Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA

Abstract

Inflammatory signaling in the central nervous system (CNS) has been shown to exacerbate both seizure activity and seizure-induced neuronal injury. However, it has not been firmly established whether neurodegeneration is a prerequisite of proconvulsant effect of neuroinflammation, or whether the latter may facilitate seizures without involving neuronal injury. We examined effects of inflammation in the rapid kindling model, where seizure progression occurs in the absence of neurodegeneration. P14 male Wistar rats were subjected to a rapid kindling procedure: 60 electrical stimulations of the hippocampus delivered every 5 min at the current that had been established to induce afterdischarge. Lipopolysaccharide (LPS) was injected (50 microg/kg, i.p., 2 h prior to the rapid kindling protocol [RKP]); IL-1Ra was injected (25 mg/kg, i.p., 2 h prior to the RKP). The effects of treatments were examined on baseline hippocampal excitability, on the progression of rapid kindling, and on the retention of rapid kindling. LPS increased baseline hippocampal excitability, evident as the decrease of hippocampal ADT. LPS also increased kindling progression. Twenty-four hours after the completion of kindling procedure, LPS-treated animals exhibited increased excitability as compared with saline-treated kindling controls. The kindling progression was blocked by IL1RA when given in combination with LPS. IL1RA was able to reverse the effect of LPS on afterdischarge duration (ADD) while IL1RA alone decreased ADT. We showed that inflammation provoked by LPS enhanced rapid kindling epileptogenesis in immature rat brains. IL1RA was also able to mitigate this augmentation of epileptogenesis enhanced by LPS.

Figure 1

Rapid kindling in P14 rats. A: representative behavioral stage 4 seizure (indicated by rearing) in a P14 rat. B: baseline EEG recording in free moving P14 rat. C: EEG recording of the afterdischarge. D: EEG recording showing the end of the afterdischarge with a return to the baseline electrical activity.

Figure 2

Afterdischarge (AD) properties before kindling, kindling progression and AD properties after rapid kindling protocol (RKP) in the studied groups. The number of animals per groups is reported. A: AD threshold (ADT) before RKP. B: AD duration (ADD) before C: number of stage 4 seizure. D: mean duration of stage 4 seizure. E: ADT 24 hours after RKP. F: ADD 24 hours after RKP. The bars indicate a significant difference (p<0.05)