Abstract
Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues.
Highlights
Epilepsy is a brain disease that affects around 65 million people worldwide (Devinski et al, 2018)
We show that lipid mediator levels apt to resolve the neuroinflammatory response are significantly altered during epileptogenesis, and describe the expression of pro-resolving receptors in mouse and human epileptogenic hippocampi versus control brain tissue
As an index of neuroinflammation, we measured Il1b and Tnfa mRNA levels by RT-qPCR in the mouse hippocampus from 2 h until 7 days post-status epilepticus to encompass the epileptogenesis phase preceding the onset of spontaneous seizures
Summary
Epilepsy is a brain disease that affects around 65 million people worldwide (Devinski et al, 2018). Neuroinflammation is characterized by increased cytokines, such as interleukin1b (IL-1b), tumour necrosis factor- (TNF- ), high mobility group box 1 (HMGB1), their cognate receptors and downstream effector molecules in glia, neurons and blood–brain barrier cellular components (Ravizza et al, 2006, 2008, 2011; Boer et al, 2008; Vezzani et al, 2013) These inflammatory molecules significantly contribute to the generation and recurrence of spontaneous seizures (Vezzani et al, 2011a, b; Terrone et al, 2017) and to neurological comorbidities (Mazarati et al, 2017) in animal models. Pharmacological or genetic interventions for increasing the endogenous anti-inflammatory IL-1 receptor antagonist (IL-1Ra, encoded by IL1RN) drastically reduced the frequency of seizures in experimental models (De Simoni et al, 2000; Vezzani et al, 2000, 2002; Librizzi et al, 2012; Bertani et al, 2017; Walker et al, 2017) and in humans (Jyonouchi, 2016; Kenney-Jung et al, 2016; DeSena et al, 2018), afforded neuroprotection (Noeet al., 2013) and rescued neurological deficits (Mazarati et al, 2017)
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