Neuroprotective effect of naringin by modulation of klotho and HMGB1- TLR4 axis in PTZ-induced kindling in mice

Background

Naringin has demonstrated various neuroprotective effects; however, its anti-inflammatory and cognitive properties, particularly through the regulation of HMGB1-TLR4 and Klotho, have not been explored in the context of epilepsy.

Method

Kindling was induced in Swiss albino mice by administering pentylenetetrazole (PTZ) 25 mg/kg intraperitoneally (i.p.). Naringin (40 mg/kg and 80 mg/kg) was administered orally for 6 weeks. The severity of seizures was assessed using the Racine scale. Cognitive function was evaluated by measuring step-down latency and transfer latency. The levels of GABA, glutamate, IL-1β, IL-1R1, IL-6, HMGB1, TLR4, TNF-α, Klotho, and ADAM-10 were quantified using enzyme-linked immunosorbent assay (ELISA) techniques.

Results

Naringin significantly attenuated PTZ-induced seizures at both doses (p < 0.01 for 40 mg/kg; p < 0.0001 for 80 mg/kg) compared to the PTZ group. Additionally, it enhanced retention latency in both step-down latency (p < 0.01 for 40 mg/kg; p < 0.0001 for 80 mg/kg) and transfer latency (p < 0.05 for both doses) compared to the PTZ group. Furthermore, it increased Klotho and ADAM-10 levels in both the hippocampus and cortex (p < 0.01 for 40 mg/kg; p < 0.001 for 80 mg/kg, respectively). Levels of HMGB1, TLR4, and pro-inflammatory cytokines were significantly decreased in both the hippocampus and cortex compared to the PTZ group.

Conclusion

Naringin exhibited anti-epileptic effects by regulating neurotransmitter levels and preventing PTZ-induced kindling. Additionally, it demonstrated neuroprotective effects on cognition and attenuated neuroinflammation. These findings suggest that naringin may be a potential therapeutic agent for epilepsy-associated cognitive dysfunction, warranting further studies for clinical translation.