Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury.
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ABSTRACT:
SUBMITTER: Dulla CG
PROVIDER: S-EPMC8608993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1? interacting with its receptors, and transforming growth factor-? signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.
| S-EPMC5237206 | biostudies-literature
Project description:BackgroundTo date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics.MethodsIn this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI.ResultsThe omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI.ConclusionThe field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future.
| S-EPMC8357753 | biostudies-literature
Project description:ObjectivePosttraumatic epilepsy (PTE) accounts for 20% of acquired epilepsies. Experimental models are important for studying epileptogenesis. We previously reported that repetitive high-frequency oscillations with spikes (rHFOSs) occur early after lateral fluid percussion injury (FPI) and may be a biomarker for PTE. The objective of this study was to use multiple electrodes in rat hippocampal and neocortical regions to describe the long-term electroencephalographic and behavioral evolution of rHFOSs and epileptic seizures after traumatic brain injury (TBI).MethodsAdult male rats underwent mild, moderate, or severe FPI or sham injury followed by video-electroencephalography (EEG) recordings with a combination of 16 neocortical and hippocampal electrodes at an early, intermediate, or late time-point after injury, up to 52 weeks. Recordings were analyzed for the presence of rHFOSs and seizures.ResultsAnalysis was done on 28 rats with FPI and 7 shams. Perilesional rHFOSs were recorded in significantly more rats after severe (70.3%) than mild (20%) injury or shams (14.3%). Frequency of occurrence was significantly highest in the early (10.8/h) versus late group (3.2/h). Late focal seizures originating from the same electrodes were recorded in significantly more rats in the late (87.5%) versus early period (22.2%), occurring almost exclusively in injured rats. Seizure duration increased significantly over time, averaging 19 s at the beginning of the early period and 27 s at the end of the late period. Seizure frequency also increased significantly over time, from 4.4 per week in the early group to 26.4 per week in the late group. Rarely, rats displayed early seizures or generalized seizures.SignificanceFPI results in early rHFOSs and later spontaneous focal seizures arising from peri-lesional neocortex, supporting its use as a model for PTE. Epilepsy severity increased over time and was related to injury severity. The association between early rHFOSs and later focal seizures suggests that rHFOSs may be a potential noninvasive biomarker of PTE.
| S-EPMC5207033 | biostudies-literature
Project description:PURPOSE OF REVIEW:The underlying mechanisms responsible for chronic and progressive neurological damage after traumatic brain injury (TBI) are poorly understood, and therefore, current treatment options are limited. Proteomics is an emerging methodology to study changes to the TBI proteome in both patients and experimental models. RECENT FINDINGS:Although experimentally complex, mass spectrometry-based proteomics approaches are converging on a set of common methods. However, these methods are being applied to an increasingly diverse range of experimental models and types of injury. SUMMARY:In this review, our aim is to briefly describe experimental TBI models and the underlying methods common to most proteomic approaches. We will then review a series of articles that have recently appeared in which these approaches have been applied to important TBI questions. We will summarize several recent experimental studies, and suggest how the results of these emerging studies might impact future research as well as patient treatment.
| S-EPMC6221404 | biostudies-other
Project description:Traumatic brain injury (TBI) is a serious condition in which trauma to the head causes damage to the brain, leading to a disruption in brain function. This is a significant health issue worldwide, with around 69 million people suffering from TBI each year. Immediately following the trauma, damage occurs in the acute phase of injury that leads to the primary outcomes of the TBI. In the hours-to-days that follow, secondary damage can also occur, leading to chronic outcomes. TBIs can range in severity from mild to severe, and can be complicated by the fact that some individuals sustain multiple TBIs, a risk factor for worse long-term outcomes. Although our knowledge about the pathophysiology of TBI has increased in recent years, unfortunately this has not been translated into effective clinical therapies. The U.S. Food and Drug Administration has yet to approve any drugs for the treatment of TBI; current clinical treatment guidelines merely offer supportive care. Outcomes between individuals greatly vary, which makes the treatment for TBI so challenging. A blow of similar force can have only mild, primary outcomes in one individual and yet cause severe, chronic outcomes in another. One of the reasons that have been proposed for this differential response to TBI is the underlying genetic differences across the population. Due to this, many researchers have begun to investigate the possibility of using precision medicine techniques to address TBI treatment. In this review, we will discuss the research detailing the identification of genetic risk factors for worse outcomes after TBI, and the work investigating personalized treatments for these higher-risk individuals. We highlight the need for further research into the identification of higher-risk individuals and the development of personalized therapies for TBI.
| S-EPMC9083178 | biostudies-literature
Project description:The rate of traumatic brain injury (TBI) in service members with wartime injuries has risen rapidly in recent years, and complex, variable links have emerged between TBI and long-term neurological disorders. The multifactorial nature of TBI secondary cellular response has confounded attempts to find cellular biomarkers for its diagnosis and prognosis or for guiding therapy for brain injury. One possibility is to apply emerging systems biology strategies to holistically probe and analyze the complex interweaving molecular pathways and networks that mediate the secondary cellular response through computational models that integrate these diverse data sets. Here, we review available systems biology strategies, databases, and tools. In addition, we describe opportunities for applying this methodology to existing TBI data sets to identify new biomarker candidates and gain insights about the underlying molecular mechanisms of TBI response. As an exemplar, we apply network and pathway analysis to a manually compiled list of 32 protein biomarker candidates from the literature, recover known TBI-related mechanisms, and generate hypothetical new biomarker candidates.
| S-EPMC3700463 | biostudies-literature
Project description:Cytosolic PSD-95 interactor (cypin), the primary guanine deaminase in the brain, plays key roles in shaping neuronal circuits and regulating neuronal survival. Despite this pervasive role in neuronal function, the ability for cypin activity to affect recovery from acute brain injury is unknown. A key barrier in identifying the role of cypin in neurological recovery is the absence of pharmacological tools to manipulate cypin activity in vivo. Here, we use a small molecule screen to identify two activators and one inhibitor of cypin's guanine deaminase activity. The primary screen identified compounds that change the initial rate of guanine deamination using a colorimetric assay, and secondary screens included the ability of the compounds to protect neurons from NMDA-induced injury and NMDA-induced decreases in frequency and amplitude of miniature excitatory postsynaptic currents. Hippocampal neurons pretreated with activators preserved electrophysiological function and survival after NMDA-induced injury in vitro, while pretreatment with the inhibitor did not. The effects of the activators were abolished when cypin was knocked down. Administering either cypin activator directly into the brain one hour after traumatic brain injury significantly reduced fear conditioning deficits 5?days after injury, while delivering the cypin inhibitor did not improve outcome after TBI. Together, these data demonstrate that cypin activation is a novel approach for improving outcome after TBI and may provide a new pathway for reducing the deficits associated with TBI in patients.
| S-EPMC6214165 | biostudies-literature
Project description:Loss to follow-up and missing outcomes data are important issues for longitudinal observational studies and clinical trials in traumatic brain injury. One popular solution to missing 6-month outcomes has been to use the last observation carried forward (LOCF). The purpose of the current study was to compare the performance of model-based single-imputation methods with that of the LOCF approach. We hypothesized that model-based methods would perform better as they potentially make better use of available outcome data. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (n = 4509) included longitudinal outcome collection at 2 weeks, 3 months, 6 months, and 12 months post-injury; a total of 8185 Glasgow Outcome Scale extended (GOSe) observations were included in the database. We compared single imputation of 6-month outcomes using LOCF, a multiple imputation (MI) panel imputation, a mixed-effect model, a Gaussian process regression, and a multi-state model. Model performance was assessed via cross-validation on the subset of individuals with a valid GOSe value within 180 ± 14 days post-injury (n = 1083). All models were fit on the entire available data after removing the 180 ± 14 days post-injury observations from the respective test fold. The LOCF method showed lower accuracy (i.e., poorer agreement between imputed and observed values) than model-based methods of imputation, and showed a strong negative bias (i.e., it imputed lower than observed outcomes). Accuracy and bias for the model-based approaches were similar to one another, with the multi-state model having the best overall performance. All methods of imputation showed variation across different outcome categories, with better performance for more frequent outcomes. We conclude that model-based methods of single imputation have substantial performance advantages over LOCF, in addition to providing more complete outcome data.
| S-EPMC7875604 | biostudies-literature
Project description:It is necessary to develop reliable biomarkers for epileptogenesis and cognitive impairment after traumatic brain injury when searching for novel antiepileptogenic and cognition-enhancing treatments. We hypothesized that a multiparametric magnetic resonance imaging (MRI) analysis along the septotemporal hippocampal axis could predict the development of post-traumatic epilepsy and cognitive impairment. We performed quantitative T2 and T2* MRIs at 2, 7 and 21 days, and diffusion tensor imaging at 7 and 21 days after lateral fluid-percussion injury in male rats. Morris water maze tests conducted between 35-39 days post-injury were used to diagnose cognitive impairment. One-month-long continuous video-electroencephalography monitoring during the 6th post-injury month was used to diagnose epilepsy. Single-parameter and regularized multiple linear regression models were able to differentiate between sham-operated and brain-injured rats. In the ipsilateral hippocampus, differentiation between the groups was achieved at most septotemporal locations (cross-validated area under the receiver operating characteristic curve (AUC) 1.0, 95% confidence interval 1.0-1.0). In the contralateral hippocampus, the highest differentiation was evident in the septal pole (AUC 0.92, 95% confidence interval 0.82-0.97). Logistic regression analysis of parameters imaged at 3.4 mm from the contralateral hippocampus's temporal end differentiated between the cognitively impaired rats and normal rats (AUC 0.72, 95% confidence interval 0.55-0.84). Neither single nor multiparametric approaches could identify the rats that would develop post-traumatic epilepsy. Multiparametric MRI analysis of the hippocampus can be used to identify cognitive impairment after an experimental traumatic brain injury. This information can be used to select subjects for preclinical trials of cognition-improving interventions.
| S-EPMC9687561 | biostudies-literature
Project description:Purpose: Traumatic brain injury (TBI) causes 10%–20% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for post-traumatic epilepsy (PTE) is a major obstacle to the development of anti-epileptogenic treatments. In this study, we conducted high throughput small RNA-Seq analysis from tail-vein plasma samples collected from a rat model of PTE to discover miRNA biomarker candidates that could serve as prognostic biomarkers for brain damage severity and the development of PTE. Methods: Epileptogenesis was induced in adult male Sprague-Dawley rats by the lateral fluid-percussion-induced TBI. Epilepsy was defined as the occurrence of at least 1 unprovoked seizure during continuous 1-month video-electroencephalography monitoring in the sixth post-TBI month. Small RNA-seq was performed from tail-vein plasma samples collected from a subset of 20 animals (4 sham-operated controls, 7 TBI rats with epilepsy, 9 TBI rats without epilepsy) at 2 days and 9 days post-TBI. RNA was extracted from 200 μl plasma using an miRNeasy Mini Kit. Small RNA-Seq was conducted by GenomeScan (Leiden, the Netherlands). Small RNA library preparation was performed using the Illumina TruSeq Small RNA Sample Prep Kit. Single-end sequencing was performed on the Illumina HiSeq 4000.
2023-02-10 | GSE222801 | GEO