Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.

Proinflammatory cytokine interleukin-1 beta (IL-1ß) may accumulate in the brain during status epilepticus, but whether it contributes to the progressive refractoriness of SE remains unclear. By using a kainic acid-induced SE mice model, we tested whether pharmacological blockade or knock-out of interleukin-1 receptor type 1 (IL-1R1) could influence the diazepam-refractory phenomenon of prolonged SE. We confirmed diazepam failed to terminate prolonged SE (allowed to continue for 40min before diazepam administration). The expression level of IL-1ß in the hippocampus during prolonged SE was significantly higher than that of baseline. Interestingly, prolonged SE was not diazepam-refractory in IL-1R1 knock-out mice. Moreover, administration of interleukin-1 receptor antagonist (IL-1RA) combined with diazepam terminated established prolonged SE, while IL-1RA alone is not capable to terminate prolonged SE. On the contrary, administration of recombinant human IL-1ß weakens the efficacy of diazepam by prolonging its latency to terminate non-prolonged SE. Thus, the present study provides direct evidence that accumulated IL-1ß contributed to the diazepam refractoriness of prolonged SE, and suggests that interleukin-1 receptor is a target for adjunctive control of diazepam-refractory SE.

[Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice].

OBJECTIVE: To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS). METHODS: The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively. RESULTS: Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01). CONCLUSION: The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.

The Pro-inflammatory Cytokine Interleukin-1ß is a Key Regulatory Factor for the Postictal Suppression in Mice.

AIMS: The postictal suppression (PS) is a common and important period following an epileptic seizure but has not been well studied. This study was designed to determine whether interleukin-1ß (IL-1ß) is involved in the PS. METHODS: The effects of IL-1ß on the PS were tested in three independent seizure models induced by hippocampal kindling, maximal electroshock seizure (MES), and 4-aminopyridine, respectively. RESULTS: IL-1R1 knockout or IL-1RA enhanced the seizure refractory phenomenon without influencing the baseline seizure threshold in intermittent MES model. IL-1ß attenuated the seizure refractory phenomenon without affecting the severity of the preceding seizures in hippocampal kindling model, while IL-1RA enhanced it. Besides, IL-1ß reduced the postictal EEG suppression period, while IL-1RA prolonged it. And IL-1ß showed no further effect on the postictal EEG suppression and seizure refractory phenomenon in IL-1R1 knockout mice. In addition, 30 min after intrahippocampal injection of 4-aminopyridine, IL-1ß increased the incidence of SE, while IL-1RA prolonged the intervals between recurrent seizures. CONCLUSIONS: This study provides the first direct evidence that IL-1ß is key regulatory factor for the PS, and its receptor IL-1R1 may be a potential target for adjuvant treatment of postictal problems.