Sphingosine-1-phosphate attenuates seizures and cognitive deficits, associated with reduced hippocampal IL-1β in a PTZ-induced epilepsy model.

BACKGROUND AND AIM: Epilepsy is a prevalent neurological disorder frequently accompanied by cognitive impairments and neuronal damage. Neuroinflammation-particularly mediated by interleukin-1β (IL-1β)-plays a critical role in epileptogenesis. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, has been implicated in neuroprotection and anti-inflammatory signaling; however, its role in epilepsy remains unclear. This study aimed to investigate the effects and underlying mechanisms of S1P in a pentylenetetrazol (PTZ)-induced mouse model of epilepsy.

METHODS

Male C57BL/6 mice were administered PTZ (33 mg/kg, i.p.) every other day for a total of 15 injections to establish a seizure-kindling model. S1P (0.5 mg/mL) was administered intraperitoneally during the subsequent treatment period. Seizure activity was assessed using electroencephalographic (EEG) recordings. Cognitive function was evaluated with the Morris water maze. Hippocampal neuronal morphology was examined via Nissl staining. The expression levels of IL-1β mRNA and precursor protein in the hippocampus were measured by qRT-PCR and Western blotting, respectively.

RESULTS

S1P treatment significantly reduced seizure frequency and amplitude, shortened seizure duration, and ameliorated EEG abnormalities in epileptic mice. In behavioral assays, S1P improved spatial learning and memory performance. Histological analysis demonstrated reduced neuronal degeneration and preservation of hippocampal architecture in S1P-treated epileptic mice. Furthermore, S1P markedly decreased hippocampal IL-1β expression at both the mRNA and protein levels.

CONCLUSIONS

S1P exerts anti-seizure and neuroprotective effects in PTZ-induced epileptic mice and attenuates IL-1β-mediated neuroinflammation. These findings suggest that the S1P-IL-1β axis may represent a promising therapeutic target for epilepsy and its associated cognitive impairments.