In search of antiepileptogenic treatments for post-traumatic epilepsy

Saletti, Patricia G.; Ali, Idrish; Casillas‐Espinosa, Pablo M.; Semple, Bridgette D.; Lisgaras, Christos Panagiotis; Moshé, Solomon L.; Galanopoulou, Aristea S.

doi:10.1016/j.nbd.2018.06.017

Cited by 66 publications

(66 citation statements)

References 231 publications

(269 reference statements)

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“…In 30-to 40-hour simultaneous video and surface EEG recordings from rats 12 to 15 weeks after sham or FPI, none of the sham rats (n = 9) showed electrographic seizures, but spontaneous electrographic and behavioral seizures were observed in 8 of 13 FPI rats (~62%; Fig 4). In rats with spontaneous seizures, the average seizure severity was Racine score 3.37 AE 0.18 (range, [3][4], and average seizure duration was 97.88 AE 10.20 seconds (range, 50-140 seconds), confirming the risk for post-traumatic epileptogenesis in the experimental model. It is possible that strain differences, use of younger juvenile rats, which are more susceptible to adverse effects of brain injury, 40 implementation of injury on the day after surgery to minimize neuroprotection due to surgical anesthesia, and inclusion criteria based on apnea duration contributed to greater proportion of rats developing spontaneous seizures compared to earlier studies.…”

Section: Systemic Tlr4 Antagonism In Vivo Has Opposing Effects On Earmentioning

confidence: 70%

“…Acquired epilepsies that develop after brain insults such as trauma are particularly refractory to treatments yet are potentially preventable if the underlying mechanisms are identified and appropriately targeted . A wealth of preclinical and clinical studies predict that neuronal excitability and plasticity act alongside inflammatory processes and contribute to epileptogenesis . However, the interaction between neurophysiological and inflammatory responses to injury and the underlying mechanisms are not fully understood .…”

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confidence: 99%

“…and contribute to epileptogenesis. [3][4][5][6][7][8][9] However, the interaction between neurophysiological and inflammatory responses to injury and the underlying mechanisms are not fully understood. 10 Activation of the innate immune receptor Toll-like receptor 4 (TLR4) by its ligand high mobility group box chromosomal protein 1 (HMGB1), which is released during neuronal damage, is thought to play a critical role in the inflammatory responses to seizures and brain injury.…”

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confidence: 99%

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Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

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Section: Systemic Tlr4 Antagonism In Vivo Has Opposing Effects On Earmentioning

confidence: 70%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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“…This could initially be tested in post‐SE epilepsy models for practical reasons, including a shorter follow‐up period and lower sample size needed for an adequately powered study due to a high rate of epilepsy in these models. However, this would then need to be followed up in post‐TBI models for evaluation of PTE, which would be laborious and expensive due to the longer timeline and need of bigger sample size in such studies, as only a proportion of animals develop PTE . This would create additional opportunities to evaluate the long‐term survival of the transplanted cells, or the resident genetically modified cells induced by viral vectors.…”

Section: Discussionmentioning

confidence: 99%

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

et al. 2020

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Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti‐inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti‐inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells—brain‐resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro‐ and anti‐inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain‐resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.

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“…107 Ultimately, successful biomarker identification can enable full-scale clinical trials for potential antiepileptogenic drugs, which may be more cost-effective, and therefore, more feasible, in the effort to control or prevent PTE.…”

Section: Discussionmentioning

confidence: 99%

Imaging biomarkers of posttraumatic epileptogenesis

et al. 2019

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Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long‐term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large‐scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.

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In search of antiepileptogenic treatments for post-traumatic epilepsy

Cited by 66 publications

References 231 publications

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

Imaging biomarkers of posttraumatic epileptogenesis

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