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Strides Made in the Understanding of Acquired Epilepsies by CURE Epilepsy Grantees

Key Points:

  • An acquired epilepsy can occur as a result of brain infection, tumor, or injury leading to spontaneous seizures.
  • Little is known about the mechanisms underlying epileptogenesis, the process by which the brain starts generating seizures following an insult or injury.
  • CURE Epilepsy grantee Dr. Annamaria Vezzani at the Mario Negri Institute for Pharmacological Research in Milan has made strides understanding the process of neuroinflammation as it relates to epileptogenesis in acquired epilepsy.
  • Her work on a molecule known as High Mobility Group Box 1 (HMGB1) gives clues as to a potential blood-based biomarker of epileptogenesis and pharmacoresistance (failure to respond to at least two anti-seizure medications (ASMs)).
  • Vezzani’s mentee and continued colleague, Dr. Teresa Ravizza, has also been funded by CURE Epilepsy and continues to drive research to understand the biological mechanisms of acquired epilepsy.

 

Deep Dive

Epilepsy (also referred to as a “seizure disorder”) is a group of conditions characterized by recurrent seizures. Epilepsy can be the result of many different underlying causes including through “acquired” physical injury, infection, brain tumor, or stroke.[1] In acquired epilepsy, spontaneous seizures start after the injury or insult to the brain has occurred. The process by which the brain starts generating seizures after a brain injury or insult is called epileptogenesis. Currently, there is no way to predict who will experience epileptogenesis, and there are no treatments that can prevent or halt epileptogenesis. If there was a way to know that epileptogenesis is taking place or predict who is at risk for it, it might be possible to gain valuable insights into treating and even preventing seizures.

CURE Epilepsy has awarded numerous grants to investigators examining diverse aspects of acquired epilepsies. A few examples of discoveries funded by CURE Epilepsy include Dr. Bruce Gluckman and Dr. Steven Schiff’s development of preclinical models to predict acquired epilepsy following a brain infection, Dr. Gerben van Hameren’s work looking at a particular part of the cell called the mitochondria as a target for post-traumatic epilepsy (PTE), and Dr. Asla Pitkanen’s work that aims to study changes in gene expression in brain tissue in a preclinical model of traumatic brain injury (TBI).

A subset of acquired epilepsies is called PTE, which develops in the months or years following a TBI.[2] TBI may be caused by blows to the head, blasts, penetrating head injuries, accidental falls, sports-related injuries, or motor vehicle accidents. It is currently not possible to predict who will develop PTE after a TBI.[3] Dr. Annamaria Vezzani, head of the Laboratory of Epilepsy and Therapeutic Strategies, Department of Acute Brain Injury at the Mario Negri Institute for Pharmacological Research in Milan, has been an important part of CURE Epilepsy’s efforts to understand acquired epilepsies for decades as an early (2002) and repeat (2015) grantee, and more recently, as part of the PTE Initiative. Dr. Vezzani’s work centers on the role of inflammation in epilepsy. Her work looks at neuroinflammation (i.e., the inflammatory response that is sustained by cells in the brain after insult or injury) and has shown that neuroinflammation can play an important role in the generation of seizures.[4] Through a study funded by CURE Epilepsy, Dr. Vezzani first studied a specific signaling pathway in the brain called interleukin-1 (IL-1) type 1 receptor/Toll-like receptor (IL-1R/TLR4). Her experiments in experimental animals showed that IL-1beta and an inflammatory molecule known as High Mobility Group Box 1 (HMGB1) are released from specific brain cells known as “glia” during seizures.[5] The levels of HMGB1 increased in the brain and the blood before animals developed epilepsy, and this increase in HMGB1 levels was maintained during the development of epilepsy.[6,7] These results gave her precise biological mechanisms that could be targeted to stop seizures.

In addition to showing that HMGB1 is closely involved with seizures, Dr. Vezzani’s work also showed that during an injury or seizures, HMGB1 moves from the nucleus to the cytoplasm of a cell, and this form of HMGB1 can also be measured in blood.[5,8,9,10] More specifically, Dr. Vezzani showed that there is a form of HMGB1 (the disulfide isoform of HMGB1) that contributes to seizures [11]; this finding may inform development of targeted therapeutic strategies. What makes this discovery on HMGB1 particularly exciting for the epilepsy community is its numerous applications: this work could lead to the development of novel drugs to target and halt epileptogenesis, and could also be a way to stop seizures once they have started. As a biomarker, increased levels of HMGB1 could be a sign that epilepsy is about to develop.[10,11] Dr. Vezzani’s work also found that a combination of anti-oxidant drugs that are already used in medical practice is capable of preventing the increase in HMGB1 and delaying the onset of seizures, as well as reducing seizure burden and the memory impairments that are seen in epilepsy.[7]

The role of HMGB1 has also been studied in people with epilepsy. Patients with epilepsy whose seizures were not adequately controlled by ASMs were found to have higher levels of HMGB1 when compared to those who responded to ASMs, and people who did not have epilepsy. Therefore, this work is evidence that HMGB1 can distinguish, with a high level of accuracy, those who respond to ASMs versus those who do not. This adds to the evidence that suggests that HMGB1 can be used as a biomarker for predicting how someone will respond to ASMs.[12] Dr. Vezzani’s more recent CURE Epilepsy-funded work looks at HMGB1 as a target and a mechanistic biomarker of epileptogenesis. HMGB1 is also being studied in people who have experienced TBI as a part of CURE Epilepsy’s PTE Initiative, which funded a diverse group of researchers, including Dr. Vezzani, to develop experimental models to study PTE and discover prediction methods to enable early intervention and eventual prevention.

In addition to her impact and contribution to epilepsy research, Dr. Vezzani is also passionate about mentorship and has guided many mentees who are now established epilepsy researchers in their own right. One of her mentees, Dr. Teresa Ravizza, also at the Mario Negri Institute for Pharmacological Research, received a Taking Flight Award from CURE Epilepsy in 2011. As part of her project, Dr. Ravizza focused on specific cells in the brain known as “astrocytes” and the role of these cells in acquired epilepsies.[13] She also looked at the mechanisms that may contribute to the breakdown of the blood-brain barrier, a network of cells that keep harmful substances from reaching the brain, as previous studies had shown that activation of inflammatory astrocytes along with a breakdown in the blood-brain barrier leads to the generation and sustaining of seizures.[14] Dr. Ravizza’s work hypothesized that the development of epileptogenesis followed by spontaneous seizures is dependent on the extent, duration, and location of blood-brain barrier breakdown. By using a host of techniques, including visualizing the brain by magnetic resonance imaging (MRI), studying the electrical activity of brain circuits, and looking at the behavior of animals, Dr. Ravizza examined whether blood-brain barrier breakdown and glia activation may predict the development of spontaneous seizures and cognitive deficits. Preliminary data support this hypothesis, suggesting that information obtained from these experiments may one day help predict the trajectory of seizures and serve as an effective therapeutic strategy for acquired epilepsies.

Drs. Vezzani and Ravizza continue their work to study neuroinflammation and the underlying mechanisms that may contribute to epileptogenesis. Their work is instrumental not only to understand why and how the brain generates and sustains seizures, but also to discover biomarkers that could predict if someone will have seizures, or how they may respond to a drug. The ultimate hope is that this work with CURE Epilepsy will lead to the ability to prevent or cure acquired epilepsies.

 

 

Literature Cited:

  1. Epilepsy. Available at: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy. Accessed May 2.
  2. Verellen RM, Cavazos JE. Post-traumatic epilepsy: an overview. Therapy. 2010;7:527-531.
  3. Annegers JF, Coan SP. The risks of epilepsy after traumatic brain injury Seizure. 2000 Oct;9:453-457.
  4. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation Exp Neurol. 2013 Jun;244:11-21.
  5. Maroso M, Balosso S, Ravizza T, Liu J, Bianchi ME, Vezzani A. Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1 J Intern Med. 2011 Oct;270:319-326.
  6. Walker LE, Frigerio F, Ravizza T, Ricci E, Tse K, Jenkins RE, et al. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy J Clin Invest. 2017 Jun 1;127:2118-2132.
  7. Terrone G, Pauletti A, Pascente R, Vezzani A. Preventing epileptogenesis: A realistic goal? Pharmacol Res. 2016 Aug;110:96-100.
  8. Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M, et al. Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures Neurobiol Dis. 2013 Oct;58:102-114.
  9. Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures J Neuroinflammation. 2011 Oct 11;8:135.
  10. Pauletti A, Terrone G, Shekh-Ahmad T, Salamone A, Ravizza T, Rizzi M, et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy Brain. 2019 Jul 1;142:e39.
  11. Ravizza T, Terrone G, Salamone A, Frigerio F, Balosso S, Antoine DJ, et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy Brain Behav Immun. 2018 Aug;72:14-21.
  12. Walker LE, Sills GJ, Jorgensen A, Alapirtti T, Peltola J, Brodie MJ, et al. High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study Epilepsia. 2022 Jan;63:e1-e6.
  13. Vezzani A, Ravizza T, Bedner P, Aronica E, Steinhäuser C, Boison D. Astrocytes in the initiation and progression of epilepsy Nat Rev Neurol. 2022 Dec;18:707-722.
  14. Vila Verde D, de Curtis M, Librizzi L. Seizure-Induced Acute Glial Activation in the in vitro Isolated Guinea Pig Brain Front Neurol. 2021;12:607603.