Showing papers on "Epileptogenesis published in 2019"
TL;DR: Targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes and may be considered for patients exposed to potential epileptogenic insults.
Abstract: Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers This evidence was validated in the hippocampus of humans who died following status epilepticus Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms These antioxidant drugs are already used in humans for other therapeutic indications This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals Treatment also decreased hippocampal neuron loss and rescued cognitive deficits Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes This intervention may be considered for patients exposed to potential epileptogenic insults
178 citations
TL;DR: Since VPA modulates DNA transcription through HDACs, recent evidences point to its use as an anti-nociceptive in migraine prophylaxis, and, even more interestingly, as a positive modulator of chemotherapy in cancer treatment.
Abstract: After more than a century from its discovery, valproic acid (VPA) still represents one of the most efficient antiepileptic drugs (AEDs). Pre and post-synaptic effects of VPA depend on a very broad spectrum of actions, including the regulation of ionic currents and the facilitation of GABAergic over glutamatergic transmission. As a result, VPA indirectly modulates neurotransmitter release and strengthens the threshold for seizure activity. However, even though participating to the anticonvulsant action, such mechanisms seem to have minor impact on epileptogenesis. Nonetheless, VPA has been reported to exert anti-epileptogenic effects. Epigenetic mechanisms, including histone deacetylases (HDACs), BDNF and GDNF modulation are pivotal to orientate neurons toward a neuroprotective status and promote dendritic spines organization. From such broad spectrum of actions comes constantly enlarging indications for VPA. It represents a drug of choice in child and adult with epilepsy, with either general or focal seizures, and is a consistent and safe IV option in generalized convulsive status epilepticus. Moreover, since VPA modulates DNA transcription through HDACs, recent evidences point to its use as an anti-nociceptive in migraine prophylaxis, and, even more interestingly, as a positive modulator of chemotherapy in cancer treatment. Furthermore, VPA-induced neuroprotection is under investigation for benefit in stroke and traumatic brain injury. Hence, VPA has still got its place in epilepsy, and yet deserves attention for its use far beyond neurological diseases. In this review, we aim to highlight, with a translational intent, the molecular basis and the clinical indications of VPA.
154 citations
TL;DR: An overview of the literature supporting the potential for a timely intervention with vitamin E therapy in clinical management of seizures and epileptogenic processes associated with excitotoxicity, neuroinflammation and lipid peroxidation, i.e. the pathogenic "triad" is provided.
91 citations
TL;DR: Overall, STRE has a good prognosis, being well controlled by antiepileptic drugs, however, up to 25% of cases become drug resistant and STRE can also result in increased morbidity, longer hospitalization, greater disability at discharge and greater resource utilization.
Abstract: Stroke is the cause of about 10% of all epilepsy and 55% of newly diagnosed seizures among the elderly. Although recent advances in acute stroke therapy have improved longevity, there has been a consequent rise in the prevalence of stroke-related epilepsy (STRE). Many clinical studies make a distinction between early (within 7 days of onset of stroke) and late (beyond 7 days of onset of stroke) seizures based on presumed pathophysiological differences. Although early seizures are thought to be the consequence of local metabolic disturbances without altered neuronal networks, late seizures are thought to occur when the brain has acquired a predisposition for seizures. Overall, STRE has a good prognosis, being well controlled by antiepileptic drugs. However, up to 25% of cases become drug resistant. STRE can also result in increased morbidity, longer hospitalization, greater disability at discharge and greater resource utilization. Additional controlled trials are needed to explore the primary and secondary prevention of STRE as well as to provide high-quality evidence on efficacy and tolerability of antiepileptic drugs to guide treatment of STRE. Robust pre-clinical and clinical prediction models of STRE are also needed to develop treatments to prevent the transformation of infarcted tissue into an epileptic focus.
89 citations
TL;DR: The pathophysiology of epilepsy is reviewed, including recent reports on the effects of oxidative stress and hypoxia, and focuses on specific biomarkers and their clinical implications, along with further perspectives in epilepsy research.
Abstract: Epilepsy is a group of chronic neurological disorders characterized by recurrent, spontaneous, and unpredictable seizures. It is one of the most common neurological disorders, affecting tens of millions of people worldwide. Comprehensive studies on epilepsy in recent decades have revealed the complexity of epileptogenesis, in which immunological processes, epigenetic modifications, and structural changes in neuronal tissues have been identified as playing a crucial role. This review discusses the recent advances in the biomarkers of epilepsy. We evaluate the possible molecular background underlying the clinical changes observed in recent studies, focusing on therapeutic investigations, and the evidence of their safety and efficacy in the human population. This article reviews the pathophysiology of epilepsy, including recent reports on the effects of oxidative stress and hypoxia, and focuses on specific biomarkers and their clinical implications, along with further perspectives in epilepsy research.
80 citations
TL;DR: This review considers the clinical and preclinical evidence that post-traumatic epilepsy acts as a 'second-hit' insult to worsen chronic behavioral outcomes for brain-injured patients, across the domains of emotional, cognitive, and psychosocial functioning.
78 citations
TL;DR: Preclinical and clinical evidences supporting the role of COx-2 in seizure-associated neuroinflammation in epilepsy and the potential clinical use of COX-2 inhibitors as a future strategy for epilepsy treatment are reviewed.
Abstract: Epilepsy, a common multifactorial neurological disease, affects about 69 million people worldwide constituting nearly 1% of the world population. Despite decades of extensive research on understanding its underlying mechanism and developing the pharmacological treatment, very little is known about the biological alterations leading to epileptogenesis. Due to this gap, the currently available antiepileptic drug therapy is symptomatic in nature and is ineffective in 30% of the cases. Mounting evidences revealed the pathophysiological role of neuroinflammation in epilepsy which has shifted the focus of epilepsy researchers towards the development of neuroinflammation-targeted therapeutics for epilepsy management. Markedly increased expression of key inflammatory mediators in the brain and blood-brain barrier may affect neuronal function and excitability and thus may increase seizure susceptibility in preclinical and clinical settings. Cyclooxygenase-2 (COX-2), an enzyme synthesizing the proinflammatory mediators, prostaglandins, has widely been reported to be induced during seizures and is considered to be a potential neurotherapeutic target for epilepsy management. However, the efficacy of such therapy involving COX-2 inhibition depends on various factors viz., therapeutic dose, time of administration, treatment duration, and selectivity of COX-2 inhibitors. This article reviews the preclinical and clinical evidences supporting the role of COX-2 in seizure-associated neuroinflammation in epilepsy and the potential clinical use of COX-2 inhibitors as a future strategy for epilepsy treatment.
70 citations
TL;DR: Therapeutic adenosine augmentation not only holds promise for the suppression of seizures in epilepsy, but moreover the prevention of epilepsy and its progression overall.
66 citations
TL;DR: A review of emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy.
Abstract: Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti-epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high-mobility group box protein 1 (HMGB1), a DNA-binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1-targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.
63 citations
TL;DR: Investigating behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects.
58 citations
TL;DR: Results indicated that amentoflavone affects epileptogenesis and exerts neuroprotective effects by inhibiting the NLRP3 inflammasome and, thus, mediating the inflammatory process in PTZ-induced kindling mice and LPS-induced BV2 microglial cells.
Abstract: Brain inflammation is one of the main causes of epileptogenesis, a chronic process triggered by various insults, including genetic or acquired factors that enhance susceptibility to seizures. Amentoflavone, a naturally occurring biflavonoid compound that has anti-inflammatory effects, exerts neuroprotective effects against nervous system diseases. In the present study, we aimed to investigate the effects of amentoflavone on epilepsy in vivo and in vitro and elucidate the underlying mechanism. The chronic epilepsy model and BV2 microglial cellular inflammation model were established by pentylenetetrazole (PTZ) kindling or lipopolysaccharide (LPS) stimulation. Cognitive dysfunction was tested by Morris water maze while hippocampal neuronal apoptosis was evaluated by immunofluorescence staining. The levels of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome complexes and inflammatory cytokines were determined using quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay. Amentoflavone reduced seizure susceptibility, minimized PTZ-induced cognitive dysfunction, and blocked the apoptosis of hippocampal neurons in PTZ-induced kindling mice. Amentoflavone also inhibited the activation of the NLRP3 inflammasome and decreased the levels of inflammatory cytokines in the hippocampus of PTZ-induced kindling mice. Additionally, amentoflavone could alleviate the LPS-induced inflammatory response by inhibiting the NLRP3 inflammasome in LPS-induced BV2 microglial cells. Our results indicated that amentoflavone affects epileptogenesis and exerts neuroprotective effects by inhibiting the NLRP3 inflammasome and, thus, mediating the inflammatory process in PTZ-induced kindling mice and LPS-induced BV2 microglial cells. Therefore, amentoflavone may be a potential treatment option for epilepsy.
TL;DR: Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury, but most TBIs also include nonfocal, diffuse injuries and it is shown that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice.
Abstract: Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.
TL;DR: An optogenetic variant of the classical kindling model of epilepsy in which activatable cells are both genetically defined and fluorescently tagged is developed, with the added benefit that the role of specific neuronal populations in epileptogenesis can be studied.
Abstract: Epileptogenesis is the gradual process by which the healthy brain develops epilepsy. However, the neuronal circuit changes that underlie epileptogenesis are not well understood. Unfortunately, current chemically or electrically induced epilepsy models suffer from lack of cell specificity, so it is seldom known which cells were activated during epileptogenesis. We therefore sought to develop an optogenetic variant of the classical kindling model of epilepsy in which activatable cells are both genetically defined and fluorescently tagged. We briefly optogenetically activated pyramidal cells (PCs) in awake behaving mice every two days and conducted a series of experiments to validate the effectiveness of the model. Although initially inert, brief optogenetic stimuli eventually elicited seizures that increased in number and severity with additional stimulation sessions. Seizures were associated with long-lasting plasticity, but not with tissue damage or astrocyte reactivity. Once optokindled, mice retained an elevated seizure susceptibility for several weeks in the absence of additional stimulation, indicating a form of long-term sensitization. We conclude that optokindling shares many features with classical kindling, with the added benefit that the role of specific neuronal populations in epileptogenesis can be studied. Links between long-term plasticity and epilepsy can thus be elucidated.
TL;DR: It is shown that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity.
Abstract: Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.
TL;DR: It is reported, for the first time, that microglia in general and microglial P2Y12 receptors in specific promote both aberrant neurogenesis and increased immature neuronal projections in epilepsy.
Abstract: Seizures are common in humans with various etiologies ranging from congenital aberrations to acute injuries that alter the normal balance of brain excitation and inhibition. A notable consequence of seizures is the induction of aberrant neurogenesis and increased immature neuronal projections. However, regulatory mechanisms governing these features during epilepsy development are not fully understood. Recent studies show that microglia, the brain's resident immune cell, contribute to normal neurogenesis and regulate seizure phenotypes. However, the role of microglia in aberrant neurogenic seizure contexts has not been adequately investigated. To address this question, we coupled the intracerebroventricular kainic acid model with current pharmacogenetic approaches to eliminate microglia in male mice. We show that microglia promote seizure-induced neurogenesis and subsequent seizure-induced immature neuronal projections above and below the pyramidal neurons between the DG and the CA3 regions. Furthermore, we identify microglial P2Y12 receptors (P2Y12R) as a participant in this neurogenic process. Together, our results implicate microglial P2Y12R signaling in epileptogenesis and provide further evidence for targeting microglia in general and microglial P2Y12R in specific to ameliorate proepileptogenic processes.SIGNIFICANCE STATEMENT Epileptogenesis is a process by which the brain develops epilepsy. Several processes have been identified that confer the brain with such epileptic characteristics, including aberrant neurogenesis and increased immature neuronal projections. Understanding the mechanisms that promote such changes is critical in developing therapies to adequately restrain epileptogenesis. We investigated the role of purinergic P2Y12 receptors selectively expressed by microglia, the resident brain immune cells. We report, for the first time, that microglia in general and microglial P2Y12 receptors in specific promote both aberrant neurogenesis and increased immature neuronal projections. These results indicate that microglia enhance epileptogenesis by promoting these processes and suggest that targeting this immune axis could be a novel therapeutic strategy in the clinic.
TL;DR: Novel conceptual and experimental advances mandate expansion of the E/I paradigm, with the expectation that new and exciting therapies will emerge from this broadened understanding of how seizures and epilepsy arise and progress.
Abstract: Mechanisms underlying seizures and epilepsy have traditionally been considered to involve abnormalities of ion channels or synaptic function. Those considerations gave rise to the excitation/inhibition (E/I) imbalance theory, whereby increased excitation, decreased inhibition, or both favor a hyperexcitable state and an increased propensity for seizure generation and epileptogenesis. Several recent findings warrant reconsideration and expansion of the E/I hypothesis: novel genetic mutations have been identified that do not overtly affect E/I balance; neurotransmitters may exert paradoxical effects, especially during development; anti-seizure medications do not necessarily work by decreasing excitation or increasing inhibition; and metabolic factors participate in the regulation of neuronal and network excitability. These novel conceptual and experimental advances mandate expansion of the E/I paradigm, with the expectation that new and exciting therapies will emerge from this broadened understanding of how seizures and epilepsy arise and progress.
TL;DR: The roles of COX-2 as a major inflammatory mediator and the receptors for prostanoids PGE2, prostaglandin D2, and PGF2α as potential therapeutic targets for inflammation-driven diseases are described.
Abstract: Introduction：A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury. Areas covered: Here we describe the roles of COX-2 as a major inflammatory mediator. In addition, we discuss the receptors for prostanoids PGE2, prostaglandin D2, and PGF2α as potential therapeutic targets for inflammation-driven diseases. The consequences of prostanoid receptor activation after seizure activity are discussed with an emphasis on the utilization of small molecules to modulate prostanoid receptor activity. Expert opinion: Limited clinical trial experience is supportive but not definitive for a role of the COX signaling cascade in epileptogenesis. The cardiotoxicity associated with chronic coxib use, and the expectation that COX-2 inhibition will influence the levels of endocannabinoids, leukotrienes, and lipoxins as well as the prostaglandins and their endocannabinoid metabolite analogs, is shifting attention toward downstream synthases and receptors that mediate inflammation in the brain.
TL;DR: It is demonstrated for the model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling.
TL;DR: It is proposed that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma‐associated epilepsy, and it is postulate that the regulatory mechanisms of glutamine Synthetase as well as the downstream effects of glutaminesynthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions.
Abstract: The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood Here we review the role of astrocytes in epilepsy development (aka epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir41, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions Currently, no antiepileptogenic therapies are available for human use The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain
TL;DR: Current evidence supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms and in both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended.
Abstract: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy. We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018. Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives. Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.
TL;DR: Imaging approach to quantitatively assess BBBD as a diagnostic, predictive, and pharmacodynamic biomarker after brain injury is developed and shown to have a role in astroglial dysfunction, neuroinflammation, increasing neural excitability, reduction of seizure threshold, excitatory synaptogenesis, impaired plasticity, and epileptogenesis.
TL;DR: An overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy is provided andidated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.
Abstract: This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.
TL;DR: The possibility of acting on the blood-brain barrier and the neurovascular unit to prevent, disrupt or treat post-traumatic epilepsy is discussed and the latest quest for biomarkers of epileptogenesis is described which may allow for a more targeted intervention.
TL;DR: The current hypothesis for ATP release during seizures and its role in epileptogenesis is described, the technical challenges involved are described and the current evidence is critically examined.
TL;DR: It is demonstrated thatAstrocytes with mGluR5 signaling during TLE development perform faster glutamate uptake in hippocampus, revealing a previously unexplored role for astrocyte mGLUR 5 signaling in hypersynchronous pathology.
Abstract: Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In the rodent brain, astrocyte mGluR5 expression is developmentally regulated and confined in expression/function to the first weeks of life, with similar observations made in human control tissue. Herein, we demonstrate that mGluR5 expression and function dramatically increase in a mouse model of temporal lobe epilepsy. Interestingly, in both male and female mice, mGluR5 function persists in the astrocyte throughout the process of epileptogenesis following status epilepticus. However, mGluR5 expression and function are transient in animals that do not develop epilepsy over an equivalent time period, suggesting that patterns of mGluR5 expression may signify continuing epilepsy development or its resolution. We demonstrate that, during epileptogenesis, astrocytes reacquire mGluR5-dependent calcium transients following agonist application or synaptic glutamate release, a feature of astrocyte-neuron communication absent since early development. Finally, we find that the selective and conditional knock-out of mGluR5 signaling from astrocytes during epilepsy development slows the rate of glutamate clearance through astrocyte glutamate transporters under high-frequency stimulation conditions, a feature that suggests astrocyte mGluR5 expression during epileptogenesis may recapitulate earlier developmental roles in regulating glutamate transporter function.SIGNIFICANCE STATEMENT In development, astrocyte mGluR5 signaling plays a critical role in regulating structural and functional interactions between astrocytes and neurons at the tripartite synapse. Notably, mGluR5 signaling is a positive regulator of astrocyte glutamate transporter expression and function, an essential component of excitatory signaling regulation in hippocampus. After early development, astrocyte mGluR5 expression is downregulated, but reemerges in animal models of temporal lobe epilepsy (TLE) development and patient epilepsy samples. We explored the hypothesis that astrocyte mGluR5 reemergence recapitulates earlier developmental roles during TLE acquisition. Our work demonstrates that astrocytes with mGluR5 signaling during TLE development perform faster glutamate uptake in hippocampus, revealing a previously unexplored role for astrocyte mGluR5 signaling in hypersynchronous pathology.
TL;DR: Examination of the chronic consequences of acute HMGB1 inhibition in the same model found that pediatric TBI resulted in short-term spatial memory and motor learning deficits alongside an apparent increase in hippocampal microglial reactivity, which was prevented in Gly-treated TBI mice.
TL;DR: 5-HT1A and 5-HT3 receptors mediate cross-talk be-tween estrogenic and serotonergic pathways, and could be well exploited for combinatorial drug therapy against epileptogen-esis.
Abstract: A burgeoning literature documents the confluence of ovarian steroids and central serotonergic systems in the injunction of epileptic seizures and epileptogenesis. Estrogen administration in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e. Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform activity in either direction i.e administration of 5-HT agonists or reuptake inhibitors leads to the activation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal excitability hence abatement of seizure threshold in experimental animal models. Serotonergic neurotransmission is influenced by the organizational activity of steroid hormones in the growing brain and the actuation effects of steroids which come in adulthood. It is further established that ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a profound effect on serotonergic transmission. This review features 5-HT1A and 5-HT3 receptors as potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous neuronal activity. Indeed 5-HT3 receptors mediate cross-talk between estrogenic and serotonergic pathways, and could be well exploited for combinatorial drug therapy against epileptogenesis.
TL;DR: Glutamate levels in acute stroke may be a biomarker for the development of post-stroke epilepsy and 7T MRI technology enables non-invasive quantification of cerebral glutamate levels.
TL;DR: The anti-apoptosis ability of FTX during epileptogenesis is demonstrated for the first time and a novel FTX-mediated mechanism in SE-induced neural apoptosis by targeting miR-21-5p/SOX7 axis is uncovered, which provides a new target in developing lncRNA-based strategies to reduceSE-induced hippocampal neuron apoptosis.
TL;DR: The prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy is tested.
Abstract: Objective Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct histopathologic and biochemical changes, which include astrogliosis and increased expression of the adenosine-metabolizing enzyme adenosine kinase (ADK; EC 2.7.1.20). Increased expression of ADK contributes to epileptogenesis and is therefore a target for therapeutic intervention. We tested the prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy. Methods We used the intrahippocampal kainic acid (KA) mouse model of temporal lobe epilepsy, which is characterized by ipsilateral hippocampal sclerosis with granule cell dispersion and the development of recurrent hippocampal paroxysmal discharges (HPDs). KA-injected mice were treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 1.6 mg/kg, b.i.d., i.p.) during the latent phase of epileptogenesis from day 3-8 after injury; the period when gradual increases in hippocampal ADK expression begin to manifest. HPDs were assessed at 6 and 9 weeks after KA administration followed by epilepsy histopathology including assessment of granule cell dispersion, astrogliosis, and ADK expression. Results 5-ITU significantly reduced the percent time in seizures by at least 80% in 56% of mice at 6 weeks post-KA. This reduction in seizure activity was maintained in 40% of 5-ITU-treated mice at 9 weeks. 5-ITU also suppressed granule cell dispersion and prevented maladaptive ADK increases in these protected mice. Significance Our results show that the transient use of a small-molecule ADK inhibitor, given during the early stages of epileptogenesis, has antiepileptogenic disease-modifying properties, which provides the rationale for further investigation into the development of a novel class of antiepileptogenic ADK inhibitors with increased efficacy for epilepsy prevention.