Project description:ObjectiveThe treatment of focal epilepsies is largely predicated on the concept that there is a "focus" from which the seizure emanates. Yet, the physiological context that determines if and how ictal activity starts and propagates remains poorly understood. To delineate these phenomena more completely, we studied activity outside the seizure-onset zone prior to and during seizure initiation.MethodsStereotactic depth electrodes were implanted in 17 patients with longstanding pharmacoresistant epilepsy for lateralization and localization of the seizure-onset zone. Only seizures with focal onset in mesial temporal structures were used for analysis. Spectral analyses were used to quantify changes in delta, theta, alpha, beta, gamma, and high gamma frequency power, in regions inside and outside the area of seizure onset during both preictal and seizure initiation periods.ResultsIn the 78 seizures examined, an average of 9.26% of the electrode contacts outside of the seizure focus demonstrated changes in power at seizure onset. Of interest, seizures that were secondarily generalized, on average, showed power changes in a greater number of extrafocus electrode contacts at seizure onset (16.7%) compared to seizures that remained focal (3.8%). The majority of these extrafocus changes occupied the delta and theta bands in electrodes placed in the ipsilateral, lateral temporal lobe. Preictally, we observed extrafocal high-frequency power decrements, which also correlated with seizure spread.SignificanceThis widespread activity at and prior to the seizure-onset time further extends the notion of the ictogenic focus and its relationship to seizure spread. Further understanding of these extrafocus, periictal changes might help identify the neuronal dynamics underlying the initiation of seizures and how therapies can be devised to control seizure activity.
Project description:Epilepsy is a serious neurological disease characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Protrudin is a neural membrane protein and is found to be mutated in hereditary spastic paraplegia that characterized by symptoms like seizures. Here, we reported that the expression of protrudin was downregulated in the temporal neocortex of epileptic patients and in the hippocampus and cortex of pentylenetetrazol and kainic acid-kindled epileptic mouse models. Behavioral and electroencephalogram analyses indicated that overexpression of protrudin in the mouse hippocampus increased the latency of the seizure and decreased the frequency and duration of seizure activity. Using whole-cell patch clamp, overexpression of protrudin in the mouse hippocampus resulted in a reduction in action potential frequency and an increase in gamma-aminobutyric acid (GABA)ergic inhibitory current amplitude. Moreover, western blot analysis showed that the membrane expression of the GABA A receptor β2/3 subunit was also upregulated after protrudin overexpression, and coimmunoprecipitation resulted in a protein-protein interaction between protrudin, GABAARβ2/3 and GABA receptor-associated protein in the hippocampus of epileptic mice. These findings suggest that protrudin probably inhibits the occurrence and development of epilepsy through the regulation of GABAA receptor-mediated synaptic transmission, and protrudin might be a promising target for the treatment of epilepsy.
Project description:The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1A2105T protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1A2105T) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans.
Project description:γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain and has been found to play an important role in the pathogenesis or the expression of many neurological diseases, including epilepsy. Although GABA can act on different receptor subtypes, the component of the GABA system that is most critical to modulation of seizure activity is the GABAA-receptor-chloride (Cl-) channel complex, which controls the movement of Cl- ions across the neuronal membrane. In the mature brain, binding of GABA to GABAA receptors evokes a hyperpolarising (anticonvulsant) response, which is mediated by influx of Cl- into the cell driven by its concentration gradient between extracellular and intracellular fluid. However, in the immature brain and under certain pathological conditions, GABA can exert a paradoxical depolarising (proconvulsant) effect as a result of an efflux of chloride from high intracellular to lower extracellular Cl- levels. Extensive preclinical and clinical evidence indicates that alterations in GABAergic inhibition caused by drugs, toxins, gene defects or other disease states (including seizures themselves) play a causative or contributing role in facilitating or maintaning seizure activity. Conversely, enhancement of GABAergic transmission through pharmacological modulation of the GABA system is a major mechanism by which different antiseizure medications exert their therapeutic effect. In this article, we review the pharmacology and function of the GABA system and its perturbation in seizure disorders, and highlight how improved understanding of this system offers opportunities to develop more efficacious and better tolerated antiseizure medications. We also review the available data for the two most recently approved antiseizure medications that act, at least in part, through GABAergic mechanisms, namely cenobamate and ganaxolone. Differences in the mode of drug discovery, pharmacological profile, pharmacokinetic properties, drug-drug interaction potential, and clinical efficacy and tolerability of these agents are discussed.
Project description:Recent reports have shown that ferrocene displays an unexpected combination of force-free stability and mechanochemical activity, as it acts as the preferred site of chain scission along the backbone of highly extended polymer chains. This observation raises the tantalizing question as to whether similar mechanochemical activity might be present in other metallocenes, and, if so, what features of metallocenes dictate their relative ability to act as mechanophores. In this work, we elucidate polymerization methodologies towards main-chain ruthenocene-based polymers and explore the mechanochemistry of ruthenocene. We find that ruthenocene, in analogy to ferrocene, acts as a highly selective site of main chain scission despite the fact that it is even more inert. A comparison of ruthenocene and ferrocene reactivity provides insights as to the possible origins of metallocene mechanochemistry, including the relative importance of structural and thermodynamic parameters such as bond length and bond dissociation energy. These results suggest that metallocenes might be privileged mechanophores through which highly inert coordination complexes can be made dynamic in a stimuli-responsive fashion, offering potential opportunities in dynamic metallo-supramolecular materials and in mechanochemical routes to reactive intermediates that are otherwise difficult to obtain.
Project description:Broad-scale untargeted biochemical phenotyping is a technology that supplements widely accepted assays, such as organic acid, amino acid, and acylcarnitine analyses typically utilized for the diagnosis of inborn errors of metabolism. In this study, we investigate the analyte changes associated with 4-aminobutyrate aminotransferase (ABAT, GABA transaminase) deficiency and treatments that affect GABA metabolism. GABA-transaminase deficiency is a rare neurodevelopmental and neurometabolic disorder caused by mutations in ABAT and resulting in accumulation of GABA in the cerebrospinal fluid (CSF). For that reason, measurement of GABA in CSF is currently the primary approach to diagnosis. GABA-transaminase deficiency results in severe developmental delay with intellectual disability, seizures, and movement disorder, and is often associated with death in childhood. Using an untargeted metabolomics platform, we analyzed EDTA plasma, urine, and CSF specimens from four individuals with GABA-transaminase deficiency to identify biomarkers by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort. Metabolomic analyses of over 1,000 clinical plasma samples revealed a rich source of biochemical information. Three out of four patients showed significantly elevated levels of the molecule 2-pyrrolidinone (Z-score ≥2) in plasma, and whole exome sequencing revealed variants of uncertain significance in ABAT. Additionally, these same patients also had elevated levels of succinimide in plasma, urine, and CSF and/or homocarnosine in urine and CSF. In the analysis of clinical EDTA plasma samples, the levels of succinimide and 2-pyrrolidinone showed a high level of correlation (R = 0.73), indicating impairment in GABA metabolism and further supporting the association with GABA-transaminase deficiency and the pathogenicity of the ABAT variants. Further analysis of metabolomic data across our patient population revealed the association of elevated levels of 2-pyrrolidinone with administration of vigabatrin, a commonly used anti-seizure medication and a known inhibitor of GABA-transaminase. These data indicate that anti-seizure medications may alter the biochemical and metabolomic data, potentially impacting the interpretation and diagnosis for the patient. Further, these data demonstrate the power of combining broad scale genotyping and phenotyping technologies to diagnose inherited neurometabolic disorders and support the use of metabolic phenotyping of plasma to screen for GABA-transaminase deficiency.
Project description:Predatory journals and conferences have little or no peer review. Their raison d'être is for making money through the article processing charges and the conference registration fees. Without a critical evaluation, predatory journals publishing flawed results and conclusions would cloud the existing scientific literature. Predatory conferences are the offshoots of predatory publishing. The conferences are not organised by learned societies, but by profit-making event organisers. There is a need for awareness among researchers and clinicians regarding predatory publishing. The scourge of predatory publishing and conferencing should be more often highlighted during scientific meetings and publication courses.
Project description:The idea of sex differences in the brain both fascinates and inflames the public. As a result, the communication and public discussion of new findings is particularly vulnerable to logical leaps and pseudoscience. A new US National Institutes of Health policy to consider both sexes in almost all preclinical research will increase the number of reported sex differences and thus the risk that research in this important area will be misinterpreted and misrepresented. In this article, I consider ways in which we might reduce that risk, for example, by (i) employing statistical tests that reveal the extent to which sex explains variation, rather than whether or not the sexes 'differ', (ii) properly characterizing the frequency distributions of scores or dependent measures, which nearly always overlap, and (iii) avoiding speculative functional or evolutionary explanations for sex-based variation, which usually invoke logical fallacies and perpetuate sex stereotypes. Ultimately, the factor of sex should be viewed as an imperfect, temporary proxy for yet-unknown factors, such as hormones or sex-linked genes, that explain variation better than sex. As scientists, we should be interested in discovering and understanding the true sources of variation, which will be more informative in the development of clinical treatments.
Project description:Modern immunosuppression regimens effectively control acute rejection and decrease graft loss in the first year after transplantation; however, these regimens do not have a durable effect on long-term graft survival owing to a combination of drug toxicities and the emergence of chronic alloimmune responses. Eliminating drugs and their toxicities while maintaining graft acceptance has been the primary aim of cellular therapies. Tregs suppress both autoimmune and alloimmune responses and are particularly effective in protecting allografts in experimental transplant models. Further, Treg-based therapies are selective, do not require harsh conditioning, and do not have a risk of graft-versus-host disease. Trial designs should consider the distinct immunological features of each transplanted organ, Treg preparations, dose, and frequency, and the ability to detect and quantify Treg effects in a given transplant environment. In this Review, we detail the ongoing clinical trials of Treg therapy in liver and kidney transplantation. Integration of Treg biology gleaned from preclinical models and experiences in human organ transplantation should allow for optimization of trial design that will determine the potential efficacy of a given therapy and provide guidelines for further therapeutic development.