- In acquired epilepsies, seizures occur as a result of a physical injury, stroke, infection, brain tumor, and various neurological diseases.
- One way that scientists study acquired epilepsies in the lab is by using an experimental model called the “status epilepticus” (SE) model.
- In people, SE is a medical emergency characterized by unrelenting generalized seizures lasting more than five minutes and that can be associated with negative cognitive impacts, an eventual epilepsy diagnosis, and even death.
- One of the hallmarks of SE is inflammation in the brain that manifests in a variety of ways. The invasion of inflammatory cells called monocytes from the blood into the brain is one facet of the inflammatory cascade.
- Nicholas H. Varvel at the Emory University School of Medicine received a CURE Epilepsy Award in 2019 to examine whether reducing the invasion of monocytes into the brain could be a therapeutic strategy for SE and potentially other acquired epilepsies.
- Dr. Varvel’s team found that using a drug to reduce the invasion of monocytes from the blood into the brain minimized the harmful effects of SE, such as a loss in functional impairment and inflammation.
- Dr. Varvel’s work provides yet another clue to our understanding of acquired epilepsies; with more experiments and evidence, drugs that block monocyte invasion could become a therapy for the prevention and cure of acquired epilepsies.
“Acquired” epilepsies are those where seizures occur as a result of a physical injury, infection, stroke, brain tumor and other insults to the brain. In past Discovery articles, we shared the work of CURE Epilepsy grantees who are researching in the field of acquired epilepsies, specifically post-traumatic epilepsies (PTE) as part of the PTE Initiative, and understanding neuroinflammation as it relates to epileptogenesis, the process by which the brain starts generating seizures after a brain injury or insult. This month’s Discovery focuses on another cause of epilepsy called “status epilepticus” (SE). Status epilepticus is a medical emergency and is characterized by unrelenting, generalized seizures lasting more than five minutes that have the potential to cause serious and lasting impacts. Indeed, more than 40% of individuals that survive SE go on to develop epilepsy within 10 years of the SE episode.
Status epilepticus can have many deleterious effects on the brain. Hardening (also called “sclerosis”) of a part of the brain called the hippocampus can take place.[4, 5] Additionally, the blood-brain barrier (BBB) – a part of the vasculature of the brain that protects the brain from harmful substances – may erode, letting in molecules that cause inflammation. In acquired epilepsies, certain inflammatory substances known as “cytokines” and “chemokines” may be activated. Additionally, there can be the invasion of inflammatory cells called monocytes from the blood into the brain. Studies in animal models suggest that reducing inflammation can relieve the negative impacts of SE, namely neuronal damage, erosion of the BBB, and behavioral deficits.[8-10]
Dr. Nicholas H. Varvel at the Emory University School of Medicine received a CURE Epilepsy Award in 2019 to investigate if stopping the invasion of monocytes into the brain could be a therapeutic target for SE and potentially other acquired epilepsies. Researchers have shown that monocytes can invade the brain from blood in other neurological conditions, and this formed the basis of Dr. Varvel’s rationale.[11, 12]
Monocytes express a receptor known as CCR2, which mediates their migration from the blood to injured tissues. Previous studies done in Dr. Varvel’s lab showed that using a genetic technique to remove CCR2 prevented the invasion of monocytes into the brain. This technique also reduced inflammation as defined by neuronal damage and erosion of the BBB. Recent work from Dr. Varvel’s lab explored if using a drug to reduce CCR2 in the days after SE could provide benefits similar to the genetic method. Understanding the consequences of early inhibition of CCR2 immediately after SE might eventually lead to the development of a therapy that could target inflammation and the harmful effects that usually follow.
In this study Dr. Varvel showed the specific involvement of monocytes in SE; blocking CCR2 (a receptor that is found on monocytes) through the use of an orally-administered drug was neuroprotective, as seen by fewer changes in inflammatory markers, the extent of erosion of the BBB, and most importantly, improved functional recovery. Hence, the CCR2 antagonist represents a strategy by which the immediate harmful effects of SE could potentially be reduced. More experiments are necessary to provide definitive answers, but one can envision a therapeutic intervention and future clinical trials, using a CCR2 antagonist that when administered to an individual after SE could reduce its harmful effects and potentially even prevent epilepsy.
- Sirven JI. Epilepsy: A Spectrum Disorder Cold Spring Harb Perspect Med. 2015 Sep 1;5:a022848.
- Iyengar SS, Lubbers LS, Harte-Hargrove L, CURE Epilepsy Post-Traumatic Initiative Advisors, Investigators. A team science approach for the preclinical and clinical characterization and biomarker development for post-traumatic epilepsy Epilepsia Open.n/a.
- Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus Ann Neurol. 1998 Dec;44:908-912.
- Lewis DV, Shinnar S, Hesdorffer DC, Bagiella E, Bello JA, Chan S, et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study Ann Neurol. 2014 Feb;75:178-185.
- Fujikawa DG, Itabashi HH, Wu A, Shinmei SS. Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy Epilepsia. 2000 Aug;41:981-991.
- van Vliet EA, da Costa Araújo S, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy Brain. 2007 Feb;130:521-534.
- Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus Proc Natl Acad Sci U S A. 2016 Sep 20;113:E5665-5674.
- Broekaart DWM, Anink JJ, Baayen JC, Idema S, de Vries HE, Aronica E, et al. Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression Epilepsia. 2018 Oct;59:1931-1944.
- Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation Proc Natl Acad Sci U S A. 2013 Feb 26;110:3591-3596.
- Rojas A, Amaradhi R, Banik A, Jiang C, Abreu-Melon J, Wang S, et al. A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats Neurotherapeutics. 2021 Apr;18:1207-1225.
- Gyoneva S, Kim D, Katsumoto A, Kokiko-Cochran ON, Lamb BT, Ransohoff RM. Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury Journal of Neuroinflammation. 2015 2015/12/03;12:228.
- Howe CL, LaFrance-Corey RG, Overlee BL, Johnson RK, Clarkson BDS, Goddery EN. Inflammatory monocytes and microglia play independent roles in inflammatory ictogenesis Journal of Neuroinflammation. 2022 2022/01/29;19:22.
- Alemán-Ruiz C, Wang W, Dingledine R, Varvel NH. Pharmacological inhibition of the inflammatory receptor CCR2 relieves the early deleterious consequences of status epilepticus Sci Rep. 2023 Apr 6;13:5651.