Harmonization of the pipeline for seizure detection to phenotype post-traumatic epilepsy in a preclinical multicenter study on post-traumatic epileptogenesis

Casillas‐Espinosa, Pablo M.; Andrade, Pedro; Santana-Gomez, Cesar; Paananen, Tomi; Smith, Gregory S.; Ali, Idrish; Ciszek, Robert; Ndode-Ekane, Xavier Ekolle; Brady, Rhys D.; Tohka, Jussi; Hudson, Matthew R.; Perucca, Piero; Braine, Emma L.; Immonen, Riikka; Puhakka, Noora; Shultz, Sandy R.; Jones, Nigel C.; Staba, Richard J.; Pitkänen, Asla; O’Brien, Terence J.

doi:10.1016/j.eplepsyres.2019.04.011

Cited by 29 publications

(13 citation statements)

References 43 publications

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“…In rats with spontaneous seizures, the average seizure severity was Racine score 3.37 ± 0.18 (range, 3–4), and average seizure duration was 97.88 ± 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, 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: Resultsmentioning

confidence: 99%

“…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. [41][42][43] To transition our findings on TLR4 modulation of excitability in ex vivo slices to in vivo, we examined whether systemic TLR4 antagonism could modify dentate excitability 1 week after injury. Sham and FPI rats were treated with CLI-095 (0.5mg/kg, subcutaneously, for 3 days) starting 20 to 24 hours after injury, and dentate excitability was examined in hippocampal slices 6 to 8 days later.…”

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

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: Resultsmentioning

confidence: 99%

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

confidence: 99%

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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“…The power calculation was based on our previous data indicating that approximately 25% of rats with severe lateral fluid-percussion-induced (FPI) traumatic brain injury (TBI) will have at least one spontaneous seizure (ie, epilepsy) during the 1-month video-electroencephalography (video-EEG) monitoring at the sixth post-TBI month. 13,18,46 Furthermore, the biomarker was expected to have an area under the curve > 0.700 in the receiver-operating characteristic (ROC) analysis. Consequently, we needed at least 22 rats with epilepsy.…”

Section: Correlationsmentioning

confidence: 99%

Postinjury weight rather than cognitive or behavioral impairment predicts development of posttraumatic epilepsy after lateral fluid‐percussion injury in rats

et al. 2020

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“…In several pilot studies, we examined and described typical alterations of brain electrical activity observed in rats subjected to penetrating TBI [6][7][8][9]. Despite the fact that a number of labs successfully apply EEG/ECoG techniques to study epileptiform activity in traumatized rats [10,11], the overall number of works currently employing these techniques to study pharmacological neuroprotection remains fairly low [12,13]. However, using EEG for this purpose has several definite advantages.…”

Section: Introductionmentioning

confidence: 99%

Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury

et al. 2021

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The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain’s electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg−1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 μg∙kg−1 did not affect the brain’s electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

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Harmonization of the pipeline for seizure detection to phenotype post-traumatic epilepsy in a preclinical multicenter study on post-traumatic epileptogenesis

Abstract: Harmonization of the pipeline for seizure detection to phenotype post-traumatic epilepsy in a preclinical multicenter study on post-traumatic epileptogenesis,

Cited by 29 publications

References 43 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

Postinjury weight rather than cognitive or behavioral impairment predicts development of posttraumatic epilepsy after lateral fluid‐percussion injury in rats

Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury

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