Kidney tubular injury induced by valproic acid: systematic literature review.

BACKGROUND: Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury. METHODS: We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered. RESULTS: For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-ß-glucosaminidase, was often noted. CONCLUSIONS: Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. A higher resolution version of the Graphical abstract is available as Supplementary information.

Anti-kindling effect of Ginkgo biloba leaf extract and L-carnitine in the pentylenetetrazol model of epilepsy.

Epilepsy is one of the most common serious brain disorders, affecting about 1% of the population all over the world. Ginkgo biloba extract (GbE) and L-carnitine (LC) reportedly possess the antioxidative activity and neuroprotective potential. In this report, we investigated the possible protective and therapeutic effects of GbE and LC against pentylenetetrazol (PTZ)-induced epileptic seizures in rat hippocampus and hypothalamus. Adult male albino rats were equally divided into eight groups: control, GbE (100 mg/kg), LC (300 mg/kg), PTZ (40 mg/kg), protective groups (GbE + PTZ and LC + PTZ), and therapeutic groups (PTZ + GbE and PTZ + LC). The oxidative stress, antioxidant, and neurochemical parameters, viz., malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), acetylcholine esterase (AchE), dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in the hippocampal and hypothalamic regions have been evaluated. PTZ injection leads to an increase in the seizure score, the levels of MDA and NO, and to a decrease in the activity of GSH, SOD, CAT, and GPx. Besides, monoamine neurotransmitters, DA, NE, and 5-HT, were depleted in PTZ-kindled rats. Furthermore, PTZ administration caused a significant elevation in the activity of AchE. Hippocampal and hypothalamic sections from PTZ-treated animals were characterized by severe histopathological alterations and, intensely, increased the ezrin immunolabeled astrocytes. Pre- and post-treatment of PTZ rats with GbE and LC suppressed the kindling acquisition process and remarkably alleviated all the aforementioned PTZ-induced effects. GbE and LC have potent protective and therapeutic effects against PTZ-induced kindling seizures via the amelioration of oxidative/antioxidative imbalance, neuromodulatory, and antiepileptic actions.

Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Indications for epilepsy monitoring in pediatric and adolescent health care.

Seizures present in childhood with infinite diversity. History alone may suffice for diagnosis in some cases; more often additional evidence is needed to clarify events of concern. Electroencephalography (EEG) is a primary methodology used for seizure identification and management. Pediatric and adolescent health care providers are increasingly asked to make decisions about when and how to refer patients for eventual monitoring and must then be able to confidently interpret any resulting report(s). Comprehensive literature review was undertaken to provide a succinct and up-to-date overview aimed at general and subspecialty non-neurologist pediatric and adolescent health care providers to not only convey a solid general understanding of EEG and what it entails for patients and their families, but also foster a deeper understanding of the indications for monitoring-and how to interpret documented findings. In plain language this resultant guide reviews EEG basics, provides a crash course in the various types of EEG available, discusses broad indications for epilepsy monitoring, guides counseling and management for patients and their families both before and after EEG, and ultimately aids in the interpretation of both findings and prognosis. This review should allow both primary and subspecialty non-neurologic pediatric and adolescent health care providers to better identify when and how to best utilize EEG as part of a larger comprehensive clinical approach, distinguishing and managing both epileptic and nonepileptic disorders of concern while fostering communication across providers to facilitate and coordinate better holistic long-term care of pediatric and adolescent patients.

Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6-/Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.

Validity, reliability and cut-offs of the Patient Health Questionnaire-9 as a screening tool for depression among patients living with epilepsy in Rwanda.

BACKGROUND: Patients with epilepsy (PwE) have an increased risk of active and lifetime depression. Two in 10 patients experience depression. Lack of trained psychiatric staff in low- and middle-income countries (LMIC) creates a need for screening tools that enable detection of depression in PwE. We describe the translation, validity and reliability assessment of the Patient Health Questionnaire-9 (PHQ-9) as a screening tool for depression among PwE in Rwanda. METHOD: PHQ-9 was translated to Kinyarwanda using translation-back translation and validated by a discussion group. For validation, PwE of ≥15 years of age were administered the PHQ-9 and Hamilton Depression Rating Scale (HDRS) by trained psychiatry staff at Visit 1. A random sample of 20% repeated PHQ-9 and HDRS after 14 days to assess temporal stability and intra-rater reliability. Internal structure, reliability and external validity were assessed using confirmatory factor analysis, reliability coefficients and HDRS-correlation, respectively. Maximal Youden's index was considered for cut-offs. RESULTS: Four hundred and thirty-four PwE, mean age 30.5 years (SD ±13.3), were included of whom 33.6%, 37.9%, 13.4%, and 15.1% had no, mild, moderate and severe depression, respectively. PHQ-9 performed well on a one-factor model (unidimensional model), with factor loadings of 0.63-0.86. Reliability coefficients above 0.80 indicated strong internal consistency. Good temporal stability was observed (0.79 [95% CI: 0.68-0.87]). A strong correlation (R = 0.66, p = 0.01) between PHQ-9 and HDRS summed scores demonstrated robust external validity. The optimal cut-off for the PHQ-9 was similar (≥5) for mild and moderate depression and ≥7 for severe depression. CONCLUSION: PHQ-9 validation in Kinyarwanda creates the capacity to screen PwE in Rwanda at scores of ≥5 for mild or moderate and ≥7 for severe depression. The availability of validated tools for screening and diagnosis for depression is a forward step for holistic care in a resource-limited environment.

Chaihu-Longgu-Muli decoction relieves epileptic symptoms by improving autophagy in hippocampal neurons.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu-Longgu-Muli decoction (CLMD) is a well-known ancient formula in traditional Chinese medicine (TCM) to relieve disorder, clear away heat, tranquilize the mind and allay excitement. It has been used for the therapy of neuropsychiatric disorders such as epilepsy, dementia, insomnia, anxiety, and depression for several centuries in China. AIM OF THE STUDY: This paper is based on the assumption that the mechanism by which CLMD relieves epileptic symptoms in rats is associated with improving autophagy. Several experimental methods are designed to testify the hypothesis. MATERIALS AND METHODS: The lithium-pilocarpine-induced epilepsy model was established in rats. The seizure frequency was recorded. Morphology and number of autophagosomes in hippocampal dentate gyrus was detected with a transmission electron microscope (TEM). Expression of Beclin-1, microtubule-associated proteins 1A/1B light chain 3 (LC3), and mammalian target of rapamycin (mTOR) in dentate gyrus was measured by immunofluorescence assay, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western-blotting. RESULTS: CLMD could significantly relieve the seizure frequency and improve autophagy in hippocampal dentate gyrus. Meanwhile, the level of Beclin-1 and LC3B decreased significantly, while mTOR increased remarkably after medical intervention. CONCLUSIONS: CLMD could improve autophagy in hippocampal dentate gyrus due to epilepsy, especially at high dose. The mechanism may be related to upregulated expression of mTOR and downregulated expression of Beclin-1 and LC3B.

Analysis of gene variants in the GASH/Sal model of epilepsy.

Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate- and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arhgef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that encode proteins with functions related to neuronal excitability, which could be implied in the phenotype of the GASH/Sal. Our findings provide valuable genetic and biological pathway data associated to the genetic burden of the audiogenic seizure susceptibility and reinforce the need to validate the role of each key mutation in the phenotype of the GASH/Sal model.

Children with epilepsy demonstrate macro- and microstructural changes in the thalamus, putamen, and amygdala.

PURPOSE: Despite evidence for macrostructural alteration in epilepsy patients later in life, little is known about the underlying pathological or compensatory mechanisms at younger ages causing these alterations. The aim of this work was to investigate the impact of pediatric epilepsy on the central nervous system, including gray matter volume, cerebral blood flow, and water diffusion, compared with neurologically normal children. METHODS: Inter-ictal magnetic resonance imaging data was obtained from 30 children with epilepsy ages 1-16 (73% F, 27% M). An atlas-based approach was used to determine values for volume, cerebral blood flow, and apparent diffusion coefficient in the cerebral cortex, hippocampus, thalamus, caudate, putamen, globus pallidus, amygdala, and nucleus accumbens. These values were then compared with previously published values from 100 neurologically normal children using a MANCOVA analysis. RESULTS: Most brain volumes of children with epilepsy followed a pattern similar to typically developing children, except for significantly larger putamen and amygdala. Cerebral blood flow was also comparable between the groups, except for the putamen, which demonstrated decreased blood flow in children with epilepsy. Diffusion (apparent diffusion coefficient) showed a trend towards higher values in children with epilepsy, with significantly elevated diffusion within the thalamus in children with epilepsy compared with neurologically normal children. CONCLUSION: Children with epilepsy show statistically significant differences in volume, diffusion, and cerebral blood flow within their thalamus, putamen, and amygdala, suggesting that epilepsy is associated with structural changes of the central nervous system influencing brain development and potentially leading to poorer neurocognitive outcomes.

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials.

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.

Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus.

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

Echinacoside, an Active Constituent of Cistanche Herba, Exerts a Neuroprotective Effect in a Kainic Acid Rat Model by Inhibiting Inflammatory Processes and Activating the Akt/GSK3ß Pathway.

Echinacoside is a major compound of Cistanche Herb and has glutamate release-inhibiting activity in the brain. Given the involvement of excitotoxicity caused by massive glutamate in the pathophysiology of epilepsy, we explored the antiepileptic effect of echinacoside on kainic acid-induced seizures in rats. The rats were intraperitoneally administrated echinacoside for 30 min prior to intraperitoneal injection with kainic acid. The results showed that kainic acid induced seizure-like behavioral patterns, increased glutamate concentrations, caused neuronal loss and microglial activation, and stimulated proinflammatory cytokine gene expression in the hippocampus. These kainic acid-induced alternations were found to be attenuated by echinacoside pretreatment. Furthermore, decreased Akt and glycogen synthase kinase 3ß (GSK3ß) phosphorylation as well as Bcl-2 expression in the hippocampus was reversed by the echinacoside pretreatment. These results demonstrate that echinacoside exert its antiepileptic and neuroprotective actions in a kainic acid rat model through suppressing inflammatory response and activating the Akt/GSK3ß signaling. Therefore, the present study suggests that echinacoside is the potentially useful in the prevention of epilepsy.

Curcumin Reduces Neuronal Loss and Inhibits the NLRP3 Inflammasome Activation in an Epileptic Rat Model.

BACKGROUND: Epilepsy is a chronic neurological disorder affecting an estimated 50 million people worldwide. Emerging evidences have accumulated over the past decades supporting the role of inflammation in the pathogenesis of epilepsy. Curcumin is a nature-derived active molecule demonstrating anti-inflammation efficacy. However, its effects on epilepsy and corresponding mechanisms remain elusive. OBJECTIVE: To investigate the effects of curcumin on epilepsy and its underlying mechanism. METHOD: Forty Sprague Dawley rats were divided into four groups: (1) control group; (2) Kainic Acid (KA)-induced epilepsy group; (3) curcumin group; and (4) curcumin pretreatment before KA stimulation group. Morris water maze was utilized to assess the effect of curcumin on KA-induced epilepsy. The hippocampi were obtained from rats and subjected to western blot. Immunohistochemistry was conducted to investigate the underlying mechanisms. RESULTS: Rats received curcumin demonstrated improvement of recognition deficiency and epilepsy syndromes induced by KA. Western blot showed that KA stimulation increased the expression of IL-1ß and NLRP3, which were reduced by curcumin treatment. Further investigations revealed that curcumin inhibited the activation of NLPR3/inflammasome in epilepsy and reduced neuronal loss in hippocampus. CONCLUSION: Curcumin inhibits KA-induced epileptic syndromes via suppression of NLRP3 inflammasome activation; therefore, offers a potential therapy for epilepsy.

Stretchable Transparent Electrode Arrays for Simultaneous Electrical and Optical Interrogation of Neural Circuits in Vivo.

Recent developments of transparent electrode arrays provide a unique capability for simultaneous optical and electrical interrogation of neural circuits in the brain. However, none of these electrode arrays possess the stretchability highly desired for interfacing with mechanically active neural systems, such as the brain under injury, the spinal cord, and the peripheral nervous system (PNS). Here, we report a stretchable transparent electrode array from carbon nanotube (CNT) web-like thin films that retains excellent electrochemical performance and broad-band optical transparency under stretching and is highly durable under cyclic stretching deformation. We show that the CNT electrodes record well-defined neuronal response signals with negligible light-induced artifacts from cortical surfaces under optogenetic stimulation. Simultaneous two-photon calcium imaging through the transparent CNT electrodes from cortical surfaces of GCaMP-expressing mice with epilepsy shows individual activated neurons in brain regions from which the concurrent electrical recording is taken, thus providing complementary cellular information in addition to the high-temporal-resolution electrical recording. Notably, the studies on rats show that the CNT electrodes remain operational during and after brain contusion that involves the rapid deformation of both the electrode array and brain tissue. This enables real-time, continuous electrophysiological monitoring of cortical activity under traumatic brain injury. These results highlight the potential application of the stretchable transparent CNT electrode arrays in combining electrical and optical modalities to study neural circuits, especially under mechanically active conditions, which could potentially provide important new insights into the local circuit dynamics of the spinal cord and PNS as well as the mechanism underlying traumatic injuries of the nervous system.

ERK activation is required for the antiepileptogenic effect of low frequency electrical stimulation in kindled rats.

INTRODUCTION: The signaling pathways involved in the antiepileptogenic effect of low frequency electrical stimulation (LFS) have not been fully understood. In the present study the role of extracellular signal-regulated kinase (ERK) signaling cascade was investigated in mediating the inhibitory effects of LFS on kindled seizures. METHODS: Animals received kindling stimulations for seven days (the mean number of stimulation days for achieving stage 5 seizure) according to semi-rapid perforant path kindling protocol (12 stimulations per day at 10 min intervals). LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) was applied at 5 min after the last kindling stimulation every day. During the kindling procedure, FR180204 (inhibitor of ERK) was daily microinjected (1 µg/µl; intracerebroventricular) immediately after the last kindling stimulation and before LFS application. The expression of activated ERK (p-ERK) in the dentate gyrus was also investigated using immunohistochemistry technique. RESULTS: Application of LFS at 5 min after the last kindling stimulation had inhibitory effect on kindling rate. FR180204 had no significant effect on seizure parameters when administered at the dose of 1 µg/µl in kindled group of animals. However, microinjection of FR180204 before LFS application reduced the inhibitory effect of LFS on seizure severity and field potential parameters (i.e. the slope of population field excitatory postsynaptic potentials and population spike amplitude) during kindling. FR180204 also blocked the preventing effects of LFS on kindling-induced increase in early (at 10-40 ms intervals) and late (at 300-1000 ms intervals) paired pulse depression. In addition, application of LFS following kindling stimulations increased the expression of p-ERK in the dentate gyrus. CONCLUSION: Obtained results showed ERK signaling pathway had important role in mediating the antiepileptogenic effect of LFS in perforant path kindling. These findings represent a promising opportunity to gain insight about LFS mechanism in epilepsy therapy.

Cognitive impairment in early onset epilepsy is associated with reduced left thalamic volume.

OBJECTIVE: The objective of this study was to investigate whether reduction of thalamic volumes in children with early onset epilepsy (CWEOE) is associated with cognitive impairment. METHODS: This is a nested case-control study including a prospectively recruited cohort of 76 children with newly-diagnosed early onset epilepsy (onset <5years age) and 14 healthy controls presenting to hospitals within NHS Lothian and Fife. Quantitative volumetric analysis of subcortical structures was performed using volumetric T1-weighted magnetic resonance imaging (MRI) and correlated with the results of formal neurocognitive and clinical assessment. False discovery rate was used to correct for multiple comparisons as appropriate with q<0.05 used to define statistical significance. RESULTS: Age, gender, and intracranial volume (ICV)-adjusted left thalamic volumes were significantly reduced in CWEOE with cognitive impairment compared to CWEOE without impairment (5295mm3 vs 6418mm3, q=0.008) or healthy controls (5295mm3 vs 6410mm3, q<0.001). The differences in left thalamic volume remained if gray matter or cortical/cerebellar volumes were used as covariates rather than ICV (q<0.05). The degree of volume reduction correlated with the severity of cognitive impairment (q=0.048). SIGNIFICANCE: Reduced left thalamic volume may be a biomarker for cognitive impairment in CWEOE and could help inform the need for further formal cognitive evaluations and interventions.

Effects of Leontice leontopetalum and Bongardia chrysogonum on oxidative stress and neuroprotection in PTZ kindling epilepsy in rats.

We investigated the effects of Leontice leontopetalum and Bongardia chrysogonum on apoptosis, gamma-aminobutyric acid (GABAA) receptor positive cell number, cyclin-B1 and bcl-2 levels and oxidative stress in pentylenetetrazol (PTZ) kindling in rats. Kindling was produced by subconvulsant doses of PTZ treatments in rats. Wistar albino rats were divided into 4 groups; Control, PTZ treated (PTZ), PTZ+L. leontopetalum extract treated (PTZ+LLE) and PTZ+B. chrysogonum extract treated (PTZ+BCE) groups. Extracts were given a dose (200 mg/kg) 2h before each PTZ injection. PTZ treatment significantly decreased the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activities and bcl-2 levels and increased the total oxidant status (TOS), malondialdehyde (MDA), cyclin B1, oxidative stress index (OSI) and number of neurons that expressed GABAA receptors when compared to the control. LLE and BCE possessed antioxidant activity in the brain and ameliorated PTZ induced oxidative stress, decreased cyclin-B1, increased bcl-2 levels, and kept the GABAA receptor number similar to that of the control despite the PTZ application.

A new description of epileptic seizures based on dynamic analysis of a thalamocortical model.

Increasing evidence suggests that the brain dynamics can be interpreted from the viewpoint of nonlinear dynamical systems. The aim of this paper is to investigate the behavior of a thalamocortical model from this perspective. The model includes both cortical and sensory inputs that can affect the dynamic nature of the model. Driving response of the model subjected to various harmonic stimulations is considered to identify the effects of stimulus parameters on the cortical output. Detailed numerical studies including phase portraits, Poincare maps and bifurcation diagrams reveal a wide range of complex dynamics including period doubling and chaos in the output. Transition between different states can occur as the stimulation parameters are changed. In addition, the amplitude jump phenomena and hysteresis are shown to be possible as a result of the bending in the frequency response curve. These results suggest that the jump phenomenon due to the brain nonlinear resonance can be responsible for the transitions between ictal and interictal states.

Inflammation and Epilepsy: Preclinical Findings and Potential Clinical Translation.

BACKGROUND: The lack of treatments which can prevent epilepsy development or improve disease prognosis represents an unmet and urgent clinical need. The development of such drugs requires a deep understanding of the mechanisms underlying disease pathogenesis. In the last decade, preclinical studies in models of acute seizures and of chronic epilepsy highlighted that neuroinflammation arising in brain areas of seizure onset and generalization is a key contributor to neuronal hyper-excitability underlying seizure generation. Microglia and astrocytes are pivotal cells involved in both the induction and perpetuation of the inflammatory response to epileptogenic injuries or seizures; other cell contributors are neurons, cell components of the blood brain barrier and leukocytes. METHODS: From the clinical standpoint, neuroinflammation is now considered an hallmark of epileptogenic foci in various forms of focal onset pharmacoresistant epilepsies. Moreover, pharmacological studies in animal model with drugs targeting specific inflammatory molecules, and changes in intrinsic seizure susceptibility of transgenic mice with perturbed neuroinflammatory mechanisms, have demonstrated that neuroinflammation is not a bystander phenomenon but has a pathogenic role in seizures, cell loss and neurological co-morbidities. Understanding the role of neuroinflammation in seizure pathogenesis is instrumental for a mechanism-based discovery of selective therapies targeting the epilepsy causes rather than its symptoms, thereby allowing the development of novel disease-modifying treatments. Notably, clinical translation of laboratory findings may take advantage of anti-inflammatory drugs already in medical use for peripheral autoinflammatory or autoimmune disorders. CONCLUSION: This review reports key preclinical and clinical findings supporting a role for brain inflammation in the pathogenesis of seizures. It also highlights the emerging proof-of-concept studies showing signs of clinical efficacy of target-specific anti-inflammatory interventions in epilepsies of differing etiologies. We will discuss the need for biomarkers and novel clinical trial designs for anti-inflammatory therapies that have a mechanism of action very different than standard antiepileptic drugs.