that epileptic activity is associated with neuronal loss, increased oxidative stress, and activation of apoptotic pathways, particularly in hippocampal regions. Liraglutide, a glucagon-like peptide-1 receptor agonist, has recently attracted attention because of its potential neuroprotective properties. This study investigated the neuroprotective effects of liraglutide, focusing on its dose-dependent effects on oxidative stress, apoptosis, and neurotrophic response in a penicillin-induced epileptic neurotoxicity model. This is the first study to examine the effects of liraglutide in a penicillin-induced epileptic neurotoxicity model.

Methods

Thirty-five male Sprague–Dawley rats were randomly divided into five groups: Sham, Control, LIR300, LIR600, and LIR1200 (n=7 per group). Epileptic neurotoxicity was induced by intracortical administration of 500 IU of penicillin. Liraglutide was administered intraperitoneally at doses of 300, 600, and 1,200 µg/kg/day for 8 consecutive days. Behavioral assessments included rotarod and Morris water maze tests to evaluate motor coordination, spatial learning, and memory. Histological and immunohistochemical analyses were performed to assess hippocampal neuronal cell density, active caspase-3, and brain-derived neurotrophic factor (BDNF) immunoreactivity in hippocampal subregions (dentate gyrus, CA1, and CA2–CA3). Serum oxidative stress was evaluated using total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). Data were analyzed using non-parametric tests (Kruskal–Wallis and Friedman) with Dunn–Bonferroni post hoc correction, and p<0.05 was considered statistically significant.

Results

Liraglutide treatment showed partial beneficial effects on behavioural, histopathological, and laboratory parameters, with effects dependent on dose and hippocampal region. In the LIR1200 group, rotarod performance improved significantly compared with the Control group over the first three days, with the following p-values: Day 1, p=0.014; Day 2, p=0.018; and Day 3, p=0.011. In addition, spatial memory performance improved (p=0.033). Liraglutide significantly increased TAS levels in all treatment groups compared with Control group (LIR300, p=0.002; LIR600, p<0.001; LIR1200, p=0.002), with no significant differences in other oxidative stress parameters. Hippocampal cell density in the CA2–CA3 region was significantly higher in the LIR300 group than in the Control group (p=0.002). Active caspase-3 reactivity in the CA1 region was significantly reduced in both the LIR600 and LIR1200 groups compared with the Control group (p=0.022 for both). Furthermore, in the LIR600 group, BDNF immunoreactivity increased significantly in both the CA1 and CA2–CA3 regions (p=0.018 and p<0.001, respectively). Although improvements were observed in various domains, these effects were not consistent across all parameters and hippocampal regions.

Conclusions

Liraglutide demonstrated partial neuroprotective effects against penicillin-induced epileptic neurotoxicity, with a non-uniform dose–response pattern. The most consistent beneficial effects were observed at 600 µg/kg, whereas the 1,200 µg/kg dose showed improvements in selected behavioural and apoptotic parameters without demonstrating clear overall superiority. The 300 µg/kg dose showed more limited but region-specific effects, particularly in neuronal cell preservation. These findings suggest that liraglutide may have potential as an adjunctive treatment for functional impairment and structural neuronal damage caused by epileptic neurotoxicity, although further studies are needed.

References

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