Abstract
Novel therapies that prevent or modify the development of epilepsy following an initiating brain insult could significantly reduce the burden of this disease. In light of evidence that immune mechanisms play an important role in generating and maintaining the epileptic condition, we evaluated the effect of a well-established immunomodulatory treatment, intravenous immunoglobulin (IVIg), on the development of epilepsy in an experimental model of epileptogenesis. In separate experiments, IVIg was administered either before (pre-treatment) or after (post-treatment) the onset of pilocarpine status epilepticus (SE). Our results show that both pre- and post-treatment with IVIg attenuated acute inflammation in the SE model. Specifically, IVIg reduced local activation of glial cells, complement system activation, and blood-brain barrier damage (BBB), which are all thought to play important roles in the development of epilepsy. Importantly, post-treatment with IVIg was also found to reduce the frequency and duration of subsequent spontaneous recurrent seizures as detected by chronic video-electroencephalographic (video-EEG) recordings. This finding supports a novel application for IVIg, specifically its repurposing as a disease-modifying therapy in epilepsy.
Highlights
Novel therapies that prevent or modify the development of epilepsy following an initiating brain insult could significantly reduce the burden of this disease
Consistent with previous reports[26], status epilepticus (SE) was associated with a significant upregulation of CD11b on resident microglia in the hippocampus of vehicle-treated animals (Fig. 1Ai); CD11b staining was notably reduced, in SE animals that were pre-treated with intravenous immunoglobulin (IVIg) (2 hours prior to SE induction; Fig. 1Aii)
Quantification of CD11b-positive cell numbers confirmed that IVIg pre-treatment significantly reduced the number of activated microglia in the CA1 and CA3 regions of the hippocampus compared to vehicle treatment (p < 0.05, one-way ANOVA with NewmanKeuls post-hoc test; Fig. 1B)
Summary
Novel therapies that prevent or modify the development of epilepsy following an initiating brain insult could significantly reduce the burden of this disease. In light of evidence that immune mechanisms play an important role in generating and maintaining the epileptic condition, we evaluated the effect of a well-established immunomodulatory treatment, intravenous immunoglobulin (IVIg), on the development of epilepsy in an experimental model of epileptogenesis. Post-treatment with IVIg was found to reduce the frequency and duration of subsequent spontaneous recurrent seizures as detected by chronic videoelectroencephalographic (video-EEG) recordings This finding supports a novel application for IVIg, its repurposing as a disease-modifying therapy in epilepsy. An antecedent brain injury, such as febrile status epilepticus (SE), precedes the development of TLE by a period free of clinical seizures lasting several years[1,2] Neurobiological changes during this period underpin epileptogenesis, the process by which the epileptic condition develops. Human IVIg crosses the mouse blood-brain barrier, reaching significant concentrations in the brain[19,20,21,22]
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