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- Autoimmune Epilepsies. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 25.
In patients with immune-associated disorders of the gray central nervous system matter (including recurrent seizures), antibodies against intracellular antigens have been discovered since the 1980s/1990s. In recent years, new antibodies against surface antigens have also been discovered. In two respects, these antibodies are even more interesting than the ones to intracellular antigens as, first, they promise a better response to immunotherapy; and, second, these antibodies contribute greatly to the understanding of the disease mechanisms. Whereas in encephalitides with antibodies against intracellular antigens, a cytotoxic T-cell-mediated response seems to be responsible for neuronal cell loss, in encephalitides with autoantibodies against surface antigens these antibodies are probably the relevant pathogenic agents in the associated disease conditions. On the one hand, antibodies to the NR1 subunit of N-methyl-D-aspartate receptors have been suggested to cause internalization and loss of these receptors without any cell destruction. This mechanism can explain the reversible functional effects caused by these antibodies. On the other hand, antibody- and complement-mediated destructive, and the irreversible effects of antibodies against the voltage-gated potassium channel antigens have been noted. These emerging findings make it plausible that immunological therapies, preferably early after characterization of the antibodies, offer opportunities to restore the health of affected patients.
- Genetic Biomarkers in Epilepsy. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 25.
The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.
- Molecular Biomarkers of Epileptogenesis. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 25.
Epileptogenesis, a process leading to a reduced threshold for seizures after transient brain insults, as well as the mechanisms underlying the propensity to generate spontaneous epileptic seizures, are highly dynamic processes. Biomarkers-objective measures of biological processes-would be excellent tools for monitoring epileptogenesis and the dynamics of increased seizure propensity, as well as the potential to interfere, for example pharmacologically, with these key pathological aspects of epilepsy. Molecular biomarkers have revolutionized therapies, as well as response prediction and monitoring of therapies in other biomedical fields. However, high-impact molecular biomarkers are still not available in the context of epilepsy. Several factors, such as the large heterogeneity of epileptic syndromes and their underlying pathological patterns, as well as the limited availability of tissue samples, represent a particular challenge to the development of molecular biomarkers in epileptogenesis and epilepsy. However, substantial technical progress has been made recently with respect to biomarker characterization and monitoring by large throughput analysis on the genomic, mRNA, and proteomic levels, starting from minute amounts of brain tissue or body fluids, for example cerebrospinal fluid, blood, serum, or plasma. Given the substantial cellular- and network-level functional pathophysiology involved in epilepsy, it may be beneficial in the future to combine molecular analysis with other methods, such as imaging and electrophysiological biomarkers.
- Epilepsy Related to Traumatic Brain Injury. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 20.
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.
- Electrophysiological Biomarkers of Epilepsy. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 12.
In patients being evaluated for epilepsy and in animal models of epilepsy, electrophysiological recordings are carried to capture seizures to determine the existence of epilepsy. Electroencephalography recordings from the scalp, or sometimes directly from the brain, are also used to locate brain areas where seizure begins, and in surgical treatment help plan the area for resection. As seizures are unpredictable and can occur infrequently, ictal recordings are not ideal in terms of time, cost, or risk when, for example, determining the efficacy of existing or new anti-seizure drugs, evaluating potential anti-epileptogenic interventions, or for prolonged intracerebral electrode studies. Thus, there is a need to identify and validate other electrophysiological biomarkers of epilepsy that could be used to diagnose, treat, cure, and prevent epilepsy. Electroencephalography recordings in the epileptic brain contain other interictal electrophysiological disturbances that can occur more frequently than seizures, such as interictal spikes (IIS) and sharp waves, and from invasive studies using wide bandwidth recording and small diameter electrodes, the discovery of pathological high-frequency oscillations (HFOs) and microseizures. Of IIS, HFOs, and microseizures, a significant amount of recent research has focused on HFOs in the pathophysiology of epilepsy. Results from studies in animals with epilepsy and presurgical patients have consistently found a strong association between HFOs and epileptogenic brain tissue that suggest HFOs could be a potential biomarker of epileptogenicity and epileptogenesis. Here, we discuss several aspects of HFOs, as well as IIS and microseizures, and the evidence that supports their role as biomarkers of epilepsy.
- Past and Present Definitions of Epileptogenesis and Its Biomarkers. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 4.
Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.
- Neuroimaging the Epileptogenic Process. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Feb 1.
Epilepsy is one of the most common chronic neurological conditions worldwide. Anti-epileptic drugs (AEDs) can suppress seizures, but do not affect the underlying epileptic state, and many epilepsy patients are unable to attain seizure control with AEDs. To cure or prevent epilepsy, disease-modifying interventions that inhibit or reverse the disease process of epileptogenesis must be developed. A major limitation in the development and implementation of such an intervention is the current poor understanding, and the lack of reliable biomarkers, of the epileptogenic process. Neuroimaging represents a non-invasive medical and research tool with the ability to identify early pathophysiological changes involved in epileptogenesis, monitor disease progression, and assess the effectiveness of possible therapies. Here we will provide an overview of studies conducted in animal models and in patients with epilepsy that have utilized various neuroimaging modalities to investigate epileptogenesis.
- Epilepsy Related to Developmental Tumors and Malformations of Cortical Development. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jan 31.
Structural abnormalities of the brain are increasingly recognized in patients with neurodevelopmental delay and intractable focal epilepsies. The access to clinically well-characterized neurosurgical material has provided a unique opportunity to better define the neuropathological, neurochemical, and molecular features of epilepsy-associated focal developmental lesions. These studies help to further understand the epileptogenic mechanisms of these lesions. Neuropathological evaluation of surgical specimens from patients with epilepsy-associated developmental lesions reveals two major pathologies: focal cortical dysplasia and low-grade developmental tumors (glioneuronal tumors). In the last few years there have been major advances in the recognition of a wide spectrum of developmental lesions associated with a intractable epilepsy, including cortical tubers in patients with tuberous sclerosis complex and hemimegalencephaly. As an increasing number of entities are identified, the development of a unified and comprehensive classification represents a great challenge and requires continuous updates. The present article reviews current knowledge of molecular pathogenesis and the pathophysiological mechanisms of epileptogenesis in this group of developmental disorders. Both emerging neuropathological and basic science evidence will be analyzed, highlighting the involvement of different, but often converging, pathogenetic and epileptogenic mechanisms, which may create the basis for new therapeutic strategies in these disorders.
- Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jan 30.
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.
- Molecular Tweezers Targeting Transthyretin Amyloidosis. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Jan 24.
Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.