The Experts below are selected from a list of 17862 Experts worldwide ranked by ideXlab platform
Asla Pitkanen - One of the best experts on this subject based on the ideXlab platform.
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Imaging microstructural damage and plasticity in the hippocampus during Epileptogenesis.
Neuroscience, 2015Co-Authors: Alejandra Sierra, Olli Gröhn, Asla PitkanenAbstract:Epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures, resulting in the development of an epileptic condition and/or progression of epilepsy after the condition is established. The hippocampus is the seizure-initiating zone in many epilepsy patients as well as in animal models of epilepsy. During Epileptogenesis, the hippocampus undergoes structural changes, including mossy fiber sprouting; alterations in dendritic branching, spine density, and shape; and neurogenesis. In vivo magnetic resonance imaging (MRI) techniques provide insights into the microstructural organization of the hippocampus. An assessment of the structural plasticity of the hippocampus may provide parameters that could be used as biomarkers for Epileptogenesis. Here we review conventional and more advanced MRI methods for detecting hippocampal tissue changes related to Epileptogenesis. In addition, we summarize how diffusion tensor imaging can reveal cellular damage and plasticity, even at the level of hippocampal subfields. Finally, we discuss challenges and future directions for using novel MRI techniques in the search of biomarkers associated with Epileptogenesis after brain injury.
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Epilepsy Related to Traumatic Brain Injury
Neurotherapeutics, 2014Co-Authors: Asla Pitkanen, Riikka ImmonenAbstract:Post-traumatic epilepsy accounts for 10–20 % of symptomatic epilepsy in the general population and 5 % of all epilepsy. During the last decade, an increasing number of laboratories have investigated the molecular and cellular mechanisms of post-traumatic Epileptogenesis in experimental models. However, identification of critical molecular, cellular, and network mechanisms that would be specific for post-traumatic Epileptogenesis remains a challenge. Despite of that, 7 of 9 proof-of-concept antiEpileptogenesis studies have demonstrated some effect on seizure susceptibility after experimental traumatic brain injury, even though none of them has progressed to clinic. Moreover, there has been some promise that new clinically translatable imaging approaches can identify biomarkers for post-traumatic Epileptogenesis. Even though the progress in combating post-traumatic Epileptogenesis happens in small steps, recent discoveries kindle hope for identification of treatment strategies to prevent post-traumatic epilepsy in at-risk patients.
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New insight on the mechanisms of Epileptogenesis in the developing brain.
Advances and technical standards in neurosurgery, 2012Co-Authors: Hana Kubová, Katarzyna Lukasiuk, Asla PitkanenAbstract:The incidence of epilepsy is at its highest in childhood and seizures can persist for a lifetime. As brain tissue from pediatric patients with epilepsy is rarely available, the analysis of molecular and cellular changes during Epileptogenesis, which could serve as targets for treatment approaches, has to rely largely on the analysis of tissue from animal models. However, these data have to be analyzed in the context of the developmental stage when the insult occurs. Here we review the current status of the available animal models, the molecular analysis done in these models, as well as treatment attempts to prevent Epileptogenesis in the immature brain. Considering that epilepsy is one of the major childhood neurological diseases, it is remarkable how little is known on Epileptogenesis in the immature brain at a molecular level. It is a true challenge for the future to expand the armamentarium of clinically relevant animal models, and systematic analysis of molecular and cellular data to enhance the probability of developing syndrome specific antiepileptogenic treatments and biomarkers for acquired pediatric Epileptogenesis.
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Therapeutic approaches to Epileptogenesis--hope on the horizon.
Epilepsia, 2010Co-Authors: Asla PitkanenAbstract:Prevention of Epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired Epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining Epileptogenesis-related terms is presented.
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Epileptogenesis | Surrogate Markers for Epileptogenesis
Encyclopedia of Basic Epilepsy Research, 2009Co-Authors: Nick M E A Hayward, K.m.a. Kurkinen, Olli Gröhn, Asla PitkanenAbstract:Magnetic resonance imaging (MRI) and proteomic methods are helping researchers to find and develop surrogate markers for Epileptogenesis. Toward these objectives, MRI of animal models of epilepsy allows visualization of the neurophysiological changes that occur during the epileptogenic process. Proteomic studies are beginning to elucidate the biochemical mechanisms behind epilepsy pathologies. The recent advances in, and some future directions of MRI and proteomic research – as related to epilepsy and Epileptogenesis – are presented here. A combination of MRI and proteomics may further our knowledge and understanding of the epilepsies, leading to novel therapeutic opportunities.
James O Mcnamara - One of the best experts on this subject based on the ideXlab platform.
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Conditional deletion of TrkC does not modify limbic Epileptogenesis.
Epilepsy research, 2012Co-Authors: A Soren Leonard, Ram S Puranam, Jeffrey Helgager, Gumei Liu, James O McnamaraAbstract:The neurotrophin receptor, tropomyosin-related kinase B (TrkB), is required for Epileptogenesis in the kindling model. The role of a closely related neurotrophin receptor, TrkC, in limbic Epileptogenesis is unknown. We examined limbic Epileptogenesis in the kindling model in TrkC conditional null mice, using a strategy that previously established a critical role of TrkB. Despite elimination of TrkC mRNA, no differences in development of kindling were detected between TrkC conditional null and wild type control mice. These findings reinforce the central role of TrkB as the principal neurotrophin receptor involved in limbic Epileptogenesis.
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Reduction of TrkB expression de novo in the adult mouse impairs Epileptogenesis in the kindling model.
Hippocampus, 2010Co-Authors: Robert Kotloski, James O McnamaraAbstract:Elucidating the mechanisms of Epileptogenesis in molecular terms can identify targets for therapies aimed at preventing Epileptogenesis or limiting its progression. Genetic perturbations have implicated signaling by the neurotrophin, BDNF, and its receptor, TrkB, in limbic Epileptogenesis. Whether this signaling is critical to Epileptogenesis in the adult brain is unclear. We sought to determine whether reduced expression of TrkB de novo in the mature brain is sufficient to impair Epileptogenesis in the kindling model. Treatment of adult Act-CreER TrkBflox/flox mice with tamoxifen resulted in modest reductions of TrkB protein expression de novo in the adult that were detected in hippocampus but not other brain regions. Modest reduction of hippocampal TrkB content inhibited Epileptogenesis induced by stimulation of hippocampus or amygdala. The data support the conclusion that reduction of TrkB expression in hippocampus de novo in the mature brain impairs Epileptogenesis in the kindling model. These findings advance TrkB and its downstream signaling pathways as attractive targets for limiting the progression of Epileptogenesis. © 2009 Wiley-Liss, Inc.
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Molecular Signaling Mechanisms Underlying Epileptogenesis
Science Signaling, 2006Co-Authors: James O Mcnamara, Yang Z. Huang, Leonard AsAbstract:Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding Epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of Epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying Epileptogenesis, focusing on limbic Epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote Epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron—the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca 2+ concentration within the spine. Various Ca 2+ -regulated enzymes found in spines have been implicated in Epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca 2+ -calmodulin–dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca 2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca 2+ concentration within dendritic spines induced by abnormal neuronal activity.
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The tyrosine receptor kinase B ligand, neurotrophin-4, is not required for either Epileptogenesis or tyrosine receptor kinase B activation in the kindling model.
Neuroscience, 2006Co-Authors: Linda S. Butler, Xin Liu, James O McnamaraAbstract:The kindling model of epilepsy is a form of neuronal plasticity induced by repeated induction of pathological activity in the form of focal seizures. A causal role for the neurotrophin receptor, tyrosine receptor kinase B, in Epileptogenesis is supported by multiple studies of the kindling model. Not only is tyrosine receptor kinase B required for Epileptogenesis in this model but enhanced activation of tyrosine receptor kinase B has been identified in the hippocampus in multiple models of limbic Epileptogenesis. The neurotrophin ligand mediating tyrosine receptor kinase B activation during limbic Epileptogenesis is unknown. We hypothesized that neurotrophin-4 (NT4) activates tyrosine receptor kinase B in the hippocampus during Epileptogenesis and that NT4-mediated activation of tyrosine receptor kinase B promotes limbic Epileptogenesis. We tested these hypotheses in NT4-deficient mice with a targeted deletion of NT4 gene using the kindling model. The development and persistence of amygdala kindling were examined in wild type (+/+) and NT4 null mutant (-/-) mice. No differences were found between +/+ and -/- mice with respect to any facet of the development or persistence of kindling. Despite the absence of NT4, activation of the tyrosine receptor kinase B receptor in the mossy fiber pathway as assessed by phospho-trk immunohistochemistry was equivalent to that of +/+ mice. Together these findings demonstrate that NT4 is not required for limbic Epileptogenesis nor is it required for activation of tyrosine receptor kinase B in hippocampus during limbic Epileptogenesis.
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conditional deletion of trkb but not bdnf prevents Epileptogenesis in the kindling model
Neuron, 2004Co-Authors: Xiaoping He, Robert Kotloski, Bryan W Luikart, Luis F Parada, James O McnamaraAbstract:Abstract Epileptogenesis is the process whereby a normal brain becomes epileptic. We hypothesized that the neurotrophin brain-derived neurotrophic factor (BDNF) activates its receptor, TrkB, in the hippocampus during Epileptogenesis and that BDNF-mediated activation of TrkB is required for Epileptogenesis. We tested these hypotheses in Synapsin-Cre conditional BDNF −/− and TrkB −/− mice using the kindling model. Despite marked reductions of BDNF expression, only a modest impairment of Epileptogenesis and increased hippocampal TrkB activation were detected in BDNF −/− mice. In contrast, reductions of electrophysiological measures and no behavioral evidence of Epileptogenesis were detected in TrkB −/− mice. Importantly, TrkB −/− mice exhibited behavioral endpoints of Epileptogenesis, tonic-clonic seizures. Whereas TrkB can be activated, and Epileptogenesis develops in BDNF −/− mice, the plasticity of Epileptogenesis is eliminated in TrkB −/− mice. Its requirement for Epileptogenesis in kindling implicates TrkB and downstream signaling pathways as attractive molecular targets for drugs for preventing epilepsy.
Wolfgang Löscher - One of the best experts on this subject based on the ideXlab platform.
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Commonalities and differences in extracellular levels of hippocampal acetylcholine and amino acid neurotransmitters during status epilepticus and subsequent Epileptogenesis in two rat models of temporal lobe epilepsy.
Brain research, 2019Co-Authors: Sebastian Meller, Claudia Brandt, Wiebke Theilmann, Jochen Klein, Wolfgang LöscherAbstract:Chemically or electrically induced status epilepticus (SE) in rodents is a commonly used method for induction of epilepsy. Structural and functional changes in the hippocampus play a pivotal role in Epileptogenesis induced by SE. Although cholinergic mechanisms have long been thought to play an important role in the onset and propagation of epileptic seizures, not much is known about the potential role of acetylcholine (ACh) in ictogenesis and Epileptogenesis in SE models of temporal lobe epilepsy. Here we used in vivo microdialysis to determine extracellular levels of ACh and, for comparison, several amino acid transmitters in the ventral hippocampus during SE, Epileptogenesis, and the chronic epileptic state in two rat models of SE-induced epilepsy. SE was either induced by lithium-pilocarpine or by sustained electrical stimulation of the basolateral amygdala (BLA). ACh increased during SE in both models. Pretreatment with the muscarinic receptor antagonist scopolamine before BLA stimulation reduced SE severity and duration. In contrast to ACh, no consistent changes in amino acid levels were found during SE in the two models. During Epileptogenesis and the chronic epileptic state, the only commonalities found in both models were a decrease in ACh in epileptic rats during the chronic epileptic state and a decrease in aspartate during Epileptogenesis. The data demonstrate complex, model-dependent alterations in extracellular levels of ACh and amino acid neurotransmitters and only few commonalities. Thus, data originating from only one model of post-SE epilepsy should not be generalized but may have a limited translational value for understanding ictogenesis or Epileptogenesis.
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the enigma of the latent period in the development of symptomatic acquired epilepsy traditional view versus new concepts
Epilepsy & Behavior, 2015Co-Authors: Wolfgang Löscher, Lawrence J. Hirsch, Dieter SchmidtAbstract:A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of Epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that Epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing Epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of Epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
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The enigma of the latent period in the development of symptomatic acquired epilepsy — Traditional view versus new concepts
Epilepsy & Behavior, 2015Co-Authors: Wolfgang Löscher, Lawrence J. Hirsch, Dieter SchmidtAbstract:A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of Epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that Epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing Epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of Epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
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prevention or modification of Epileptogenesis after brain insults experimental approaches and translational research
Pharmacological Reviews, 2010Co-Authors: Wolfgang Löscher, Claudia BrandtAbstract:Diverse brain insults, including traumatic brain injury, stroke, infections, tumors, neurodegenerative diseases, and prolonged acute symptomatic seizures, such as complex febrile seizures or status epilepticus (SE), can induce “Epileptogenesis,” a process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. Furthermore, Epileptogenesis operates in cryptogenic causes of epilepsy. In view of the accumulating information about cellular and molecular mechanisms of Epileptogenesis, it should be possible to intervene in this process before the onset of seizures and thereby either prevent the development of epilepsy in patients at risk or increase the potential for better long-term outcome, which constitutes a major clinical need. For identifying pharmacological interventions that prevent, interrupt or reverse the epileptogenic process in people at risk, two groups of animal models, kindling and SE-induced recurrent seizures, have been recommended as potentially useful tools. Furthermore, genetic rodent models of Epileptogenesis are increasingly used in assessing antiepileptogenic treatments. Two approaches have been used in these different model categories: screening of clinically established antiepileptic drugs (AEDs) for antiepileptogenic or disease-modifying potential, and targeting the key causal mechanisms that underlie Epileptogenesis. The first approach indicated that among various AEDs, topiramate, levetiracetam, carisbamate, and valproate may be the most promising. On the basis of these experimental findings, two ongoing clinical trials will address the antiepileptogenic potential of topiramate and levetiracetam in patients with traumatic brain injury, hopefully translating laboratory discoveries into successful therapies. The second approach has highlighted neurodegeneration, inflammation and up-regulation of immune responses, and neuronal hyperexcitability as potential targets for antiEpileptogenesis or disease modification. This article reviews these areas of progress and discusses the challenges associated with discovery of antiepileptogenic therapies.
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Epileptogenesis and rational therapeutic strategies.
Acta neurologica Scandinavica, 2006Co-Authors: Hermann Stefan, Wolfgang Löscher, F.h. Lopes Da Silva, D. Schmidt, Emilio Perucca, Martin J. Brodie, Paul Boon, William H. Theodore, Solomon L. MoshéAbstract:The understanding of neurobiological mechanisms of Epileptogenesis is essential for rational approaches for a possible disease modification as well as treatment of underlying causes of the epilepsies. More effort is necessary to translate results from basic investigations into new approaches for clinical research and to better understand a relationship with findings from clinical studies. The following report is a condensed synapsis in which molecular mechanisms of Epileptogenesis, pharmacological modulation of Epileptogenesis, evidence based therapy, refractoriness and prediction of outcome is provided in order to stimulate further collaborative international research.
Dieter Schmidt - One of the best experts on this subject based on the ideXlab platform.
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the enigma of the latent period in the development of symptomatic acquired epilepsy traditional view versus new concepts
Epilepsy & Behavior, 2015Co-Authors: Wolfgang Löscher, Lawrence J. Hirsch, Dieter SchmidtAbstract:A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of Epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that Epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing Epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of Epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
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The enigma of the latent period in the development of symptomatic acquired epilepsy — Traditional view versus new concepts
Epilepsy & Behavior, 2015Co-Authors: Wolfgang Löscher, Lawrence J. Hirsch, Dieter SchmidtAbstract:A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of Epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that Epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing Epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of Epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
Doodipala Samba Reddy - One of the best experts on this subject based on the ideXlab platform.
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neuroimaging biomarkers of experimental Epileptogenesis and refractory epilepsy
International Journal of Molecular Sciences, 2019Co-Authors: Sandesh D Reddy, Iyan Younus, Vidya Sridhar, Doodipala Samba ReddyAbstract: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.
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Novel therapeutic approaches for disease-modification of Epileptogenesis for curing epilepsy
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Bryan L. Clossen, Doodipala Samba ReddyAbstract:This article describes the recent advances in Epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of Epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger Epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for Epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger Epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating Epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of Epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.
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Role of hormones and neurosteroids in Epileptogenesis
Frontiers in cellular neuroscience, 2013Co-Authors: Doodipala Samba ReddyAbstract:This article describes the emerging evidence of hormonal influence on Epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger Epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on Epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the Epileptogenesis. Corticosterone has excitatory effects and triggers Epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in Epileptogenesis.
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Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of Epileptogenesis.
Epilepsy & behavior : E&B, 2012Co-Authors: Doodipala Samba Reddy, G. RamanathanAbstract:Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt Epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of Epileptogenesis. However, the mechanisms underlying the protective effects of P against Epileptogenesis remain unclear. In this study, we investigated the role of P-derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5α-reductase converts P to allopregnanolone and related neurosteroids that retard Epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of Epileptogenesis and investigated the effect of finasteride, a 5α-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of Epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic Epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic Epileptogenesis and temporal lobe epilepsy.
