Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood-brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid-induced epileptic rats.

PubMed

Chen, Ying-Chuan; Zhu, Guan-Yu; Wang, Xiu; Shi, Lin; Du, Ting-Ting; Liu, De-Feng; Liu, Yu-Ye; Jiang, Yin; Zhang, Xin; Zhang, Jian-Guo

2017-12-01

Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood-brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti-inflammatory effect in epileptic models.

Imaging DC MEG Fields Associated with Epileptic Onset

NASA Astrophysics Data System (ADS)

Weiland, B. J.; Bowyer, S. M.; Moran, J. E.; Jenrow, K.; Tepley, N.

2004-10-01

Magnetoencephalography (MEG) is a non-invasive brain imaging modality, with high spatial and temporal resolution, used to evaluate and quantify the magnetic fields associated with neuronal activity. Complex partial epileptic seizures are characterized by hypersynchronous neuronal activity believed to arise from a zone of epileptogenesis. This study investigated the characteristics of direct current (DC) MEG shifts arising at epileptic onset. MEG data were acquired with rats using a six-channel first order gradiometer system. Limbic status epilepticus was induced by IA (femoral) administration of kainic acid. DC-MEG shifts were observed at the onset of epileptic spike train activity and status epilepticus. Epilepsy is also being studied in patients undergoing presurgical mapping from the Comprehensive Epilepsy Center at Henry Ford Hospital using a whole head Neuromagnetometer. Preliminary data analysis shows that DC-MEG waveforms, qualitatively similar to those seen in the animal model, are evident prior to seizure activity in human subjects.

Neuroprotective Effects of the Absence of JNK1 or JNK3 Isoforms on Kainic Acid-Induced Temporal Lobe Epilepsy-Like Symptoms.

PubMed

de Lemos, Luisa; Junyent, Felix; Camins, Antoni; Castro-Torres, Rubén Darío; Folch, Jaume; Olloquequi, Jordi; Beas-Zarate, Carlos; Verdaguer, Ester; Auladell, Carme

2018-05-01

The activation of c-Jun-N-terminal kinases (JNK) pathway has been largely associated with the pathogenesis and the neuronal death that occur in neurodegenerative diseases. Altogether, this justifies why JNKs have become a focus of screens for new therapeutic strategies. The aim of the present study was to identify the role of the different JNK isoforms (JNK1, JNK2, and JNK3) in apoptosis and inflammation after induction of brain damage. To address this aim, we induced excitotoxicity in wild-type and JNK knockout mice (jnk1 -/- , jnk2 -/- , and jnk3 -/- ) via an intraperitoneal injection of kainic acid, an agonist of glutamic-kainate-receptors, that induce status epilepticus.Each group of animals was divided into two treatments: a single intraperitoneal dose of saline solution, used as a control, and a single intraperitoneal dose (30 mg/kg) of kainic acid. Our results reported a significant decrease in neuronal degeneration in the hippocampus of jnk1 -/- and jnk3 -/- mice after kainic acid treatment, together with reduced or unaltered expression of several apoptotic genes compared to WT treated mice. In addition, both jnk1 -/- and jnk3 -/- mice exhibited a reduction in glial reactivity, as shown by the lower expression of inflammatory genes and a reduction of JNK phosphorylation. In addition, in jnk3 -/- mice, the c-Jun phosphorylation was also diminished.Collectively, these findings provide compelling evidence that the absence of JNK1 or JNK3 isoforms confers neuroprotection against neuronal damage induced by KA and evidence, for the first time, the implication of JNK1 in excitotoxicity. Accordingly, JNK1 and/or JNK3 are promising targets for the prevention of cell death and inflammation during epileptogenesis.

Kainic acid-mediated increase of preprotachykinin-A messenger RNA expression in the rat hippocampus and a region-selective attenuation by dexamethasone.

PubMed

Brené, S; Lindefors, N; Ballarin, M; Persson, H

1992-10-01

The hippocampus contains the highest number of glucocorticoid-sensitive neurons in the rat brain and excessive exposure to glucocorticoids can cause damage to hippocampal neurons and impair the capacity of the hippocampus to survive neuronal insults. In this study in situ hybridization combined with quantitative image analysis was used to study preprotachykinin-A mRNA levels after administration of a toxic dose of kainic acid in animals pretreated with glucocorticoids. Kainic acid was injected into dorsal hippocampus CA3 region in animals pretreated with the synthetic glucocorticoid receptor agonist dexamethasone and in control animals. Preprotachykinin-A mRNA was not detected in the hippocampus of untreated animals or in animals analysed 30 min after a kainic acid injection. However, 4 h after injection of kainic acid, the level of preprotachykinin-A mRNA increased to 20-times above the detection limit both in the dentate gyrus and the CA3 region of the hippocampus. Treatment of kainic acid-injected animals with dexamethasone 30 min before and 2 h after the injection attenuated the increase in the granule cells of the dentate gyrus by 50%. In contrast, dexamethasone pretreatment had no significant effect on the kainic acid-induced increase of preprotachykinin-A mRNA in pyramidal cells in regions CA3 or CA1. These results show that an excitatory stimulus within the hippocampus causes a substantial increase in the level of preprotachykinin-A mRNA in hippocampal granule and pyramidal cells and suggest that in granule cells of the dentate gyrus this increase can be modulated by glucocorticoids.

Conformation of kainic acid in solution from molecular modelling and NMR spectra.

PubMed

Falk, M; Sidhu, P; Walter, J A

1998-01-01

Conformational behaviour of kainic acid in aqueous solution was elucidated by molecular mechanics and dynamics. The pucker of the five-membered ring in kainic acid was examined and compared with that of model compounds. In cyclopentane there is no barrier to pseudorotation, so that all puckered states coexist. In pyrrolidinium, the presence of a hetero-atom in the ring introduces a small barrier (about 0.6 kcal mol(-1)) to pseudorotation, separating two stable regions, A and B, which are equivalent by symmetry. In proline, the presence of the carboxylate group on C2 removes the symmetry but two stable conformational minima, A and B, remain. In kainic acid, the presence of side-chains on C3 and C4 introduces complications resulting in additional sub-minima in both regions, A and B. In solution, kainic acid is a complex mixture of conformers with comparable energies, because of the combination of several stable states of the pyrrolidinium ring with the torsional degrees of freedom arising from the two side-chains. The individual geometries, energies, and estimates of relative populations of these conformers were obtained from molecular dynamics simulations. The calculations were validated by a comparison of predicted inter-proton distances and vicinal proton coupling constants with the experimental quantities derived from NMR spectra.

Effect of infrared laser irradiation on amino acid neurotransmitters in an epileptic animal model induced by pilocarpine.

PubMed

Radwan, Nasr Mahmoud; El Hay Ahmed, Nawal Abd; Ibrahim, Khayria Mansour; Khedr, Mona Emam; Aziz, Mona A; Khadrawy, Yasser Ashry

2009-06-01

The aim of the present study was to investigate the effect of daily laser irradiation on the levels of amino acid neurotransmitters in the cortex and hippocampus in an epileptic animal model induced by pilocarpine. It has been claimed that at specific wavelengths and energy densities, laser irradiation is a novel and useful tool for the treatment of peripheral and central nervous system injuries and disorders. Adult male albino rats were divided into three groups: control rats, pilocarpinized rats (epileptic animal model), and pilocarpinized rats treated daily with laser irradiation (90 mW at 830 nm) for 7 d. The following parameters were assayed in cortex and hippocampus: amino acid neurotransmitters (excitatory: glutamic acid and aspartate; and inhibitory: gamma-aminobutyric acid [GABA], glycine, and taurine) by high-performance liquid chromatography (HPLC), glucose content, and the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), using a spectrophotometer. Significant increases in the concentrations of glutamic acid, glutamine, glycine, and taurine were recorded in the cortices of pilocarpinized rats, and they returned to initial levels after laser treatment. In the hippocampus, a moderate increase in aspartate accompanied by a significant increase in glycine were observed in the epileptic animal model, and these dropped to near-control values after laser treatment. In addition, a significant increase in cortical AST activity and a significant decrease in ALT activity and glucose content were obtained in the pilocarpinized animals and pilocarpinized rats treated with laser irradiation. In the hippocampus, significant decreases in the activity of AST and ALT and glucose content were recorded in the epileptic animals and in the epileptic animals treated with laser irradiation. Based on the results obtained in this study, it may be suggested that nearinfrared laser irradiation may reverse the neurochemical changes in amino acid

Emodin plays an interventional role in epileptic rats via multidrug resistance gene 1 (MDR1).

PubMed

Yang, Tao; Kong, Bin; Kuang, Yongqin; Cheng, Lin; Gu, Jianwen; Zhang, Junhai; Shu, Haifeng; Yu, Sixun; Yang, Xiaokun; Cheng, Jingming; Huang, Haidong

2015-01-01

To observe the interventional effects of emodin in epileptic rats and elucidate its possible mechanism of action. Thirty-six female Wistar rats were randomly divided into normal control group, model group (intraperitoneal injection of kainic acid) and emodin group (intraperitoneal injection of kainic acid+emodin intervention). The rat epilepsy model was confirmed by behavioral tests and electroencephalography. The protein levels of P-glycoprotein and N-methyl-D-aspartate (NMDA) receptor in cerebral vascular tissue were analyzed by western blotting, and mRNA levels of multidrug resistance gene 1 (MDR1) and cyclooxygenase-2 (COX-2) were analyzed by real-time PCR. COX-2 and P-glycoprotein levels in the brains were detected by immunohistochemical assay. The seizures were relieved in emodin group. Laser scanning confocal microscopy showed P-glycoprotein fluorescence increased significantly after seizures, indicating that epilepsy can induce overexpression of P-glycoprotein. Compared with control group, protein levels of P-glycoprotein and NMDA receptor in cerebral vascular tissue were significantly higher in model group, and mRNA levels of MDR1 and COX-2 were also significantly increased. Compared with model group, P-glycoprotein and NMDA receptor levels in cerebral vascular tissue were significantly decreased in emodin group (P<0.05), and the levels of MDR1 and COX-2 were down-regulated (P<0.05). In the rat brain, seizures could significantly increase COX-2 and P-glycoprotein levels, while emodin intervention was able to significantly reduce the levels of both. These findings suggest that epileptic seizures are tightly associated with up-regulated MDR1 gene, and emodin shows good antagonistic effects on epileptic rats, possibly through inhibition of MDR1 gene and its associated genes.

Chemically Induced Damage to the Hippocampal Formation,

DTIC Science & Technology

1986-05-01

Ottersen, 0 P and Meldrum , B S (1980): The role of epileptic activity in hippocanpal and "remote" cerebral lesions induced by kainic acid , Brain Res...Toxicology (in press). PAPFR III: (manuscript) Naalsund, L U and Fonnum, F, 1986, Pifferences in anionic dependence of the synaptic efflux of D-aspartic acid ...and y-amino butyric acid , J Neurochem (in press). PAPER IV: (manuscript) Naalsund, L U, 1986, Hippocampal EEC in rats after chronic toluene inhalation

Comparative effects of kainic, quisqualic, and ibotenic acids on phenylethanolamine-N-methyltransferase-containing cells of rat retina.

PubMed

Cohen, J

1989-02-01

Phenylethanolamine-N-methyltransferase (PNMT) activity is located in a subpopulation of amacrine cells in the inner nuclear layer of the rat retina. Kainic, quisqualic, and ibotenic acids, all of which are analogues of glutamic acid, were injected intravitreally to the right and saline to the contralateral left eyes of adult male rats in order to determine the effect of these agents upon retinal PNMT activity. Animals were sacrificed 1 week later for tissue removal. The effect of these agents was measured by radiometric assay for PNMT. The fall in PNMT activity was used to measure the sensitivity of the PNMT-containing cells to these agents. Kainic acid was the most potent, producing the greatest reduction in PNMT activity in the smallest doses. Quisqualic acid was intermediate in potency to that of kainic and ibotenic acids. Ibotenic acid reduced PNMT activity only in extremely high doses. The PNMT-containing cells are sensitive to the toxic actions of kainic and quisqualic acids, but relatively insensitive to the actions of ibotenic acid.

Role of oxidative stress in epileptic seizures

PubMed Central

Shin, Eun-Joo; Jeong, Ji Hoon; Chung, Yoon Hee; Kim, Won-Ki; Ko, Kwang-Ho; Bach, Jae-Hyung; Hong, Jau-Shyong; Yoneda, Yukio; Kim, Hyoung-Chun

2013-01-01

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetically epilepsy-prone rats, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment. PMID:21672578

Effects of oxcarbazepine on monoamines content in hippocampus and head and body shakes and sleep patterns in kainic acid-treated rats.

PubMed

Alfaro-Rodríguez, Alfonso; González-Piña, Rigoberto; Bueno-Nava, Antonio; Arch-Tirado, Emilio; Ávila-Luna, Alberto; Uribe-Escamilla, Rebeca; Vargas-Sánchez, Javier

2011-09-01

The aim of this work was to analyze the effect of oxcarbazepine (OXC) on sleep patterns, "head and body shakes" and monoamine neurotransmitters level in a model of kainic-induced seizures. Adult Wistar rats were administered kainic acid (KA), OXC or OXC + KA. A polysomnographic study showed that KA induced animals to stay awake for the whole initial 10 h. OXC administration 30 min prior to KA diminished the effect of KA on the sleep parameters. As a measure of the effects of the drug treatments on behavior, head and body shakes were visually recorded for 4 h after administration of KA, OXC + KA or saline. The presence of OXC diminished the shakes frequency. 4 h after drug application, the hippocampus was dissected out, and the content of monoamines was analyzed. The presence of OXC still more increased serotonin, 5-hidroxyindole acetic acid, dopamine, and homovanilic acid, induced by KA.

Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

PubMed Central

Mohd Sairazi, Nur Shafika; Sirajudeen, K. N. S.; Asari, Mohd Asnizam; Muzaimi, Mustapha; Mummedy, Swamy; Sulaiman, Siti Amrah

2015-01-01

Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS). In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA). KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration. PMID:26793262

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy.

PubMed

Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen; Michel, Cole R; Gomez, Joe; Vassilopoulos, Athanassios; Reisdorph, Nichole; Fritz, Kristofer S; Patel, Manisha

2018-08-01

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy. Copyright © 2018 Elsevier Inc. All rights reserved.

Activation of AKT/GSK3β pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice.

PubMed

Bhowmik, Malay; Khanam, Razia; Saini, Neeru; Vohora, Divya

2015-01-01

Activation of glycogen synthase kinase3β (GSK3β), an enzyme that regulates a multitude of cellular signaling pathways, is implicated in neurodegenerative processes observed in an array of CNS diseases. We examined the hypothesis that the pathological changes in an acute kainic acid (KA) induced excitotoxicity model, relevant to human temporal lobe epilepsy (TLE), could be sensitive to inhibition of GSK3β by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) treatment in Swiss albino mice. Immediate seizure responses due to KA were recorded. Neurodegenerative and morphogenic changes were examined by western blot analysis and light microscopy, respectively, 48 h after KA administration. Although tonic-clonic seizure episodes evoked by KA were unaffected, TDZD-8 pretreatment decreased KA mediated elevation in caspase-3 cleavage as well as increased Bcl2 and phospho-GSK3β (Ser9; pGSK3β(Ser9)) expression. Likewise, microscopic examination also revealed that pretreatment with TDZD-8 attenuated cell damage elicited by KA in the CA1, CA3 and DG regions. In all the above parameters, the combined effect of a sub-effective dose of sodium valproate (SVP) with TDZD-8 was higher than that of solitary TDZD-8 treatment. The findings suggest that activated GSK3β orchestrated neurodegenerative alterations following KA treatment and its inhibition by TDZD-8 affords a distinct neuroprotective profile by activating Akt/GSK3β pathway which might act upstream of Bax/Bcl2 and caspase-3 pathways. Compounds targeting GSK3β activity might represent a novel therapeutic option for exploration as an adjunct to conventional anti-epileptic drugs in preventing neurodegenerative processes in TLE. Copyright © 2014 Elsevier Inc. All rights reserved.

Epileptogenesis following Kainic Acid-Induced Status Epilepticus in Cyclin D2 Knock-Out Mice with Diminished Adult Neurogenesis

PubMed Central

Kondratiuk, Ilona; Plucinska, Gabriela; Miszczuk, Diana; Wozniak, Grazyna; Szydlowska, Kinga; Kaczmarek, Leszek; Filipkowski, Robert K.; Lukasiuk, Katarzyna

2015-01-01

The goal of this study was to determine whether a substantial decrease in adult neurogenesis influences epileptogenesis evoked by the intra-amygdala injection of kainic acid (KA). Cyclin D2 knockout (cD2 KO) mice, which lack adult neurogenesis almost entirely, were used as a model. First, we examined whether status epilepticus (SE) evoked by an intra-amygdala injection of KA induces cell proliferation in cD2 KO mice. On the day after SE, we injected BrdU into mice for 5 days and evaluated the number of DCX- and DCX/BrdU-immunopositive cells 3 days later. In cD2 KO control animals, only a small number of DCX+ cells was observed. The number of DCX+ and DCX/BrdU+ cells/mm of subgranular layer in cD2 KO mice increased significantly following SE (p<0.05). However, the number of newly born cells was very low and was significantly lower than in KA-treated wild type (wt) mice. To evaluate the impact of diminished neurogenesis on epileptogenesis and early epilepsy, we performed video-EEG monitoring of wt and cD2 KO mice for 16 days following SE. The number of animals with seizures did not differ between wt (11 out of 15) and cD2 KO (9 out of 12) mice. The median latency to the first spontaneous seizure was 4 days (range 2 – 10 days) in wt mice and 8 days (range 2 – 16 days) in cD2 KO mice and did not differ significantly between groups. Similarly, no differences were observed in median seizure frequency (wt: 1.23, range 0.1 – 3.4; cD2 KO: 0.57, range 0.1 – 2.0 seizures/day) or median seizure duration (wt: 51 s, range 23 – 103; cD2 KO: 51 s, range 23 – 103). Our results indicate that SE-induced epileptogenesis is not disrupted in mice with markedly reduced adult neurogenesis. However, we cannot exclude the contribution of reduced neurogenesis to the chronic epileptic state. PMID:26020770

Kainic Acid-Induced Post-Status Epilepticus Models of Temporal Lobe Epilepsy with Diverging Seizure Phenotype and Neuropathology

PubMed Central

Bertoglio, Daniele; Amhaoul, Halima; Van Eetveldt, Annemie; Houbrechts, Ruben; Van De Vijver, Sebastiaan; Ali, Idrish; Dedeurwaerdere, Stefanie

2017-01-01

The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced status epilepticus (KASE) rat model is a widely used, well-validated model for temporal lobe epilepsy (TLE). As we noted significant variability within the model between labs potentially related to the rat strain used, we aimed to describe two variants of this model with diverging seizure phenotype and neuropathology. In addition, we evaluated two different protocols to induce status epilepticus (SE). Wistar Han (Charles River, France) and Sprague-Dawley (Harlan, The Netherlands) rats were subjected to KASE using the Hellier kainic acid (KA) and a modified injection scheme. Duration of SE and latent phase were characterized by video-electroencephalography (vEEG) in a subgroup of animals, while animals were sacrificed 1 week (subacute phase) and 12 weeks (chronic phase) post-SE. In the 12 weeks post-SE groups, seizures were monitored with vEEG. Neuronal loss (neuronal nuclei), microglial activation (OX-42 and translocator protein), and neurodegeneration (Fluorojade C) were assessed. First, the Hellier protocol caused very high mortality in WH/CR rats compared to SD/H animals. The modified protocol resulted in a similar SE severity for WH/CR and SD/H rats, but effectively improved survival rates. The latent phase was significantly shorter (p < 0.0001) in SD/H (median 8.3 days) animals compared to WH/CR (median 15.4 days). During the chronic phase, SD/H rats had more seizures/day compared to WH/CR animals (p < 0.01). However, neuronal degeneration and cell loss were overall more extensive in WH/CR than in SD/H rats; microglia activation was similar between the two strains 1 week post-SE, but higher in WH/CR rats 12 weeks post-SE. These neuropathological differences may be more related to the distinct neurotoxic effects of KA in the two rat strains than being the outcome of seizure burden

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood

PubMed Central

Wong-Goodrich, Sarah J.E.; Tognoni, Christina M.; Mellott, Tiffany J.; Glenn, Melissa J.; Blusztajn, Jan K.; Williams, Christina L.

2011-01-01

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12–17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. PMID:21840511

Association of Omega-3 Fatty Acid and Epileptic Seizure in Epileptic Patients: A Systematic Review.

PubMed

Pourmasoumi, Makan; Vosoughi, Nooshin; Derakhshandeh-Rishehri, Seyedeh-Masoumeh; Assarroudi, Mostafa; Heidari-Beni, Motahar

2018-01-01

The evidence on the association between omega-3 consumption and epileptic seizure is inconsistent. Therefore, we have conducted this systematic review to clarify the possible relationship. Original articles were searched in electronic databases (PubMed, Scopus, Google Scholar, Cochrane, and Ovid) and by reviewing the reference lists of retrieved articles. The main evaluated outcome was the epileptic seizures. We included the English language studies that reported the original data on the effect of omega-3 on epileptic human patients. We included the nine articles with 230 patients in the present systematic review. The mean ± standard deviation age of them was about 31.01 ± 14.99 years. The average of study duration was 22 ± 15.27 weeks. Omega-3 fatty acid supplements were defined as the sum of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (1100 mg/d); as the sum of EPA, DHA, and alpha-linolenic acid (5 g/d); and as the sum of EPA alone (565 mg/d) in different studies. Among the nine studies, four studies reported a significant positive association between omega-3 fatty acids and epileptic seizures. However, power and quality of these studies are low, and we cannot consider the beneficial effect of omega-3 on seizures. In addition, five studies did not reveal any significant effect. Majority of the included studies did not show a significant association between omega-3 and epileptic seizure in epileptic patients, but further studies are necessary. It is controversial whether omega-3 fatty acids can produce positive effects on epileptic patients or not.

An electron spin resonance study for real-time detection of ascorbyl free radicals after addition of dimethyl sulfoxide in murine hippocampus or plasma during kainic acid-induced seizures.

PubMed

Matsumoto, Shigekiyo; Shingu, Chihiro; Koga, Hironori; Hagiwara, Satoshi; Iwasaka, Hideo; Noguchi, Takayuki; Yokoi, Isao

2010-07-01

Electron spin resonance (ESR)-silent ascorbate solutions generate a detectable, likely concentration-dependent signal of ascorbyl free radicals (AFR) immediately upon addition of a molar excess of dimethyl sulfoxide (DMSO). We aimed to perform quantitative ESR analysis of AFR in real time after addition of DMSO (AFR/DMSO) to evaluate ascorbate concentrations in fresh hippocampus or plasma following systemic administration of kainate in mice. Use of a special tissue-type quartz cell allowed immediate detection of AFR/DMSO ESR spectra in fresh tissues from mice. AFR/DMSO content was increased significantly in fresh hippocampus or plasma obtained during kainate-induced seizures of mice, reaching maximum levels at 90 min after intraperitoneal administration of 50 mg/kg kainic acid. This suggests that oxidative injury of the hippocampus resulted from the accumulation of large amounts of ascorbic acid in the brain after kainic acid administration. AFR/DMSO content measured on an ESR spectrometer can be used for real-time evaluation of ascorbate content in fresh tissue. Due to the simplicity, good performance, low cost and real-time monitoring of ascorbate, this method may be applied to clinical research and treatment in the future.

Targeting of microRNA-21-5p protects against seizure damage in a kainic acid-induced status epilepticus model via PTEN-mTOR.

PubMed

Tang, Chongyang; Gu, Yunhe; Wang, Haiyang; Wu, Hongmei; Wang, Yu; Meng, Yao; Han, Zhibin; Gu, Yifei; Ma, Wei; Jiang, Zhenfeng; Song, Yuanyuan; Na, Meng; Lu, Dunyue; Lin, Zhiguo

2018-05-04

Studies have shown that microRNAs play a role in the development of epilepsy by regulating downstream target messenger (m)RNA. The present study aims to determine the changes associated with microRNA-21-5p (miR-21-5p) during epileptogenesis in a kainic acid rat model, and to assess whether the PTEN-mTOR pathway is a target of miR-21-5p. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the quantitative expressions of miR-21-5p and PTEN, and Western blotting was used to test the activity of mTOR in the acute, latent, and chronic stages of epileptogenesis. The antagomir of miR-21-5p was injected into the intracerebroventricular space using a microsyringe. Neuronal death and epilepsy discharge were assessed by Nissl staining and electroencephalography (EEG), respectively. The Morris water maze (MWM) was used to assess the cognitive impairment in rats after status epilepticus (SE). Both miR-21-5p and mTOR were upregulated and PTEN was downregulated in rats during acute, latent, and chronic stages of epileptogenesis when compared with those of the control. After using antagomir miR-21-5p in vivo, miR-21-5p and mTOR decreased and the expression of PTEN increased compared with that in the SE model. The silencing of miR-21-5p diminished the number of abnormal spikes on EEG and decreased the number of neuron deletions on Nissl staining. The cognitive and memory impairment caused by epilepsy could also be improved after miR-21-5p knockdown in vivo. The results of the present study demonstrate that PTEN-mTOR is the target of miR-21-5p in a kainic acid model of epilepsy. The knockout of miR-21-5p decreases the neuronal damage in stages of epileptogenesis. The miR-21-5p/PTEN/mTOR axis may be a potential target for preventing and treating seizures and epileptic damage. Copyright © 2018 Elsevier B.V. All rights reserved.

Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model

PubMed Central

Kim, Chea-Ha

2015-01-01

We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level. PMID:25792867

Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model.

PubMed

Kim, Chea-Ha; Hong, Jae-Seung

2015-03-01

We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level.

Amino terminus of substance P potentiates kainic acid-induced activity in the mouse spinal cord.

PubMed

Larson, A A; Sun, X

1992-12-01

Sensitization to the behavioral effects produced by repeated injections of kainic acid (KA) into the mouse spinal cord area has been previously shown to be abolished by pretreatment with capsaicin, a neurotoxin of substance P (SP)-containing primary afferent C-fibers. While SP has a variety of well characterized biological actions that are mediated by interactions of its COOH terminus with neurokinin receptors, more recently we have characterized an amino-terminally directed SP binding site. The present studies were initiated to determine whether behavioral sensitization to repeated injections of intrathecally administered KA is mediated by the COOH or NH2 terminal of SP. In the present studies, pretreatment with SP(1-7), an NH2-terminal fragment of SP, but not SP(5-11), a COOH-terminal fragment, potentiated KA-induced behavioral activity in mice. Pretreatment with [D-Pro2,D-Phe7]SP(1-7), an inhibitor of SP NH2-terminal binding, blocked the potentiative effect of SP(1-7) as well as the sensitization to repeated injections of KA. In contrast, [D-Pro2,D-Trp7,9]SP, a neurokinin antagonist, had little effect on behavioral sensitization to KA. The present study suggests that SP has an important modulatory role on excitatory amino acid activity in the spinal cord that is mediated by an action of the NH2 terminal of SP at a non-neurokinin receptor.

A tachykinin NK1 receptor antagonist, CP-122,721-1, attenuates kainic acid-induced seizure activity.

PubMed

Zachrisson, O; Lindefors, N; Brené, S

1998-10-01

Substance P (SP) can play an important role in neuronal survival. To analyze the role of SP in excitotoxicity, kainic acid (KA) was administered to rats and in situ hybridization was used to analyze the levels of the SP encoding preprotachykinin-A (PPT-A) mRNA in striatal and hippocampal subregions 1, 4, and 24 h and 7 days after KA. In striatum and piriform cortex, PPT-A mRNA peaked 4 h after KA while in hippocampus, levels peaked after 24 h. KA caused seizures and neuronal toxicity as indicated by a reduction of the number of neurons in the hippocampal CA1 subregion after 7 days. KA was later administered alone or following pretreatment with the tachykinin NK1 receptor antagonist CP-122,721-1 (0.3 mg/kg). The pretreatment decreased seizure activity and a negative correlation was found between seizure activity and survival of CA1 neurons. Conclusively, treatment with CP-122,721-1 has a seizure inhibiting property and may possibly counteract KA-induced nerve cell death in CA1. Copyright 1998 Elsevier Science B.V.

Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures.

PubMed

Yang, Ming-Tao; Lin, Yi-Chin; Ho, Whae-Hong; Liu, Chao-Lin; Lee, Wang-Tso

2017-01-21

Microglia is responsible for neuroinflammation, which may aggravate brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) kinase is related to microglial activation with subsequent neuroinflammation. In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation. In vitro, we treated BV2 cells with KA and LPS. In vivo, KA was used to induce seizures on postnatal day 25 in B6.129P-Cx3cr1 tm1Litt /J mice. Rapamycin and everolimus were evaluated in their modulation of neuroinflammation detected by real-time PCR, Western blotting, and immunostaining. Everolimus was significantly more effective than rapamycin in inhibiting iNOS and mTOR signaling pathways in both models of neuroinflammation (LPS) and seizure (KA). Everolimus significantly attenuated the mRNA expression of iNOS by LPS and nitrite production by KA and LPS than that by rapamycin. Only everolimus attenuated the mRNA expression of mTOR by LPS and KA treatment. In the present study, we also found that the modulation of mTOR under LPS and KA treatment was not mediated by Akt pathway but was primarily mediated by ERK phosphorylation, which was more significantly attenuated by everolimus. This inhibition of ERK phosphorylation and microglial activation in the hippocampus by everolimus was also confirmed in KA-treated mice. Rapamycin and everolimus can block the activation of inflammation-related molecules and attenuated the microglial activation. Everolimus had better efficacy than rapamycin, possibly mediated by the inhibition of ERK phosphorylation. Taken together, mTOR inhibitor can be a potential pharmacological target of anti-inflammation and seizure treatment.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood.

PubMed

Wong-Goodrich, Sarah J E; Tognoni, Christina M; Mellott, Tiffany J; Glenn, Melissa J; Blusztajn, Jan K; Williams, Christina L

2011-09-21

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. Copyright © 2011 Elsevier B.V. All rights reserved.

Neuroprotective and anti-inflammatory effects of lidocaine in kainic acid-injected rats.

PubMed

Chiu, Kuan Ming; Lu, Cheng Wei; Lee, Ming Yi; Wang, Ming Jiuh; Lin, Tzu Yu; Wang, Su Jane

2016-05-04

Lidocaine, the most commonly used local anesthetic, inhibits glutamate release from nerve terminals. Given the involvement of glutamate neurotoxicity in the pathogenesis of various neurological disorders, this study investigated the role of lidocaine in hippocampal neuronal death and inflammatory events induced by an i.p. injection of kainic acid (KA) (15 mg/kg), a glutamate analog. The results showed that KA significantly led to neuronal death in the CA3 pyramidal layers of the hippocampus and this effect was attenuated by the systemic administration of lidocaine (0.8 or 4 mg/kg, i.p.) 30 min before KA injection. Moreover, KA-induced microglia activation and gene expression of proinflammatory cytokines, namely, interleukin-1β, interleukin-6, and tumor necrosis factor-α, in the hippocampus were reduced by the lidocaine pretreatment. Altogether, the results suggest that lidocaine can effectively treat glutamate excitotoxicity-related brain disorders.

Effects of kainic acid on rat body temperature: unmasking by dizocilpine.

PubMed

Ahlenius, S; Oprica, M; Eriksson, C; Winblad, B; Schultzberg, M

2002-07-01

The effects of intraperitoneal (i.p.) administration of kainic acid (KA) and dizocilpine, alone or in combination, on body temperature of freely moving rats were examined. Injection of saline or dizocilpine (3.0 or 5.0 mg/kg) was followed after an hour by injection of saline or KA (10 mg/kg) and the body temperature was measured at different time points during the first 5 h. KA alone produced an initial short-lasting hypothermia followed by a longer-lasting hyperthermic effect. Administration of dizocilpine alone produced an early increase in core temperature. Pretreatment of KA-injected rats with dizocilpine potentiated the KA-induced hypothermic effect at 30 min and dose-dependently reduced the temperature measured at 1 h after KA-injection without influencing the ensuing hyperthermia.These data suggest that the KA-induced changes in body temperature do not necessarily involve the activation of NMDA-receptors as opposed to KA-induced behavioural changes that are blocked by dizocilpine in a dose-dependent manner. It is unlikely, therefore, that the KA-induced hyperthermia is a result of the KA-induced seizure motor activity. Furthermore, our findings indicate that KA-induced changes in core temperature may be used as a criterion of drug-responsiveness when the behavioural changes are blocked, e.g. with dizocilpine.

Kainic acid-induced albumin leak across the blood-brain barrier facilitates epileptiform hyperexcitability in limbic regions.

PubMed

Noé, Francesco M; Bellistri, Elisa; Colciaghi, Francesca; Cipelletti, Barbara; Battaglia, Giorgio; de Curtis, Marco; Librizzi, Laura

2016-06-01

Systemic administration of kainic acid (KA) is a widely used procedure utilized to develop a model of temporal lobe epilepsy (TLE). Despite its ability to induce status epilepticus (SE) in vivo, KA applied to in vitro preparations induces only interictal-like activity and/or isolated ictal discharges. The possibility that extravasation of the serum protein albumin from the vascular compartment enhances KA-induced brain excitability is investigated here. Epileptiform activity was induced by arterial perfusion of 6 μm KA in the in vitro isolated guinea pig brain preparation. Simultaneous field potential recordings were carried out bilaterally from limbic (CA1, dentate gyrus [DG], and entorhinal cortex) and extralimbic regions (piriform cortex and neocortex). Blood-brain barrier (BBB) breakdown associated with KA-induced epileptiform activity was assessed by parenchymal leakage of intravascular fluorescein-isothiocyanate albumin. Seizure-induced brain inflammation was evaluated by western blot analysis of interleukin (IL)-1β expression in brain tissue. KA infusion caused synchronized activity at 15-30 Hz in limbic (but not extralimbic) cortical areas, associated with a brief, single seizure-like event. A second bolus of KA, 60 min after the induction of the first ictal event, did not further enhance excitability. Perfusion of serum albumin between the two administrations of KA enhanced epileptiform discharges and allowed a recurrent ictal event during the second KA infusion. Our data show that arterial KA administration selectively alters the synchronization of limbic networks. However, KA is not sufficient to generate recurrent seizures unless serum albumin is co-perfused during KA administration. These findings suggest a role of serum albumin in facilitating acute seizure generation. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice.

PubMed

Iqbal, Ramsha; Jain, Gaurav K; Siraj, Fouzia; Vohora, Divya

2018-07-01

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABA A receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-β estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17β-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an

Antiepileptic Effect of Uncaria rhynchophylla and Rhynchophylline Involved in the Initiation of c-Jun N-Terminal Kinase Phosphorylation of MAPK Signal Pathways in Acute Seizures of Kainic Acid-Treated Rats

PubMed Central

Hsu, Hsin-Cheng; Tang, Nou-Ying; Liu, Chung-Hsiang

2013-01-01

Seizures cause inflammation of the central nervous system. The extent of the inflammation is related to the severity and recurrence of the seizures. Cell surface receptors are stimulated by stimulators such as kainic acid (KA), which causes intracellular mitogen-activated protein kinase (MAPK) signal pathway transmission to coordinate a response. It is known that Uncaria rhynchophylla (UR) and rhynchophylline (RP) have anticonvulsive effects, although the mechanisms remain unclear. Therefore, the purpose of this study is to develop a novel strategy for treating epilepsy by investigating how UR and RP initiate their anticonvulsive mechanisms. Sprague-Dawley rats were administered KA (12 mg/kg, i.p.) to induce seizure before being sacrificed. The brain was removed 3 h after KA administration. The results indicate that pretreatment with UR (1.0 g/kg), RP (0.25 mg/kg), and valproic acid (VA, 250 mg/kg) for 3 d could reduce epileptic seizures and could also reduce the expression of c-Jun aminoterminal kinase phosphorylation (JNKp) of MAPK signal pathways in the cerebral cortex and hippocampus brain tissues. Proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α remain unchanged, indicating that the anticonvulsive effect of UR and RP is initially involved in the JNKp MAPK signal pathway during the KA-induced acute seizure period. PMID:24381640

Antiepileptic Effect of Uncaria rhynchophylla and Rhynchophylline Involved in the Initiation of c-Jun N-Terminal Kinase Phosphorylation of MAPK Signal Pathways in Acute Seizures of Kainic Acid-Treated Rats.

PubMed

Hsu, Hsin-Cheng; Tang, Nou-Ying; Liu, Chung-Hsiang; Hsieh, Ching-Liang

2013-01-01

Seizures cause inflammation of the central nervous system. The extent of the inflammation is related to the severity and recurrence of the seizures. Cell surface receptors are stimulated by stimulators such as kainic acid (KA), which causes intracellular mitogen-activated protein kinase (MAPK) signal pathway transmission to coordinate a response. It is known that Uncaria rhynchophylla (UR) and rhynchophylline (RP) have anticonvulsive effects, although the mechanisms remain unclear. Therefore, the purpose of this study is to develop a novel strategy for treating epilepsy by investigating how UR and RP initiate their anticonvulsive mechanisms. Sprague-Dawley rats were administered KA (12 mg/kg, i.p.) to induce seizure before being sacrificed. The brain was removed 3 h after KA administration. The results indicate that pretreatment with UR (1.0 g/kg), RP (0.25 mg/kg), and valproic acid (VA, 250 mg/kg) for 3 d could reduce epileptic seizures and could also reduce the expression of c-Jun aminoterminal kinase phosphorylation (JNKp) of MAPK signal pathways in the cerebral cortex and hippocampus brain tissues. Proinflammatory cytokines interleukin (IL)-1 β , IL-6, and tumor necrosis factor- α remain unchanged, indicating that the anticonvulsive effect of UR and RP is initially involved in the JNKp MAPK signal pathway during the KA-induced acute seizure period.

Behavior-associated Neuronal Activation After Kainic Acid-induced Hippocampal Neurotoxicity is Modulated in Time.

PubMed

Aguilar-Arredondo, Andrea; López-Hernández, Fernanda; García-Velázquez, Lizbeth; Arias, Clorinda; Zepeda, Angélica

2017-02-01

Kainic acid-induced (KA) hippocampal damage leads to neuronal death and further synaptic plasticity. Formation of aberrant as well as of functional connections after such procedure has been documented. However, the impact of such structural plasticity on cell activation along time after damage and in face of a behavioral demand has not been explored. We evaluated if the mRNA and protein levels of plasticity-related protein synaptophysin (Syp and SYP, respectively) and activity-regulated cytoskeleton-associated protein mRNA and protein levels (Arc and Arc, respectively) in the dentate gyrus were differentially modulated in time in response to a spatial-exploratory task after KA-induced hippocampal damage. In addition, we analyzed Arc+/NeuN+ immunopositive cells in the different experimental conditions. We infused KA intrahippocampally to young-adult rats and 10 or 30 days post-lesion (dpl) animals performed a hippocampus-activating spatial-exploratory task. Our results show that Syp mRNA levels significantly increase at 10dpl and return to control levels after 30dpl, whereas SYP protein levels are diminished at 10dpl, but significantly increase at 30dpl, as compared to 10dpl. Arc mRNA and protein levels are both increased at 30dpl as compared to sham. Also the number of NeuN+/Arc+ cells significantly increases at 30dpl in the group with a spatial-exploratory demand. These results provide information on the long-term modifications associated to structural plasticity and neuronal activation in the dentate gyrus after excitotoxic damage and in face of a spatial-exploratory behavior. Anat Rec, 300:425-432, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Behavioral Consequences of Kainic Acid Lesions and Fetal Transplants of the Striatum

DTIC Science & Technology

1984-06-12

Selected sections were also stained with cresyl violet in order to facilitate the visualization of neuronal cytology and morphology. All sections...tendency to mutism and depression with frequent suicidal ideation (Bruyn, 1973). The Westphal variant of HD, also called the rigid-hypokinetic...1978). In situ injections of kainic acid: A new method for selectively lesioning neuronal cell bodies while sparing axons of passage. Journal of

SYSTEMIC ADMINISTRATION OF KAINIC ACID INCREASES GABA LEVELS IN PERFUSATE FROM THE HIPPOCAMPUS OF RATS IN VIVO

EPA Science Inventory

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. n order to measure GABA...

PHARMACOLOGIC SUPPRESSION OF OXIDATIVE DAMAGE AND DENDRITIC DEGENERATION FOLLOWING KAINIC ACID-INDUCED EXCITOTOXICITY IN MOUSE CEREBRUM

PubMed Central

Zaja-Milatovic, Snjezana; Gupta, Ramesh C.; Aschner, Michael; Montine, Thomas J.; Milatovic, Dejan

2008-01-01

Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 μl) was injected intracerebroventricularly to C57Bl/6 mice. F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p<0.001) increase in F2-IsoPs, F4-NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p<0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F2-IsoP, F4-NeuroPs and citrulline levels were found in mice pretreated with Vitamin E (α-tocopherol, 100 mg/kg, ip) for 3 days, or with N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, ip) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 μg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F2-IsoPs and F4-NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders. PMID:18556069

Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (MIQ) Jack and Gastrodia elata Bl., in kainic acid-treated rats.

PubMed

Hsieh, C L; Tang, N Y; Chiang, S Y; Hsieh, C T; Lin, J G

1999-01-01

Uncaria rhynchophylla (Miq.) Jack (UR) and Gastrodia elata BI. (GE) are traditional Chinese herbs that are usually used in combination to treat convulsive disorders, such as epilepsy, in China. The aim of this study was to compare the anticonvulsive and free radical scavenging activities of UR alone and UR in combination with GE in rats. For the in vitro studies, brain tissues from 6 male Sprague-Dawley (SD) rats were treated with 120 microg/ml kainic acid (KA), with or without varied concentrations of UR or UR plus GE. For the in vivo studies, male SD rats (6 per group) received intraperitoneal (i.p.) injection of KA 12 mg/kg to induce epileptic seizures and generation of free radicals, with or without oral administration of UR 1 g/kg alone or UR 1 g/kg plus GE 1 g/kg. Epileptic seizures were verified by behavioral observations, and electroencephalography (EEG) and electromyography (EMG) recordings. These results showed that UR alone decreased KA-induced lipid peroxide levels in vitro, whereas UR plus GE did not produce a greater effect than UR alone. UR significantly reduced counts of wet dog shakes (WDS), paw tremor (PT) and facial myoclonia (FM) in KA-treated rats and significantly delayed the onset time of WDS, from 27 min in the control group to 40 min in the UR group. UR plus GE did not inhibit seizures more effectively than UR alone, but did further prolong the onset time of WDS to 63 min (P < 0.05 vs. UR alone). UR alone reduced the levels of free radicals in vivo, as measured by lipid peroxidation in the brain and luminol-chemiluminescence (CL) counts and lucigenin-CL counts in the peripheral whole blood, but the combination of GE and UR did not reduce free radical levels more markedly than UR alone. In conclusion, our results indicate that UR has anticonvulsive and free radical scavenging activities, and UR combined with GE exhibit greater inhibition on the onset time of WDS than UR alone. These findings suggest that the anticonvulsive effects of UR and

Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures

PubMed Central

Drexel, M.; Preidt, A.P.; Kirchmair, E.; Sperk, G.

2011-01-01

The subiculum is the major output area of the hippocampus. It is closely interconnected with the entorhinal cortex and other parahippocampal areas. In animal models of temporal lobe epilepsy (TLE) and in TLE patients it exerts increased network excitability and may crucially contribute to the propagation of limbic seizures. Using immunohistochemistry and in situ-hybridization we now investigated neuropathological changes affecting parvalbumin and calretinin containing neurons in the subiculum and other parahippocampal areas after kainic acid-induced status epilepticus. We observed prominent losses in parvalbumin containing interneurons in the subiculum and entorhinal cortex, and in the principal cell layers of the pre- and parasubiculum. Degeneration of parvalbumin-positive neurons was associated with significant precipitation of parvalbumin-immunoreactive debris 24 h after kainic acid injection. In the subiculum the superficial portion of the pyramidal cell layer was more severely affected than its deep part. In the entorhinal cortex, the deep layers were more severely affected than the superficial ones. The decrease in number of parvalbumin-positive neurons in the subiculum and entorhinal cortex correlated with the number of spontaneous seizures subsequently experienced by the rats. The loss of parvalbumin neurons thus may contribute to the development of spontaneous seizures. On the other hand, surviving parvalbumin neurons revealed markedly increased expression of parvalbumin mRNA notably in the pyramidal cell layer of the subiculum and in all layers of the entorhinal cortex. This indicates increased activity of these neurons aiming to compensate for the partial loss of this functionally important neuron population. Furthermore, calretinin-positive fibers terminating in the molecular layer of the subiculum, in sector CA1 of the hippocampus proper and in the entorhinal cortex degenerated together with their presumed perikarya in the thalamic nucleus reuniens. In

Resistance of neurofilaments to degradation, and lack of neuronal death and mossy fiber sprouting after kainic acid-induced status epilepticus in the developing rat hippocampus.

PubMed

Lopez-Picon, Francisco; Puustinen, Niina; Kukko-Lukjanov, Tiina-Kaisa; Holopainen, Irma E

2004-12-01

Neurofilament (NF) proteins, the major constituent of intermediate filaments in neurons, have an important role in cellular stability and plasticity. We have now studied the short-term (hours) and long-term (up to 1 week) effects of kainic acid (KA)-induced status epilepticus (SE) on the reactivity of NF proteins, and mossy fiber (MF) sprouting and neuronal death up to 4 weeks in 9-day-old rats. In Western blotting, the expression of the phosphorylation-independent epitopes of NF-L, NF-M, and NF-H rapidly but transiently increased after the treatment, whereas the phosphorylated NF-M remained elevated for 7 days. However, the treatment did not change the immunoreactivity of NF proteins, and no neuronal death or mossy fiber sprouting was detected at any time point. Our findings indicate seizure-induced reactivity of NF proteins but their resistance to degradation, which could be of importance in neuronal survival and may also prevent MF sprouting in the developing hippocampus.

Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration.

PubMed

Auladell, Carme; de Lemos, Luisa; Verdaguer, Ester; Ettcheto, Miren; Busquets, Oriol; Lazarowski, Alberto; Beas-Zarate, Carlos; Olloquequi, Jordi; Folch, Jaume; Camins, Antoni

2017-01-01

Chemoconvulsants that induce status epilepticus in rodents have been widely used over the past decades due to their capacity to reproduce with high similarity neuropathological and electroencephalographic features observed in patients with temporal lobe epilepsy (TLE). Kainic acid  is one of the most used chemoconvulsants in experimental models. KA administration mainly induces neuronal loss in the hippocampus. We focused the present review inthe c-Jun N-terminal kinase-signaling pathway (JNK), since it has been shown to play a key role in the process of neuronal death following KA activation. Among the three isoforms of JNK (JNK1, JNK2, JNK3), JNK3 is widely localized in the majority of areas of the hippocampus, whereas JNK1 levels are located exclusively in the CA3 and CA4 areas and in dentate gyrus. Disruption of the gene encoding JNK3 in mice renders neuroprotection to KA, since these animals showed a reduction in seizure activity and a diminution in hippocampal neuronal apoptosis. In light of this, JNK3 could be a promising subcellular target for future therapeutic interventions in epilepsy.

Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment.

PubMed

Macias, Matylda; Blazejczyk, Magdalena; Kazmierska, Paulina; Caban, Bartosz; Skalecka, Agnieszka; Tarkowski, Bartosz; Rodo, Anna; Konopacki, Jan; Jaworski, Jacek

2013-01-01

Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors support, cellular energy level, cellular stress, and neurotransmitters and adjusts cellular metabolism accordingly. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Consequently, changes in mTOR activity are often observed in neuropathology. Recently, several groups reported that seizures increase mammalian target of rapamycin (mTOR) kinase activity, and such increased activity in genetic models can contribute to spontaneous seizures. However, the current knowledge about the spatiotemporal pattern of mTOR activation induced by proconvulsive agents is rather rudimentary. Also consequences of insufficient mTOR activity on a status epilepticus are poorly understood. Here, we systematically investigated these two issues. We showed that mTOR signaling was activated by kainic acid (KA)-induced status epilepticus through several brain areas, including the hippocampus and cortex as well as revealed two waves of mTOR activation: an early wave (2 h) that occurs in neurons and a late wave that predominantly occurs in astrocytes. Unexpectedly, we found that pretreatment with rapamycin, a potent mTOR inhibitor, gradually (i) sensitized animals to KA treatment and (ii) induced gross anatomical changes in the brain.

Spatiotemporal Characterization of mTOR Kinase Activity Following Kainic Acid Induced Status Epilepticus and Analysis of Rat Brain Response to Chronic Rapamycin Treatment

PubMed Central

Macias, Matylda; Blazejczyk, Magdalena; Kazmierska, Paulina; Caban, Bartosz; Skalecka, Agnieszka; Tarkowski, Bartosz; Rodo, Anna; Konopacki, Jan; Jaworski, Jacek

2013-01-01

Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors support, cellular energy level, cellular stress, and neurotransmitters and adjusts cellular metabolism accordingly. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Consequently, changes in mTOR activity are often observed in neuropathology. Recently, several groups reported that seizures increase mammalian target of rapamycin (mTOR) kinase activity, and such increased activity in genetic models can contribute to spontaneous seizures. However, the current knowledge about the spatiotemporal pattern of mTOR activation induced by proconvulsive agents is rather rudimentary. Also consequences of insufficient mTOR activity on a status epilepticus are poorly understood. Here, we systematically investigated these two issues. We showed that mTOR signaling was activated by kainic acid (KA)-induced status epilepticus through several brain areas, including the hippocampus and cortex as well as revealed two waves of mTOR activation: an early wave (2 h) that occurs in neurons and a late wave that predominantly occurs in astrocytes. Unexpectedly, we found that pretreatment with rapamycin, a potent mTOR inhibitor, gradually (i) sensitized animals to KA treatment and (ii) induced gross anatomical changes in the brain. PMID:23724051

Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid.

PubMed

Widenfalk, J; Lundströmer, K; Jubran, M; Brene, S; Olson, L

2001-05-15

Delivery of neurotrophic factors to the injured spinal cord has been shown to stimulate neuronal survival and regeneration. This indicates that a lack of sufficient trophic support is one factor contributing to the absence of spontaneous regeneration in the mammalian spinal cord. Regulation of the expression of neurotrophic factors and receptors after spinal cord injury has not been studied in detail. We investigated levels of mRNA-encoding neurotrophins, glial cell line-derived neurotrophic factor (GDNF) family members and related receptors, ciliary neurotrophic factor (CNTF), and c-fos in normal and injured spinal cord. Injuries in adult rats included weight-drop, transection, and excitotoxic kainic acid delivery; in newborn rats, partial transection was performed. The regulation of expression patterns in the adult spinal cord was compared with that in the PNS and the neonate spinal cord. After mechanical injury of the adult rat spinal cord, upregulations of NGF and GDNF mRNA occurred in meningeal cells adjacent to the lesion. BDNF and p75 mRNA increased in neurons, GDNF mRNA increased in astrocytes close to the lesion, and GFRalpha-1 and truncated TrkB mRNA increased in astrocytes of degenerating white matter. The relatively limited upregulation of neurotrophic factors in the spinal cord contrasted with the response of affected nerve roots, in which marked increases of NGF and GDNF mRNA levels were observed in Schwann cells. The difference between the ability of the PNS and CNS to provide trophic support correlates with their different abilities to regenerate. Kainic acid delivery led to only weak upregulations of BDNF and CNTF mRNA. Compared with several brain regions, the overall response of the spinal cord tissue to kainic acid was weak. The relative sparseness of upregulations of endogenous neurotrophic factors after injury strengthens the hypothesis that lack of regeneration in the spinal cord is attributable at least partly to lack of trophic support.

Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death.

PubMed

Pérez-Juárez, Angélica; Chamorro, Germán; Alva-Sánchez, Claudia; Paniagua-Castro, Norma; Pacheco-Rosado, Jorge

2016-08-01

Context Arthrospira (Spirulina) platensis (SP) is a cyanobacterium which has attracted attention because of its nutritional value and pharmacological properties. It was previously reported that SP reduces oxidative stress in the hippocampus and protects against damaging neurobehavioural effects of systemic kainic acid (KA). It is widely known that the systemic administration of KA induces neuronal damage, specifically in the CA3 hippocampal region. Objective The present study determines if the SP sub-chronic treatment has neuroprotective properties against KA. Materials and methods Male SW mice were treated with SP during 24 d, at doses of 0, 200, and 800 mg/kg, once daily, and with KA (35 mg/kg, ip) as a single dose on day 14. After the treatment, a histological analysis was performed and the number of atrophic neuronal cells in CA3 hippocampal region was quantified. Results Pretreatment with SP does not protect against seizures induced by KA. However, mortality in the SP 200 and the SP 800 groups was of 20%, while for the KA group, it was of 60%. A single KA ip administration produced a considerable neuronal damage, whereas both doses of SP sub-chronic treatment reduced the number of atrophic neurons in CA3 hippocampal region with respect to the KA group. Discussion The SP neurobehaviour improvement after KA systemic administration correlates with the capacity of SP to reduce KA-neuronal death in CA3 hippocampal cells. This neuroprotection may be related to the antioxidant properties of SP. Conclusion SP reduces KA-neuronal death in CA3 hippocampal cells.

Establishment of a rhesus monkey model of chronic temporal lobe epilepsy using repetitive unilateral intra-amygdala kainic acid injections.

PubMed

Chi, Yajie; Wu, Bolin; Guan, Jianwei; Xiao, Kuntai; Lu, Ziming; Li, Xiao; Xu, Yuting; Xue, Shan; Xu, Qiang; Rao, Junhua; Guo, Yanwu

2017-09-01

Temporal lobe epilepsy (TLE) is a common type of acquired epilepsy refractory to medical treatment. As such, establishing animal models of this disease is critical to developing new and effective treatment modalities. Because of their small head size, rodents are not suitable for comprehensive electroencephalography (EEG) evaluation via scalp or subdural electrodes. Therefore, a larger primate model that closely recapitulates signs of TLE is needed; here we describe a rhesus monkey model resembling chronic TLE. Eight monkeys were divided into two groups: kainic acid (KA) group (n=6) and saline control group (n=2). Intra-amygdala KA injections were performed biweekly via an Ommaya device until obvious epileptiform discharges were recorded. Video-EEG recording was conducted intermittently throughout the experiment using both scalp and subdural electrodes. Brains were then analyzed for Nissl and glial fibrillary acid protein (GFAP) immunostaining. After 2-4 injections of KA (approximately 1.2-2.4mg, 0.12-0.24mg/kg), interictal epileptiform discharges (IEDs) were recorded in all KA-treated animals. Spontaneous recurrent seizures (SRSs) accompanied by symptoms mimicking temporal lobe absence (undetectable without EEG recording), but few mild motor signs, were recorded in 66.7% (four of six) KA-treated animals. Both IEDs and seizures indicated a primary epileptic zone in the right temporal region and contralateral discharges were later detected. Segmental pyramidal cell loss and gliosis were detected in the brain of a KA-treated monkey. Through a modified protocol of unilateral repetitive intra-amygdala KA injections, a rhesus monkey model with similar behavioral and brain electrical features as TLE was developed. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of pertussis and cholera toxins administered supraspinally on CA3 hippocampal neuronal cell death and the blood glucose level induced by kainic acid in mice.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Sharma, Naveen; Kim, Sung-Su; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-12-01

The effect of cholera toxin (CTX) or pertussis toxin (PTX) administered supraspinally on hippocampal neuronal cell death in CA3 region induced by kainic acid (KA) was examined in mice. After the pretreatment with either PTX or CTX intracerebroventricularly (i.c.v.), mice were administered i.c.v. with KA. The i.c.v. treatment with KA caused a neuronal cell death in CA3 region and PTX, but not CTX, attenuated the KA-induced neuronal cell death. In addition, i.c.v. treatment with KA caused an elevation of the blood glucose level. The i.c.v. PTX pretreatment alone caused a hypoglycemia and inhibited KA-induced hyperglycemic effect. However, i.c.v. pretreatment with CTX did not affect the basal blood glucose level and KA-induced hyperglycemic effect. Moreover, KA administered i.c.v. caused an elevation of corticosterone level and reduction of the blood insulin level. Whereas, i.c.v. pretreatment with PTX further enhanced KA-induced up-regulation of corticosterone level. Furthermore, i.c.v. administration of PTX alone increased the insulin level and KA-induced hypoinsulinemic effect was reversed. In addition, PTX pretreatment reduces the KA-induced seizure activity. Our results suggest that supraspinally administered PTX, exerts neuroprotective effect against KA-induced neuronal cells death in CA3 region and neuroprotective effect of PTX is mediated by the reduction of KA-induced blood glucose level. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Effects of nateglinide and repaglinide administered intracerebroventricularly on the CA3 hippocampal neuronal cell death and hyperglycemia induced by kainic acid in mice.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-05-01

Meglitinides (nateglinide and repaglinide) are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of meglinitides administered supraspinally on kainic acid (KA)-induced hippocampal neuronal cell death and hyperglycemia were studied in ICR mice. Mice were pretreated intracerebroventricularly (i.c.v.) with 30 μg of nateglinide and repaglinide for 10 min and then, mice were administered i.c.v. with KA (0.1 μg). The neuronal cell death in the CA3 region in the hippocampus was assessed 24h after KA administration and the blood glucose level was measured 30, 60, and 120 min after KA administration. We found that i.c.v. pretreatment with repaglinide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. However, nateglinide pretreated i.c.v. did not affect the KA-induced neuronal cell death and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. Furthermore, i.c.v. pretreatment with repaglinide attenuated KA-induced up-regulation of plasma corticosterone level. Furthermore, i.c.v. administration of repaglinide alone increased plasma insulin level and repaglinide pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered repaglinide, but not nateglinide, exerts a protective effect against the KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of repaglinide appears to be mediated by lowering the blood glucose level induced by KA. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of tolbutamide, glyburide and glipizide administered supraspinally on CA3 hippocampal neuronal cell death and hyperglycemia induced by kainic acid in mice.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-05-20

Sulfonylureas are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of sulfonylureas administered supraspinally on kainic acid (KA)-induced hippocampal neuronal cell death and hyperglycemia were studied in ICR mice. Mice were pretreated intracerebroventricularly (i.c.v.) with 30μg of tolbutamide, glyburide or glipizide for 10min and then, mice were administered i.c.v. with KA (0.1μg). The neuronal cell death in the CA3 region in the hippocampus was assessed 24h after KA administration and the blood glucose level was measured 30, 60, and 120min after KA administration. We found that i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. The i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated KA-induced increase of plasma corticosterone level. Furthermore, i.c.v. pretreatment with tolbutamide, glyburide or glipizide causes an elevation of plasma insulin level. Glipizide, but not tolbutamide or glyburide, pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered tolbutamide, glyburide and glipizide exert a protective effect against KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of tolbutamide, glyburide and glipizide appears to be mediated by lowering the blood glucose level induced by KA. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemokine CCL2–CCR2 Signaling Induces Neuronal Cell Death via STAT3 Activation and IL-1β Production after Status Epilepticus

PubMed Central

Tian, Dai-Shi; Feng, Li-Jie; Liu, Jun-Li

2017-01-01

Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2–CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1GFP/+:CCR2RFP/+ double-transgenic mice, we demonstrated that CCL2–CCR2 signaling has a role in resident microglial activation and blood-derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1β production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066 reduced seizure-induced IL-1β production and subsequent neuronal death. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2–CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1β production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy. SIGNIFICANCE STATEMENT Epilepsy is a global concern and epileptic seizures occur in many neurological conditions. Neuroinflammation associated with microglial activation and monocyte infiltration are characteristic of epileptic brains. However, molecular mechanisms underlying neuroinflammation in neuronal death following epilepsy remain to be elucidated. Here we demonstrate that CCL2–CCR2 signaling is

Extracellular chelation of zinc does not affect hippocampal excitability and seizure-induced cell death in rats

PubMed Central

Lavoie, Nathalie; Peralta, Modesto R; Chiasson, Marilou; Lafortune, Kathleen; Pellegrini, Luca; Seress, László; Tóth, Katalin

2007-01-01

In the nervous system, zinc can influence synaptic responses and at extreme concentrations contributes to epileptic and ischaemic neuronal injury. Zinc can originate from synaptic vesicles, the extracellular space and from intracellular stores. In this study, we aimed to determine which of these zinc pools is responsible for the increased hippocampal excitability observed in zinc-depleted animals or following zinc chelation. Also, we investigated the source of intracellularly accumulating zinc in vulnerable neurons. Our data show that membrane-permeable and membrane-impermeable zinc chelators had little or no effect on seizure activity in the CA3 region. Furthermore, extracellular zinc chelation could not prevent the accumulation of lethal concentrations of zinc in dying neurons following epileptic seizures. At the electron microscopic level, zinc staining significantly increased at the presynaptic membrane of mossy fibre terminals in kainic acid-treated animals. These data indicate that intracellular but not extracellular zinc chelators could influence neuronal excitability and seizure-induced zinc accumulation observed in the cytosol of vulnerable neurons. PMID:17095563

Regulatory impairments following selective kainic acid lesions of the neostriatum.

PubMed

Dunnett, S B; Iversen, S D

1980-12-01

Kainic acid lesions were made to the anteromedial (AMC) or ventrolateral (VLC) caudate nucleus and the projection areas of medial and sulcal prefrontal cortex (PFC), respectively. By the second day following lesion, all control and AMC rats had recovered normal food and water intake. By contrast, VLC lesions resulted in severe aphagia and adipsia lasting 3-15 days, accompanied by a rapid loss in weight. Animals were kept alive by palatable food supplement and force-feeding as required. Once all animals had recovered normal food and water intake (3-5 weeks) drinking to various physiological challenges--5% hypertonic saline s.c., food deprivation, quinine adulteration of water and 40% polyethylene glycol--were found to be normal in both lesion groups. By 3 months after lesion the groups did not differ in weight. Acute aphagia and adipsia had been reported following ablation of the sulcal but not the medial PFC in rats. The present experiment obtains parallel results in the PFC projection areas within the neostriatum.

Expression pattern of NMDA receptors reveals antiepileptic potential of apigenin 8-C-glucoside and chlorogenic acid in pilocarpine induced epileptic mice.

PubMed

Aseervatham, G Smilin Bell; Suryakala, U; Doulethunisha; Sundaram, S; Bose, P Chandra; Sivasudha, T

2016-08-01

The present study was aimed to evaluate the effect of apigenin 8-C-glucoside (Vitexin) and chlorogenic acid on epileptic mice induced by pilocarpine and explored its possible mechanisms. Intraperitonial administration of pilocarpine (85mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p>0.05) reduced by apigenin 8-C-glucoside (AP8CG) (10mg/kg) and chlorogenic acid (CA) (5mg/kg), similar to diazepam. Seizure was accompanied by an imbalance in the levels of Gamma-aminobutyric acid (GABA) and glutamate in the pilocarpine administered group. Moreover, convulsion along with reduced acetylcholinesterase, increased monoamine oxidase and oxidative stress was observed in epileptic mice brain. AP8CG and CA significantly restored back to normal levels even at lower doses. Further, increased lipid peroxidation and nitrite content was also significantly attenuated by AP8CG and CA. However, CA was found to be more effective when compared to AP8CG. In addition, the mRNA expression of N-methyl-d-aspartate receptor (NMDAR), mGluR1 and mGlu5 was significantly (P≤0.05) inhibited by AP8CG and CA in a lower dose. The mRNA expression of GRIK1 did not differ significantly in any of the group and showed a similar pattern of expression. Our result shows that AP8CG and CA selectively inhibit NMDAR, mGluR1 and mGlu5 expression. Modification in the provoked NMDAR calcium response coupled with neuronal death. Hence, these findings underline that the polyphenolics, AP8CG and CA have exerted antiepileptic and neuroprotective activity by suppressing glutamate receptors. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Regulation of blood glucose level by kainic acid in mice: involvement of glucocorticoid system and non-NMDA receptors.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Jung, Jun-Sub; Sharma, Naveen; Suh, Hong-Won

2017-02-28

Kainic acid (KA) is a well-known excitatory neurotoxic substance. In the present study, effects of KA-injected intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level were investigated in ICR mice. We found that KA administered intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) increased the blood glucose and corticosterone levels, suggesting that KA-induced hyperglycemia appeared to be due to increased blood corticosterone level. In support of this finding, adrenalectomy causes a reduction of KA-induced hyperglycemia and neuronal cell death in CA3 regions of the hippocampus. In addition, pretreatment with i.c.v. or i.t. injection of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione; a non-NMDA receptor blocker) attenuated the i.p. and i.c.v. administered KA-induced hyperglycemia. KA administered i.c.v. caused an elevation of the blood corticosterone level whereas the plasma insulin level was reduced. Moreover, i.c.v. pretreatment with CNQX inhibited the decrease of plasma insulin level induced by KA i.c.v. injection, whereas the KA-induced plasma corticosterone level was further enhanced by CNQX pretreatment. Our results suggest that KA administered systemically or centrally produces hyperglycemia. A glucocorticoid system appears to be involved in KA-induced hyperglycemia. Furthermore, central non-N-methyl-D-aspartate receptors may be responsible for KA-induced hyperglycemia.

Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs.

PubMed

Shubina, Liubov; Aliev, Rubin; Kitchigina, Valentina

2017-04-15

Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. The cannabinoid CB1 receptor antagonist AM251 was also tested. Coadministration of AM404 or URB597 with KA reduced acute behavioral seizures, but electrographic seizures were still registered. During the three months following KA injection, various trends in the oscillatory activities were observed, including an increase in activity power at all frequency bands in the hippocampus and a progressive long-term decrease in the medial septum. In the KA- and KA/AM251-treated animals, disturbances of the oscillatory activities were accompanied by cell loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. Injections of AM404 or URB597 softened alterations in electrical activity of the brain and prevented hippocampal neuron loss and synaptic reorganization. Our results demonstrate the protective potential of the eCB system during excitotoxic influences. Copyright © 2017 Elsevier B.V. All rights reserved.

Decrease in level of APG-2, a member of the heat shock protein 110 family, in murine brain following systemic administration of kainic acid.

PubMed

Ogita, K; Takagi, R; Oyama, N; Okuda, H; Ito, F; Okui, M; Shimizu, N; Yoneda, Y

2001-09-01

APG-2 belongs to the heat shock protein 110 family. Although kainic acid (KA)-induced seizures are known to elicit expression of inducible heat shock protein 70 (HSP70) in the brain, no investigation has been carried out on the APG-2 level after excitatory amino acid-induced seizures. By means of an immunoblot assay, we determined the levels of HSP70 and APG-2 in discrete brain structures of mice after a single intraperitoneal injection of KA or N-methyl-D-aspartic acid (NMDA). APG-2 level was significantly decreased in frontal cortex, hippocampus, and striatum three days after the administration of KA, while HSP70 level was increased in these regions following the administration. In any of these regions, APG-2 levels were returned to the control levels 10 days after the administration. However, no significant changes were observed in levels of both HSP70 and APG-2 in hypothalamus, midbrain, medulla-pons, and cerebellum of the mice. By contrast, NMDA administration did not significantly affect both levels in any of the regions examined. These findings indicate that the transient decrease in APG-2 expression is one of the intracellular events elicited by signals peculiar to KA, but not by those peculiar to NMDA, in telencephalon of murine brain.

Prenatal ethanol exposure decreases hippocampal /sup 3/H-vinylidene kainic acid binding in 45-day-old rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farr, K.L.; Montano, C.Y.; Paxton, L.L.

1988-11-01

The effect of prenatal ethanol exposure on the kainate-sensitive subtype of glutamate receptor binding sites was studied using in vitro /sup 3/H-vinylidene kainic acid (VKA) autoradiography. Pregnant Sprague-Dawley rats were fed a liquid diet containing either 3.35% or 6.7% ethanol throughout gestation. Pair-fed dams received isocalorically matched liquid diets and a lab chow ad lib group served as control for paired feeding. At 45 days of age, the offspring were sacrificed and their brains analyzed for specific /sup 3/H-VKA binding. Compared to pair-fed controls, specific /sup 3/H-VKA binding was reduced by 13% to 32% in dorsal and ventral hippocampal CA3more » stratum lucidum, entorhinal cortex and cerebellum of 45-day-old rats whose mothers consumed either 3.35% or 6.7% ethanol diets. The binding site reductions were statistically significant only in the ventral hippocampal formation and entorhinal cortex of the 3.35% ethanol diet group rats. Saturation of binding studies in the ventral hippocampal formation of 3.35% ethanol rats indicated that the decrease in specific /sup 3/H-VKA binding was due to a decrease in the total number of binding sites. Given the excitatory effect of kainic acid on the spontaneous firing rate of hippocampal CA3 pyramidal neurons, the reduction of kainate-sensitive glutamate binding in this region is consistent with the electrophysiological observation of decreased spontaneous activity of CA3 pyramidal neurons in fetal alcohol rats.« less

Uric acid is released in the brain during seizure activity and increases severity of seizures in a mouse model for acute limbic seizures.

PubMed

Thyrion, Lisa; Raedt, Robrecht; Portelli, Jeanelle; Van Loo, Pieter; Wadman, Wytse J; Glorieux, Griet; Lambrecht, Bart N; Janssens, Sophie; Vonck, Kristl; Boon, Paul

2016-03-01

Recent evidence points at an important role of endogenous cell-damage induced pro-inflammatory molecules in the generation of epileptic seizures. Uric acid, under the form of monosodium urate crystals, has shown to have pro-inflammatory properties in the body, but less is known about its role in seizure generation. This study aimed to unravel the contribution of uric acid to seizure generation in a mouse model for acute limbic seizures. We measured extracellular levels of uric acid in the brain and modulated them using complementary pharmacological and genetic tools. Local extracellular uric acid levels increased three to four times during acute limbic seizures and peaked between 50 and 100 min after kainic acid infusion. Manipulating uric acid levels through administration of allopurinol or knock-out of urate oxidase significantly altered the number of generalized seizures, decreasing and increasing them by a twofold respectively. Taken together, our results consistently show that uric acid is released during limbic seizures and suggest that uric acid facilitates seizure generalization. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

PubMed Central

Krajewska, Maryla; You, Zerong; Rong, Juan; Kress, Christina; Huang, Xianshu; Yang, Jinsheng; Kyoda, Tiffany; Leyva, Ricardo; Banares, Steven; Hu, Yue; Sze, Chia-Hung; Whalen, Michael J.; Salmena, Leonardo; Hakem, Razqallah; Head, Brian P.; Reed, John C.; Krajewski, Stan

2011-01-01

Background Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8 −/−), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system. Methodology/Principal Findings Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8 −/− mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging. Conclusions Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional

The Inhibitory Effects of Npas4 on Seizures in Pilocarpine-Induced Epileptic Rats

PubMed Central

Guo, Jiamei; Yang, Guang; Long, Xianghua; Hu, Rong; Shen, Wenjing; Wang, Xuefeng; Zeng, Kebin

2014-01-01

To explore the effects of neuronal Per-Arnt-Sim domain protein 4 (Npas4) on seizures in pilocarpine-induced epileptic rats, Npas4 expression was detected by double-label immunofluorescence, immunohistochemistry, and Western blotting in the brains of pilocarpine-induced epileptic model rats at 6 h, 24 h, 72 h, 7 d, 14 d, 30 d, and 60 d after status epilepticus. Npas4 was localized primarily in the nucleus and in the cytoplasm of neurons. The Npas4 protein levels increased in the acute phase of seizures (between 6 h and 72 h) and decreased in the chronic phases (between 7 d and 60 d) in the rat model. Npas4 expression was knocked down by specific siRNA interference. Then, the animals were treated with pilocarpine, and the effects on seizures were evaluated on the 7th day. The onset latencies of pilocarpine-induced seizures were decreased, while the seizure frequency, duration and attack rate increased in these rats. Our study indicates that Npas4 inhibits seizure attacks in pilocarpine-induced epileptic rats. PMID:25536221

The inhibitory effects of Npas4 on seizures in pilocarpine-induced epileptic rats.

PubMed

Wang, Dan; Ren, Min; Guo, Jiamei; Yang, Guang; Long, Xianghua; Hu, Rong; Shen, Wenjing; Wang, Xuefeng; Zeng, Kebin

2014-01-01

To explore the effects of neuronal Per-Arnt-Sim domain protein 4 (Npas4) on seizures in pilocarpine-induced epileptic rats, Npas4 expression was detected by double-label immunofluorescence, immunohistochemistry, and Western blotting in the brains of pilocarpine-induced epileptic model rats at 6 h, 24 h, 72 h, 7 d, 14 d, 30 d, and 60 d after status epilepticus. Npas4 was localized primarily in the nucleus and in the cytoplasm of neurons. The Npas4 protein levels increased in the acute phase of seizures (between 6 h and 72 h) and decreased in the chronic phases (between 7 d and 60 d) in the rat model. Npas4 expression was knocked down by specific siRNA interference. Then, the animals were treated with pilocarpine, and the effects on seizures were evaluated on the 7th day. The onset latencies of pilocarpine-induced seizures were decreased, while the seizure frequency, duration and attack rate increased in these rats. Our study indicates that Npas4 inhibits seizure attacks in pilocarpine-induced epileptic rats.

Uric acid and allopurinol aggravate absence epileptic activity in Wistar Albino Glaxo Rijswijk rats.

PubMed

Lakatos, Renáta Krisztina; Dobolyi, Árpád; Kovács, Zsolt

2018-05-01

Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete. Thus, the main aim of this study was the investigation of the effect of uric acid on absence epileptic seizures (spike-wave discharges: SWDs) in a model of human absence epilepsy, the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. We investigated the influence of intraperitoneally (i.p.) injected uric acid (100 mg/kg and 200 mg/kg), allopurinol (50 mg/kg and 100 mg/kg), a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) and inosine (500 mg/kg) alone and the combined application of allopurinol (50 mg/kg) with uric acid (100 mg/kg) or inosine (500 mg/kg) as well as indomethacin (10 mg/kg) with uric acid (100 mg/kg) and inosine (500 mg/kg) with uric acid (100 mg/kg) on absence epileptic activity. We demonstrated that both uric acid and allopurinol alone significantly increased the number of SWDs whereas indomethacin abolished the uric acid-evoked increase in SWD number. Our results suggest that uric acid and allopurinol have proepileptic effects in WAG/Rij rats. Copyright © 2018 Elsevier B.V. All rights reserved.

Substance P in the dorsal vagal complex inhibits medullary TRH-induced gastric acid secretion in rats.

PubMed

Yang, H; Taché, Y

1997-05-01

Neurons that contain substance P (SP) and thyrotropin-releasing hormone (TRH) in medullary midline raphe nuclei project to the dorsal vagal complex (DVC). The modulatory role of SP on basal gastric acid secretion (GAS) and TRH on DVC-induced stimulation of GAS was studied in urethan-anesthetized rats. The stable SP agonist, DiMe-C7 ([pGlu5, MePhe8, MeGly9]SP5-11, 50 and 100 pmol), injected unilaterally into the DVC reduced the GAS response (47 +/- 12 mumol/60 min) to coinjected TRH analog, RX 77368 (25 pmol), by 53% and 85%, respectively, whereas DiMe-C7 (100 pmol) alone had no effect on basal and pentagastrin-stimulated GAS. DiMe-C7 (100 pmol/site) inhibited the GAS response to kainic acid injected into the raphe pallidus (Rpa) when it was injected bilaterally into the DVC but not the hypoglossal nuclei. The SP nourokinin-1-receptor antagonist, CP-96,345, injected bilaterally into the DVC (1 nmol/ site) increased basal GAS (33 +/- 8 mumol/90 min) and potentiated the GAS response to kainic acid injected into the Rpa by 40%. These results suggest that SP acts on neurokinin-1 receptors in the DVC to reduce medullary TRH-induced stimulation of GAS in rats.

Strain-dependent effects of long-term treatment with melatonin on kainic acid-induced status epilepticus, oxidative stress and the expression of heat shock proteins.

PubMed

Atanasova, Milena; Petkova, Zlatina; Pechlivanova, Daniela; Dragomirova, Petya; Blazhev, Alexander; Tchekalarova, Jana

2013-10-01

Oxidative stress is implicated in the pathogenesis of both hypertension and epileptogenesis, therefore it could be used as a tool for studying co-morbidity of hypertension and epilepsy. Clinical data suggest that melatonin is a potent antioxidant that is effective in the adjunctive therapy of hypertension and neurodegenerative diseases. The present study aimed to explore and compare the efficacy of chronic pretreatment with melatonin infused via subcutaneous osmotic mini-pumps for 14 days (10 mg/kg per day) on kainic acid (KA)-induced status epilepticus, oxidative stress and expression of heat shock protein (HSP) 72 in spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. SHRs showed higher lipid peroxidation (LP) in the frontal cortex and hippocampus and decreased cytosolic superoxide dismutase (SOD/CuZn) production in the frontal cortex compared to Wistar rats. Status epilepticus (SE) induced by KA (12 mg/kg, i.p.) was accompanied by increased LP and expression of HSP 72 in the hippocampus of the two strains and increased SOD/CuZn production in the frontal cortex of SHRs. Melatonin failed to suppress seizure incidence and intensity though the latency for seizure onset was significantly increased in SHRs. Melatonin attenuated the KA-induced increase in the level of LP in the hippocampus both in SHRs and Wistar rats. However, an increased activity in SOD/CuZn and mitochondrial SOD Mn as well as reduced expression of HSP 72 in the hippocampus was observed only in Wistar rats pretreated with melatonin. Taken together, the observed strain differences in the efficacy of chronic melatonin exposure before SE suggest a lack of a direct link between the seizure activity and the markers of oxidative stress and neurotoxicity. © 2013.

Stimulus-induced Epileptic Spike-Wave Discharges in Thalamocortical Model with Disinhibition

NASA Astrophysics Data System (ADS)

Fan, Denggui; Liu, Suyu; Wang, Qingyun

2016-11-01

Epileptic absence seizure characterized by the typical 2-4 Hz spike-wave discharges (SWD) are known to arise due to the physiologically abnormal interactions within the thalamocortical network. By introducing a second inhibitory neuronal population in the cortical system, here we propose a modified thalamocortical field model to mathematically describe the occurrences and transitions of SWD under the mutual functions between cortex and thalamus, as well as the disinhibitory modulations of SWD mediated by the two different inhibitory interneuronal populations. We first show that stimulation can induce the recurrent seizures of SWD in the modified model. Also, we demonstrate the existence of various types of firing states including the SWD. Moreover, we can identify the bistable parametric regions where the SWD can be both induced and terminated by stimulation perturbations applied in the background resting state. Interestingly, in the absence of stimulation disinhibitory functions between the two different interneuronal populations can also both initiate and abate the SWD, which suggests that the mechanism of disinhibition is comparable to the effect of stimulation in initiating and terminating the epileptic SWD. Hopefully, the obtained results can provide theoretical evidences in exploring dynamical mechanism of epileptic seizures.

Uncaria rhynchophylla (miq) Jack plays a role in neuronal protection in kainic acid-treated rats.

PubMed

Tang, Nou-Ying; Liu, Chung-Hsiang; Su, Shan-Yu; Jan, Ya-Min; Hsieh, Ching-Tou; Cheng, Chin-Yi; Shyu, Woei-Cherng; Hsieh, Ching-Liang

2010-01-01

Uncaria rhynchophylla (Miq) Jack (UR) is one of many Chinese herbs. Our previous studies have shown that UR has both anticonvulsive and free radical-scavenging activities in kainic acid (KA)-treated rats. The aim of the present study was to use the effect of UR on activated microglia, nitric oxide synthase, and apoptotic cells to investigate its function in neuroproction in KA-treated rats. UR of 1.0 or 0.5 g/kg was orally administered for 3 days (first day, second day, and 30 min prior to KA administration on the third day), or 10 mg/kg (intraperitoneal injection, i.p.) N-nitro-L-arginine methyl ester (L-NAME) 30 min prior to KA (2 microg/2 microl) was injected into the right hippocampus region of Sprague-Dawly rats. ED1 (mouse anti rat CD68), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) immunoreactive cells and apoptotic cells were observed in the hippocampus region. The results indicated that 1.0 g/kg, 0.5 g/kg of UR and 10 mg/kg of L-NAME reduced the counts of ED1, nNOS, iNOS immunoreactive cells and apoptotic cells in KA-treated rats. This study demonstrates that UR can reduce microglia activation, nNOS, iNOS and apoptosis, suggesting that UR plays a neuro-protective role against neuronal damage in KA-treated rats.

Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients

PubMed Central

Tartara, A.; Galimberti, C.A.; Manni, R.; Parietti, L.; Zucca, C.; Baasch, H.; Caresia, L.; Mück, W.; Barzaghi, N.; Gatti, G.; Perucca, E.

1991-01-01

1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P < 0.01) in patients taking enzyme-inducing anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate. 3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls. PMID:1777370

Topiramate-induced paresthesia is more frequently reported by migraine than epileptic patients.

PubMed

Sedighi, Behnaz; Shafiei, Kaveh; Azizpour, Iman

2016-04-01

Topiramate is an approved and effective drug in migraine prophylaxis. Paresthesia is the most commonly reported side effect. The primary objective of this study was to compare the frequency of topiramate-induced paresthesia in migraine headache to epileptic patients. Patients with migraine without aura and epilepsy were enrolled in this observational study. All cases were interviewed by telephone about their history of paresthesia. Confounding factors were controlled through logistic regression. The odds ratio of developing topiramate-induced paresthesia in migraine compared to epilepsy patients was 3.4. Three factors were independent contributors to developing topiramate-induced paresthesia: female sex (odds ratio 2.1), topiramate dosage (odds ratio 0.3) and duration of therapy. Our findings indicate an independent association between migraine and development of paresthesia. Migraineurs were more likely than epileptic patients to report paresthesia as topiramate adverse effects. Female sex, treatment duration and topiramate dosage contribute significantly to subsequent development of paresthesia.

Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma

PubMed Central

Engel, Tobias; Murphy, Brona M.; Hatazaki, Seiji; Jimenez-Mateos, Eva M.; Concannon, Caoimhin G.; Woods, Ina; Prehn, Jochen H. M.; Henshall, David C.

2010-01-01

The functional significance of neuronal death for pathogenesis of epilepsy and the underlying molecular mechanisms thereof remain incompletely understood. The p53 transcription factor has been implicated in seizure damage, but its target genes and the influence of cell death under its control on epilepsy development are unknown. In the present study, we report that status epilepticus (SE) triggered by intra-amygdala kainic acid in mice causes rapid p53 accumulation and subsequent hippocampal damage. Expression of p53-up-regulated mediator of apoptosis (Puma), a proapoptotic Bcl-2 homology domain 3-only protein under p53 control, was increased within a few hours of SE. Induction of Puma was blocked by pharmacologic inhibition of p53, and hippocampal damage was also reduced. Puma induction was also blocked in p53-deficient mice subject to SE. Compared to Puma-expressing mice, Puma-deficient mice had significantly smaller hippocampal lesions after SE. Long-term, continuous telemetric EEG monitoring revealed a ∼60% reduction in the frequency of epileptic seizures in the Puma-deficient mice compared to Puma-expressing mice. These are the first data showing genetic deletion of a proapoptotic protein acting acutely to influence neuronal death subsequently alters the phenotype of epilepsy in the long-term, supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis.—Engel, T., Murphy, B. M., Hatazaki, S., Jimenez-Mateos, E. M., Concannon, C. G., Woods, I., Prehn, J. H. M., Henshall, D. C. Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma. PMID:19890018

Elevated VGKC-Complex Antibodies in a Boy with Fever-Induced Refractory Epileptic Encephalopathy in School-Age Children (FIRES)

ERIC Educational Resources Information Center

Illingworth, Marjorie A.; Hanrahan, Donncha; Anderson, Claire E.; O'Kane, Kathryn; Anderson, Jennifer; Casey, Maureen; de Sousa, Carlos; Cross, J. Helen; Wright, Sukvhir; Dale, Russell C.; Vincent, Angela; Kurian, Manju A.

2011-01-01

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and…

Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

PubMed

Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

2003-10-10

The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures.

PubMed

Meloni, Bruno P; Craig, Amanda J; Milech, Nadia; Hopkins, Richard M; Watt, Paul M; Knuckey, Neville W

2014-03-01

Cell-penetrating peptides (CPPs) are small peptides (typically 5-25 amino acids), which are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids, or drugs into cells. However, several recent studies have demonstrated that the TAT CPP has neuroprotective properties. Therefore, in this study, we assessed the TAT and three other CPPs (penetratin, Arg-9, Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose deprivation). Arg-9, penetratin, and TAT-D displayed consistent and high level neuroprotective activity in both the glutamic acid (IC50: 0.78, 3.4, 13.9 μM) and kainic acid (IC50: 0.81, 2.0, 6.2 μM) injury models, while Pep-1 was ineffective. The TAT-D isoform displayed similar efficacy to the TAT-L isoform in the glutamic acid model. Interestingly, Arg-9 was the only CPP that displayed efficacy when washed-out prior to glutamic acid exposure. Neuroprotection following in vitro ischemia was more variable with all peptides providing some level of neuroprotection (IC50; Arg-9: 6.0 μM, TAT-D: 7.1 μM, penetratin/Pep-1: >10 μM). The positive control peptides JNKI-1D-TAT (JNK inhibitory peptide) and/or PYC36L-TAT (AP-1 inhibitory peptide) were neuroprotective in all models. Finally, in a post-glutamic acid treatment experiment, Arg-9 was highly effective when added immediately after, and mildly effective when added 15 min post-insult, while the JNKI-1D-TAT control peptide was ineffective when added post-insult. These findings demonstrate that different CPPs have the ability to inhibit neurodamaging events/pathways associated with excitotoxic and ischemic injuries. More importantly, they highlight the need to interpret neuroprotection studies when using CPPs as delivery agents with caution. On a positive note, the cytoprotective properties of CPPs suggests they are ideal carrier molecules to

Contribution of early Alzheimer's Disease-related Pathophysiology to the Development of Acquired epilepsy.

PubMed

Gschwind, Tilo; Lafourcade, Carlos; Gfeller, Tim; Zaichuk, Mariana; Rambousek, Lukas; Knuesel, Irene; Fritschy, Jean-Marc

2018-06-04

Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAβ mice whether AD-like pathology renders neuronal networks more susceptible to development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAβ mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP, and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAβ mice compared to wildtype littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibers and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aβ species by intracerebroventricular Aβ-specific antibody application mitigated the hyperexcitable phenotype of ArcticAβ mice and prevented early SRS onset. Therefore, development of seizures at early stages of AD is mediated primarily by Aβ species causing widespread changes in synaptic function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

PubMed Central

GIACCONE, M.; BARTOLI, A.; GATTI, G.; MARCHISELLI, R.; PISANI, F.; LATELLA, M.A.; PERUCCA, E.

1996-01-01

1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., P<0.001) and higher apparent oral clearance (CL/ F) values (15.3±3.8 vs 9.2±1.9 ml kg−1 h−1, P<0.001). The apparent volume of distribution ( V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1 l kg−1, P<0.05). 3These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients. PMID:8799524

JNK1 inhibition by Licochalcone A leads to neuronal protection against excitotoxic insults derived of kainic acid.

PubMed

Busquets, Oriol; Ettcheto, Miren; Verdaguer, Ester; Castro-Torres, Ruben D; Auladell, Carme; Beas-Zarate, Carlos; Folch, Jaume; Camins, Antoni

2018-03-15

The mitogen-activated protein kinase family (MAPK) is an important group of enzymes involved in cellular responses to diverse external stimuli. One of the members of this family is the c-Jun-N-terminal kinase (JNK). The activation of the JNK pathway has been largely associated with the pathogenesis that occurs in epilepsy and neurodegeneration. Kainic acid (KA) administration in rodents is an experimental approach that induces status epilepticus (SE) and replicates many of the phenomenological features of human temporal lobe epilepsy (TLE). Recent studies in our group have evidenced that the absence of the JNK1 gene has neuroprotective effects against the damage induced by KA, as it occurs with the absence of JNK3. The aim of the present study was to analyse whether the pharmacological inhibition of JNK1 by Licochalcone A (Lic-A) had similar effects and if it may be considered as a new molecule for the treatment of SE. In order to achieve this objective, animals were pre-treated with Lic-A and posteriorly administered with KA as a model for TLE. In addition, a comparative study with KA was performed between wild type pre-treated with Lic-A and single knock-out transgenic mice for the Jnk1 -/- gene. Our results showed that JNK1 inhibition by Lic-A, previous to KA administration, caused a reduction in the convulsive pattern. Furthermore, it reduced phosphorylation levels of the JNK, as well as its activity. In addition, Lic-A prevented hippocampal neuronal degeneration, increased pro-survival anti-apoptotic mechanisms, reduced pro-apoptotic biomarkers, decreased cellular stress and neuroinflammatory processes. Thus, our results suggest that inhibition of the JNK1 by Lic-A has neuroprotective effects and that; it could be a new potential approach for the treatment of SE and neurodegeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Subventricular Zone-Derived Neural Stem Cell Grafts Protect Against Hippocampal Degeneration and Restore Cognitive Function in the Mouse Following Intrahippocampal Kainic Acid Administration

PubMed Central

Miltiadous, Panagiota; Kouroupi, Georgia; Stamatakis, Antonios; Koutsoudaki, Paraskevi N.

2013-01-01

Temporal lobe epilepsy (TLE) is a major neurological disease, often associated with cognitive decline. Since approximately 30% of patients are resistant to antiepileptic drugs, TLE is being considered as a possible clinical target for alternative stem cell-based therapies. Given that insulin-like growth factor I (IGF-I) is neuroprotective following a number of experimental insults to the nervous system, we investigated the therapeutic potential of neural stem/precursor cells (NSCs) transduced, or not, with a lentiviral vector for overexpression of IGF-I after transplantation in a mouse model of kainic acid (KA)-induced hippocampal degeneration, which represents an animal model of TLE. Exposure of mice to the Morris water maze task revealed that unilateral intrahippocampal NSC transplantation significantly prevented the KA-induced cognitive decline. Moreover, NSC grafting protected against neurodegeneration at the cellular level, reduced astrogliosis, and maintained endogenous granule cell proliferation at normal levels. In some cases, as in the reduction of hippocampal cell loss and the reversal of the characteristic KA-induced granule cell dispersal, the beneficial effects of transplanted NSCs were manifested earlier and were more pronounced when these were transduced to express IGF-I. However, differences became less pronounced by 2 months postgrafting, since similar amounts of IGF-I were detected in the hippocampi of both groups of mice that received cell transplants. Grafted NSCs survived, migrated, and differentiated into neurons—including glutamatergic cells—and not glia, in the host hippocampus. Our results demonstrate that transplantation of IGF-I producing NSCs is neuroprotective and restores cognitive function following KA-induced hippocampal degeneration. PMID:23417642

[A case of non-photosensitive, self-induced epileptic seizures with pacygyria].

PubMed

Nagai, H; Shikata, A; Sato, N; Takeuchi, Y; Sawada, T

1998-09-01

We report an 11-year-old boy with a non-photosensitive epileptic self-induced seizures, pacygyria and familial ataxia. His grandmother and aunts had dysarthria, and his mother had developed progressive ataxia and myoclonus since 40 years old. His older sister had ataxia, mental retardation and epilepsy. As for the boy, motor developmental delay with muscle hypertonicity of left extremities was recognized at the age of 5 months. Mental retardation and ataxia was recognized at the age of 3 years and slight mental regression is recognized at the age of 11 years. No special findings were detected in an examination of his blood and cerebrospinal fluid, including amino acids, lysosomal enzymes activity and genetic analysis for dentatorubralpallidoluysian atrophy. Brain magnetic resonance imaging revealed pachygyria of the right cerebral cortecies. At the age of two, he began to induce seizures with impairment of consciousness in himself by waving his right hand over his face which was directed toward a source of bright light. At the age of seven, he developed spontaneous seizures with impairment of consciousness. An EEG showed frequent spikes in the occipital areas, on the right and left sides occurring either independently or synchronously. Intermittent photic stimulation and pattern stimulation did not induce a paroxysmal discharge in EEG. Ictal EEG suggested that the origin of the seizures was the occipital lobe. Treatment with valporate and zonisamide was effective in reducing the seizures. The findings of our case imply the pathogenesis of self-induced seizures and the relationship between PME and neuronal migration disorders.

Role of the NH2-terminus of substance P in the inhibition by capsaicin of behavioral sensitization to kainic acid-induced activity in the adult mouse.

PubMed

Larson, A A; Sun, X

1994-01-01

Activation of primary afferent C-fibers by repeated intrathecal injection of kainic acid (KA) in mice is inhibited after pretreatment with capsaicin. The increased behavioral response to multiple injections of KA is thought to be brought about by an action of the NH2-terminus of substance P (SP). In light of our recent observation that the antinociceptive effect of capsaicin may also involve an action of the NH2-terminus of SP, we tested the hypothesis that capsaicin inhibits behavioral sensitization to KA by a desensitization to the action of the NH2-terminus of SP. Using adult mice, pretreatment (24 hr) with either capsaicin (0.8 micrograms) or SP(1-7) (1 and 10 nmol) attenuated sensitization of the behavioral response to four injections of 25 pmol of KA at 2-min intervals. Pretreatment with 10 nmol of the COOH-terminal SP fragment, SP(5-11), had no effect. [D-Pro2,D-Phe7]-SP(1-7), a SP NH2-terminal antagonist, injected 5 min before capsaicin or SP(1-7), inhibited the effects of both capsaicin and SP(1-7) on KA sensitization whereas the COOH-terminal neurokinin antagonist, [D-Pro2,D-Trp7,9]-SP, did not. The similarities in behavioral responses after treatment with SP(1-7) or capsaicin, together with the sensitivity of these effects to D-SP(1-7), suggest that SP released in response to capsaicin may inhibit subsequent KA-induced activity 24 hr later. This action of SP appears to be brought about by its NH2-terminus and/or an accumulation of its NH2-terminal metabolites after capsaicin treatment.

Prenatal corticosteroid exposure alters early developmental seizures and behavior

PubMed Central

Velíšek, Libor

2011-01-01

In humans, corticosteroids are often administered prenatally to improve lung development in preterm neonates. Studies in exposed children as well as in children, whose mothers experienced significant stress during pregnancy indicate behavioral problems and possible increased occurrence of epileptic spasms. This study investigated whether prenatal corticosteroid exposure alters early postnatal seizure susceptibility and behaviors. On gestational day 15, pregnant rats were injected i.p. with hydrocortisone (2× 10 mg/kg), betamethasone (2× 0.4 mg/kg) or vehicle. On postnatal day (P)15, seizures were induced by flurothyl or kainic acid (3.5 or 5.0 mg/kg). Horizontal bar holding was determined prior to seizures and again on P17. Performance in the elevated plus maze was assessed on P20-22. Prenatal exposure to betamethasone decreased postnatal susceptibility to flurothyl-induced clonic seizures but not to kainic acid-induced seizures. Prenatal hydrocortisone decreased postnatal weight but did not affect seizure susceptibility. Hydrocortisone alone did not affect performance in behavioral tests except for improving horizontal bar holding on P17. A combination of prenatal hydrocortisone and postnatal seizures resulted in increased anxiety. Prenatal exposure to mineralocorticoid receptor blocker canrenoic acid did not attenuate, but surprisingly amplified the effects of hydrocortisone on body weight and significantly worsened horizontal bar performance. Thus, prenatal exposure to excess corticosteroids alters postnatal seizure susceptibility and behaviors. Specific effects may depend on corticosteroid species. PMID:21429712

[Convulsions due to an interaction between anti-epileptic drugs and rifampicin].

PubMed

Hanrath, Maarten A; Swart, Eleonora L

2014-01-01

Anti-epileptic drugs (AEDs) have a small therapeutic window, so it is important to monitor plasma levels. Inadequate plasma levels may lead to convulsions. Many AEDs are cleared hepatically, and there are many drug interactions that are known to lead to changes in plasma levels. A 54-year-old woman with known epilepsy developed convulsions after using rifampicin and flucloxacillin, despite the use of maintenance treatment in the form of carbamazepine, valproic acid and clonazepam. Since rifampicin is known to induce several cytochrome P450 enzymes and clearance of the anti-epileptic drug used may be affected by this, it can be assumed that the convulsions were caused by rifampicin. This interaction is however not mentioned in the Dutch 'G-standard' database. Rifampicin is known to be a strong inducer of various cytochrome P450 enzymes. This case description shows that the use of rifampicin may lead to convulsions. For this reason, these interactions should be included in the Dutch G-standard database.

Effects of glutamic acid analogues on identifiable giant neurones, sensitive to beta-hydroxy-L-glutamic acid, of an African giant snail (Achatina fulica Férussac).

PubMed Central

Nakajima, T.; Nomoto, K.; Ohfune, Y.; Shiratori, Y.; Takemoto, T.; Takeuchi, H.; Watanabe, K.

1985-01-01

The effects of the seven glutamic acid analogues, alpha-kainic acid, alpha-allo-kainic acid, domoic acid, erythro-L-tricholomic acid, DL-ibotenic acid, L-quisqualic acid and allo-gamma-hydroxy-L-glutamic acid were examined on six identifiable giant neurones of an African giant snail (Achatina fulica Férussac). The neurones studied were: PON (periodically oscillating neurone), d-RPLN (dorsal-right parietal large neurone), VIN (visceral intermittently firing neurone), RAPN (right anterior pallial neurone), FAN (frequently autoactive neurone) and v-RCDN (ventral-right cerebral distinct neurone). Of these, d-RPLN and RAPN were excited by the two isomers (erythro- and threo-) of beta-hydroxy-L-glutamic acid (L-BHGA), whereas PON, VIN, FAN and v-RCDN were inhibited. L-Glutamic acid (L-Glu) had virtually no effect on these neurones. alpha-Kainic acid and domoic acid showed marked excitatory effects, similar to those of L-BHGA, on d-RPLN and RAPN. Their effective potency quotients (EPQs), relative to the more effective isomer of L-BHGA were: 0.3 for both substances on d-RPLN, and 1 for alpha-kainic acid and 3-1 for domoic acid on RAPN. alpha-Kainic acid also had excitatory effects on FAN and v-RCDN (EPQ for both: 0.3), which were inhibited by L-BHGA but excited by gamma-aminobutyric acid (GABA). Erythro-L-tricholomic acid showed marked effects, similar to those of L-BHGA, on VIN (EPQ: 0.3) and RAPN (EPQ: 3-1), but produced weaker effects on PON and d-RPLN (EPQ: 0.1). DL-Ibotenic acid produced marked effects, similar to those of L-BHGA, on PON, VIN (EPQ for both: 1) and RAPN (EPQ: 1-0.3), but had weak effects on d-RPLN (EPQ: less than 0.1) and FAN (EPQ: 0.1). It had excitatory effects on v-RCDN (EPQ: 0.1). This neurone was inhibited by L-BHGA but excited by GABA. L-Quisqualic acid showed the same effects as L-BHGA on all of the neurones examined (EPQ range 30-0.1). It was the most potent of the compounds tested on RAPN (EPQ: 30-10), FAN (EPQ: 30) and v-RCDN (EPQ: 3). alpha-Allo-kainic

Propolis ameliorates tumor nerosis factor-α, nitric oxide levels, caspase-3 and nitric oxide synthase activities in kainic acid mediated excitotoxicity in rat brain.

PubMed

Swamy, Mummedy; Suhaili, Dian; Sirajudeen, K N S; Mustapha, Zulkarnain; Govindasamy, Chandran

2014-01-01

Increased nitric oxide (NO), neuronal inflammation and apoptosis have been proposed to be involved in excitotoxicity plays a part in many neurodegenerative diseases. To understand the neuro-protective effects of propolis, activities of Nitric oxide synthase (NOS) and caspase-3 along with NO and tumor necrosis factor-α (TNF-α) levels were studied in cerebral cortex (CC), cerebellum (CB) and brain stem (BS) in rats supplemented with propolis prior to excitotoxic injury with kainic acid (KA). Male Sprague-Dawley rats were divided into four groups (n=6 rats per group) as Control, KA, Propolis and KA+Propolis. The control group and KA group have received vehicle and saline. Propolis group and propolis + KA group were orally administered with propolis (150 mg/kg body weight), five times every 12 hours. KA group and propolis +KA group were injected subcutaneously with kainic acid (15 mg/kg body weight) and were sacrificed after 2 hrs. CC, CB and BS were separated, homogenized and used for estimation of NOS, caspase-3, NO and TNF-α by commercial kits. Results were analyzed by one way ANOVA, reported as mean + SD (n=6 rats), and p<0.05 was considered statistically significant. The concentration of NO, TNF-α, NOS and caspase-3 activity were increased significantly (p<0.001) in all the three brain regions tested in KA group compared to the control. Propolis supplementation significantly (p<0.001) prevented the increase in NOS, NO, TNF-α and caspase-3 due to KA. Results of this study clearly demonstrated that the propolis supplementation attenuated the NOS, caspase-3 activities, NO, and TNF-α concentration and in KA mediated excitotoxicity. Hence propolis can be a possible potential protective agent against excitotoxicity and neurodegenerative disorders.

Effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazol-induced epileptic behaviors in infant and prepubertal rats.

PubMed

Ebrahimi, Loghman; Saboory, Ehsan; Roshan-Milani, Shiva; Hashemi, Paria

2014-09-01

Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. Many reports have shown an interaction between morphine- and stress-induced behavioral changes in adult rats. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazole (PTZ)-induced epileptic behaviors was investigated in rat offspring to address effect of the interaction between morphine and stress. Pregnant rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, the rats were placed in 25 °C water on 17-19 days of pregnancy. In the morphine/saline group, the rats received morphine/saline on the same days. In the morphine/saline-stressed group, they were exposed to stress and received morphine/saline simultaneously. On postnatal day 15 (P15), blood samples were collected to determine corticosterone (COS) level. On P15 and P25, PTZ was injected to the rest of pups to induce seizure. Then, epileptic behaviors of each rat were individually observed. Latency of tonic-colonic seizures decreased in control-morphine and stressed-saline groups while increasing in stressed-morphine rats compared to control-saline group on P15. Duration of tonic-colonic seizures significantly increased in control-morphine and stressed-saline rats compared to stressed-morphine and control-saline rats on P15, but not P25. COS levels increased in stressed-saline group but decreased in control-morphine group compared to control-saline rats. Body weight was significantly higher in morphine groups than saline treated rats. Prenatal exposure to forced-swim stress potentiated PTZ-induced seizure in the offspring rats. Co-administration of morphine attenuated effect of stress on body weight, COS levels, and epileptic behaviors. © 2014 Wiley Periodicals, Inc.

Increased excitability and metabolism in pilocarpine induced epileptic rats: effect of Bacopa monnieri.

PubMed

Mathew, Jobin; Paul, Jes; Nandhu, M S; Paulose, C S

2010-09-01

We have evaluated the acetylcholine esterase and malate dehydrogenase activity in the muscle, epinephrine, norepinephrine, insulin and T3 content in the serum of epileptic rats. Acetylcholine esterase and malate dehydrogenase activity increased in the muscle and decreased in the heart of the epileptic rats compared to control. Insulin and T3 content were increased significantly in the serum of the epileptic rats. Our results suggest that repetitive seizures resulted in increased metabolism and excitability in epileptic rats. Bacopa monnieri and Bacoside-A treatment prevents the occurrence of seizures there by reducing the impairment on peripheral nervous system. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.

PubMed

Warner, Timothy A; Kang, Jing-Qiong; Kennard, John A; Harrison, Fiona E

2015-02-01

Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish).

PubMed

Torres-Hernández, Bianca A; Del Valle-Mojica, Lisa M; Ortíz, José G

2015-07-14

Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of valerenic acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, valerenic acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with valerenic acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p < 0.05 level of significance. All treatments were compared with the untreated animals and with the other pretreatments. After exposure to pentylenetetrazole, zebrafish exhibited a series of stereotypical behaviors prior to the appearance of clonic-like movements--convulsions. Both valerenic acid and valerian extracts (aqueous and ethanolic) significantly extended the latency period to the onset of seizure (convulsion) in adult zebrafish. The ethanolic valerian extract was a more potent anticonvulsant than the aqueous extract. Valerenic acid and both valerian extracts interacted synergistically with clonazepam to extended the

Cortical GABAergic excitation contributes to epileptic activities around human glioma

PubMed Central

Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

A KCNQ channel opener for experimental neonatal seizures and status epilepticus

PubMed Central

Raol, YogendraSinh H.; Lapides, David A.; Keating, Jeffery; Brooks-Kayal, Amy R.; Cooper, Edward C.

2009-01-01

Objective Neonatal seizures occur frequently, are often refractory to anticonvulsants, and are associated with considerable morbidity and mortality. Genetic and electrophysiological evidence indicates that KCNQ voltage-gated potassium channels are critical regulators of neonatal brain excitability. This study tests the hypothesis that selective openers of KCNQ channels may be effective for treatment of neonatal seizures. Methods We induced seizures in postnatal day 10 rats with either kainic acid or flurothyl. We measured seizure activity using quantified behavioral rating and electrocorticography. We compared the efficacy of flupirtine, a selective KCNQ channel opener, with phenobarbital and diazepam, two drugs in current use for neonatal seizures. Results Unlike phenobarbital or diazepam, flupirtine prevented animals from developing status epilepticus (SE) when administered prior to kainate. In the flurothyl model, phenobarbital and diazepam increased latency to seizure onset, but flupirtine completely prevented seizures throughout the experiment. Flupirtine was also effective in arresting electrographic and behavioral seizures when administered after animals had developed continuous kainate-induced SE. Flupirtine caused dose-related sedation and suppressed EEG activity, but did not result in respiratory suppression or result in any mortality. Interpretation Flupirtine appears more effective than either of two commonly used anti-epileptic drugs, phenobarbital and diazepam, in preventing and suppressing seizures in both the kainic acid and flurothyl models of symptomatic neonatal seizures. KCNQ channel openers merit further study as potential treatments for seizures in infants and children. PMID:19334075

A role for synaptic and network plasticity in controlling epileptiform activity in CA1 in the kainic acid-lesioned rat hippocampus in vitro.

PubMed Central

Bernard, C; Wheal, H V

1996-01-01

1. Stimulation of the surviving afferents in the stratum radiatum of the CA1 area in kainic acid-lesioned hippocampal slices produced graded epileptiform activity, part of which (> 20%) involved the activation of N-methyl-D-aspartate (NMDA) receptors. There was also a failure of synaptic inhibition in this region. In this preparation, we have tested the effects of low-frequency stimulation (LFS; 1 Hz for 15 min) on synaptic responses and epileptiform activity. 2. LFS resulted in long-term depression (LTD) of excitatory synaptic potentials (EPSPs), long-term decrease of population spike amplitudes (PSAs) and EPSP-spike (E-S) potentiation. Evoked epileptiform activity was reduced but neurons had a higher probability of discharge. LTD could be reversed by subsequent tetanic stimulation whereas E-S dissociation remained unchanged. Synaptic and network responses could be saturated towards either potentiation or depression. However, E-S potentiation was maximal following the first conditioning stimulus. 3. NMDA receptor-mediated responses were pharmacologically isolated. LFS resulted in LTD of synaptic responses, long-term decrease of PSAs and E-S depression. These depressions could not be reversed by subsequent tetanic stimulation. alpha-Amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and NMDA receptor-mediated responses were then measured in isolation before and following conditioning stimuli. LFS was shown to simultaneously produce LTD of AMPA and NMDA receptor-mediated responses. E-S potentiation of the AMPA component and E-S depression of the NMDA component occurred coincidentally. 4. LTD of AMPA and NMDA receptor-mediated responses were shown to be NMDA dependent. In contrast, E-S potentiation and depression occurred even when NMDA receptors were pharmacologically blocked. 5. These findings indicate that synaptic responses could be modified bidirectionally in the CA1 area of kainic acid-lesioned rat hippocampus in an NMDA receptor-dependent manner. However

Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol

PubMed Central

Hilton, Genell D.; Nunez, Joseph L.; Bambrick, Linda; Thompson, Scott M.; McCarthy, Margaret M.

2008-01-01

Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate. PMID:17156362

Differential regulation of preprotachykinin-A mRNA expression in striatum by excitation of hippocampal neurons.

PubMed

Brené, S; Lindefors, N; Herrera-Marschitz, M; Persson, H

1993-07-01

In this report we have studied the influence of hippocampal neurons on neuropeptide mRNA expression in both dorsal and ventral striatum in the rat. Intrahippocampal unilateral kainic acid injections were performed in control animals and in animals with a unilateral 6-hydroxydopamine-induced dopamine deafferentation of the striatum. In situ hybridization combined with quantitative image analysis was used to study the expression of preprotachykinin A mRNA encoding the neuropeptides substance P and neurokinin A. The 6-hydroxydopamine-induced lesion caused a decrease of preprotachykinin A mRNA levels in the ipsilateral dorsal striatum and in both sides of the ventral striatum. In normal rats, the intrahippocampal kainic acid injection caused a twofold increase in preprotachykinin A mRNA in the limbic parts of the striatum, which are innervated by the hippocampus. No effect of the kainic acid injection was seen in the lateral parts of the dorsal striatum, a region which does not appear to be innervated by the hippocampus. Animals with a 6-hydroxydopamine lesion showed a similar kainic acid-mediated increase in preprotachykinin A mRNA in parts of the ventral striatum. In the dopamine-lesioned dorsal striatum and ventral striatum the decreased preprotachykinin A mRNA levels were normalized by the intrahippocampal kainic acid injection. These results show that kainic acid-mediated excitation of hippocampal neurons causes a dopamine-independent induction of preprotachykinin A mRNA expression in parts of the ventral striatum, and reverses the dopamine deafferentation-induced decrease of preprotachykinin A mRNA in both dorsal and ventral striatum. Combined, our results suggest that hippocampal neurons can regulate preprotachykinin A mRNA expression in both the ventral and the dorsal striatum.

E-p-Methoxycinnamic acid protects cultured neuronal cells against neurotoxicity induced by glutamate

PubMed Central

Kim, So Ra; Sung, Sang Hyun; Jang, Young Pyo; Markelonis, George J; Oh, Tae H; Kim, Young Choong

2002-01-01

We previously reported that four new phenylpropanoid glycosides and six known cinnamate derivatives isolated from roots of Scrophularia buergeriana Miquel (Scrophulariaceae) protected cultured cortical neurons from neurotoxicity induced by glutamate. Here, we have investigated the structure-activity relationships in the phenylpropanoids using our primary culture system. The α,β-unsaturated ester moiety and the para-methoxy group in the phenylpropanoids appeared to play a vital role in neuroprotective activity. This suggested that E-p-methoxycinnamic acid (E-p-MCA) might be a crucial component for their neuroprotective activity within the phenylpropanoid compounds. E-p-MCA significantly attenuated glutamate-induced neurotoxicity when added prior to an excitotoxic glutamate challenge. The neuroprotective activity of E-p-MCA appeared to be more effective in protecting neurons against neurotoxicity induced by NMDA than from that induced by kainic acid. E-p-MCA inhibited the binding of [propyl-2,3-3H]-CGP39653 and [2-3H]-glycine to their respective binding sites on rat cortical membranes. However, even high concentrations of E-p-MCA failed to inhibit completely [propyl-2,3-3H]-CGP39653 and [2-3H]-glycine binding. Indeed, E-p-MCA diminished the calcium influx that routinely accompanies glutamate-induced neurotoxicity, and inhibited the subsequent overproduction of nitric oxide and cellular peroxide in glutamate-injured neurons. Thus, our results suggest that E-p-MCA exerts significant protective effects against neurodegeneration induced by glutamate in primary cultures of cortical neurons by an action suggestive of partial glutamatergic antagonism. PMID:11877337

Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy.

PubMed

Maia, Gisela H; Brazete, Cátia S; Soares, Joana I; Luz, Liliana L; Lukoyanov, Nikolai V

2017-09-01

Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of hypersynchrony in the cortical network during chemoconvulsant-induced epileptic seizures in vivo.

PubMed

Cymerblit-Sabba, Adi; Schiller, Yitzhak

2012-03-01

The prevailing view of epileptic seizures is that they are caused by increased hypersynchronous activity in the cortical network. However, this view is based mostly on electroencephalography (EEG) recordings that do not directly monitor neuronal synchronization of action potential firing. In this study, we used multielectrode single-unit recordings from the hippocampus to investigate firing of individual CA1 neurons and directly monitor synchronization of action potential firing between neurons during the different ictal phases of chemoconvulsant-induced epileptic seizures in vivo. During the early phase of seizures manifesting as low-amplitude rhythmic β-electrocorticography (ECoG) activity, the firing frequency of most neurons markedly increased. To our surprise, the average overall neuronal synchronization as measured by the cross-correlation function was reduced compared with control conditions with ~60% of neuronal pairs showing no significant correlated firing. However, correlated firing was not uniform and a minority of neuronal pairs showed a high degree of correlated firing. Moreover, during the early phase of seizures, correlated firing between 9.8 ± 5.1% of all stably recorded pairs increased compared with control conditions. As seizures progressed and high-frequency ECoG polyspikes developed, the firing frequency of neurons further increased and enhanced correlated firing was observed between virtually all neuronal pairs. These findings indicated that epileptic seizures represented a hyperactive state with widespread increase in action potential firing. Hypersynchrony also characterized seizures. However, it initially developed in a small subset of neurons and gradually spread to involve the entire cortical network only in the later more intense ictal phases.

Cyclooxygenase system contributes to the maintenance of post convulsive period of epileptic phenomena in the genetically epileptic El mice.

PubMed

Okada, Kazumasa; Yamashita, Uki; Tsuji, Sadatoshi

2006-09-01

Recent studies have shown that cytokines and cyclooxygenase (COX)-2 are up-regulated in the brain of human epilepsy patients and animal models of epilepsy. We investigated the effect of inflammatory responses induced by intramuscular injection of turpentine on the epileptic phenomenon in genetically epileptic El mice. As parameters of epileptic seizure, seizure threshold (number of toss-ups to induce convulsion), duration of actual convulsion and duration of post actual convulsive period (period from the offset of convulsion to full recovery) were evaluated. The post actual convulsive period was prolonged without any change of seizure threshold or duration of actual convulsion 24 h after turpentine injection. Although pretreatment with indomethacin for one week did not change the seizure parameters, indomethacin suppressed the prolongation of the post actual convulsive period induced by turpentine. The mRNA expression of IL-1beta, IL-6 and COX-2 in the cerebral cortex was detected by RT-PCR. There was no difference in the mRNA expression in the cerebral cortex before and 24 h after seizure. The mRNA levels of IL-1beta, IL-6 and COX-2 in the cerebral cortex were up-regulated 24 h after turpentine injection. On the other hand, the up-regulated mRNA levels of IL-1beta, IL-6 and COX-2 in the cerebral cortex after turpentine treatment were not suppressed by indomethacin. These results suggest that prostaglandins induced with COX-2 in the cerebral cortex seem to play an important role in the maintenance of the post convulsive period, but not in induction and maintenance of the actual convulsive state.

Involvement of Thalamus in Initiation of Epileptic Seizures Induced by Pilocarpine in Mice

PubMed Central

Li, Yong-Hua; Li, Jia-Jia; Lu, Qin-Chi; Gong, Hai-Qing; Liang, Pei-Ji

2014-01-01

Studies have suggested that thalamus is involved in temporal lobe epilepsy, but the role of thalamus is still unclear. We obtained local filed potentials (LFPs) and single-unit activities from CA1 of hippocampus and parafascicular nucleus of thalamus during the development of epileptic seizures induced by pilocarpine in mice. Two measures, redundancy and directionality index, were used to analyze the electrophysiological characters of neuronal activities and the information flow between thalamus and hippocampus. We found that LFPs became more regular during the seizure in both hippocampus and thalamus, and in some cases LFPs showed a transient disorder at seizure onset. The variation tendency of the peak values of cross-correlation function between neurons matched the variation tendency of the redundancy of LFPs. The information tended to flow from thalamus to hippocampus during seizure initiation period no matter what the information flow direction was before the seizure. In some cases the information flow was symmetrically bidirectional, but none was found in which the information flowed from hippocampus to thalamus during the seizure initiation period. In addition, inactivation of thalamus by tetrodotoxin (TTX) resulted in a suppression of seizures. These results suggest that thalamus may play an important role in the initiation of epileptic seizures. PMID:24778885

Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms.

PubMed

van Vliet, Erwin A; Otte, Willem M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

2016-01-01

Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activity during the chronic epileptic phase. Given rapamycin's role in growth and immune response, the potential therapeutic effects of rapamycin after status epilepticus with emphasis on brain inflammation and brain vasculature were investigated. Seven weeks after kainic acid-induced status epilepticus, rats were perfusion fixed and (immuno)histochemistry was performed using several glial and vascular markers. In addition, an in vitro model for the human BBB was used to determine the effects of rapamycin on transendothelial electrical resistance as a measure for BBB integrity. (Immuno)histochemistry showed that local blood vessel density, activated microglia, and astrogliosis were reduced in rapamycin-treated rats compared to vehicle-treated rats. In vitro studies showed that rapamycin could attenuate TNFα-induced endothelial barrier breakdown. These data suggest that rapamycin improves BBB function during the chronic epileptic phase by a reduction of local brain inflammation and blood vessel density that can contribute to a milder form of epilepsy. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Protection against Acetylcholinesterase Inhibitor Toxicity by Alpha- Adrenergic Agonists

DTIC Science & Technology

1992-10-28

acetvlthiocholine iodide (substrate). and 6.9 mM Dithiosnitrobenzoic acid . The absorbance at 412 nm was recorded for 2 rain. 1~1 RESULTS PART I...however, the drug has been shown to be quite effective in limiting seizure production in the audiogenic 1261 and kainic acid [31 animal models of...acetyicholinesterase inhibitor soman. Neurosci.Ltt. 78: 107-112. 3. Baran, H., Hortnagi, H. and Homykiewicz, 0. (1989). Kainic acid -induced seizures

Effects of anticonvulsants and inactivity on bone disease in epileptics

PubMed Central

Murchison, Lilian E.; Bewsher, P. D.; Chesters, Marion; Gilbert, J.; Catto, G.; Law, Elizabeth; McKay, E.; Ross, H. S.

1975-01-01

No significant biochemical or radiological features of vitamin D deficiency were found in groups of juvenile and adult epileptics and control groups of non-epileptic patients in hospitals for the mentally retarded. There was evidence of hepatic enzyme induction in patients on anticonvulsants, in that urinary D-glucaric acid concentration and excretion were raised. No effect was found of prolonged anticonvulsant therapy on bone densitometry, but in children immobility was closely associated with decreased bone density. The evidence suggests that disuse osteoporosis is the major bone disease in these mentally retarded children. PMID:1161672

Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy.

PubMed

Pittschieler, Sabine; Brezinka, Christoph; Jahn, Beate; Trinka, Eugen; Unterberger, Iris; Dobesberger, Judith; Walser, Gerald; Auckenthaler, Andrea; Embacher, Norbert; Bauer, Gerhard; Luef, Gerhard

2008-12-01

Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. Prospective examination of 104 patients, registered in EURAP from 1999-2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. 388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.

Differentiating epileptic from non-epileptic high frequency intracerebral EEG signals with measures of wavelet entropy.

PubMed

Mooij, Anne H; Frauscher, Birgit; Amiri, Mina; Otte, Willem M; Gotman, Jean

2016-12-01

To assess whether there is a difference in the background activity in the ripple band (80-200Hz) between epileptic and non-epileptic channels, and to assess whether this difference is sufficient for their reliable separation. We calculated mean and standard deviation of wavelet entropy in 303 non-epileptic and 334 epileptic channels from 50 patients with intracerebral depth electrodes and used these measures as predictors in a multivariable logistic regression model. We assessed sensitivity, positive predictive value (PPV) and negative predictive value (NPV) based on a probability threshold corresponding to 90% specificity. The probability of a channel being epileptic increased with higher mean (p=0.004) and particularly with higher standard deviation (p<0.0001). The performance of the model was however not sufficient for fully classifying the channels. With a threshold corresponding to 90% specificity, sensitivity was 37%, PPV was 80%, and NPV was 56%. A channel with a high standard deviation of entropy is likely to be epileptic; with a threshold corresponding to 90% specificity our model can reliably select a subset of epileptic channels. Most studies have concentrated on brief ripple events. We showed that background activity in the ripple band also has some ability to discriminate epileptic channels. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Aspirin attenuates spontaneous recurrent seizures in the chronically epileptic mice.

PubMed

Zhu, Kun; Hu, Ming; Yuan, Bo; Liu, Jian-Xin; Liu, Yong

2017-08-01

Neuroinflammatory processes are pathologic hallmarks of both experimental and human epilepsy, and could be implicated in the neuronal hyperexcitability. Aspirin represents one of the non-selective nonsteroidal anti-inflammatory drugs with fewer side effects in long-term application. This study was carried out to assess the anti-epileptic effects of aspirin when administered during the chronic stage of temporal lobe epilepsy [TLE] in mice. The alteration of hippocampal neurogenesis was also examined for raising a possible mechanism underlying the protective effect of anti-inflammatory treatment in the TLE. Two months after pilocarpine-induced status epilepticus, the chronically epileptic mice were treated with aspirin (20 mg, 60 mg or 80 mg/kg) once a day for 10 weeks. Spontaneous recurrent seizures were monitored by video camera for 2 weeks. To evaluate the profile of hippocampal neurogenesis, the newly generated cells in the dentate gyrus were labeled by the proliferation marker BrdU. The newborn neurons that extended axons to CA3 area were visualized by cholera toxin B subunit retrograde tracing. Administration of aspirin with a dosage of 60 mg or 80 mg/kg initiated at 2 months after pilocarpine-induced status epilepticus significantly reduced the frequency and duration of spontaneous recurrent seizures. Aspirin treatment also increased the number of newborn neurons with anatomic integration through improving the survival of the newly generated cells. Aspirin treatment during the chronic stage of TLE could attenuate the spontaneous recurrent seizures in mice. Promotion of hippocampal neurogenesis and inhibition of COX-PGE2 pathway might partly contribute to this anti-epileptic effect. Highlights • Aspirin attenuates spontaneous recurrent seizures of chronically epileptic mice • Aspirin increases neurogenesis of chronically epileptic hippocampus by improving the survival of newly generated cells • Promotion of hippocampal neurogenesis and inhibition

[Occupational health problems in epileptics].

PubMed

Romankow, Jacek

2005-01-01

From the point of view of occupational medicine some questions are important for epileptics; amongst others: falling, behavior during the paroxysm, shift work dependence of attack, behaviour after an epileptic episode. Occupational capacity depends on the process of epileptic episodes and their frequency. The development of neurology has rendered numerous cures from epilepsy, but the the occupational stigma is difficult in many professions--electrical engineering, working with machinery, milling machines and others. In some professions a care must be taken when hiring epileptics--for instance professions with a fall hazard, jobs connected with public transport or involving crane or excavator operation.

Functional neuroimaging in epileptic encephalopathies.

PubMed

Siniatchkin, Michael; Capovilla, Giuseppe

2013-11-01

Epileptic encephalopathies (EEs) represent a group of severe epileptic disorders associated with cognitive and behavioral disturbances. The mechanisms of cognitive disability in EEs remain unclear. This review summarized neuroimaging studies that have tried to describe specific fingerprints of brain activation in EE. Although the epileptic activity can be generated individually in different brain regions, it seems likely that the activity propagates in a syndrome-specific way. In some EEs, the epileptiform discharges were associated with an interruption of activity in the default mode network. In another EE, other mechanisms seem to underlie cognitive disability associated with epileptic activity, for example, abnormal connectivity pattern or interfering activity in the thalamocortical network. Further neuroimaging studies are needed to investigate the short-term and long-term impact of epileptic activity on cognition and development. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Human iPSC-Derived GABA Ergic Precursor Cell Therapy for Chronic Epilepsy

DTIC Science & Technology

2015-10-01

1) Induction of status epilepticus (SE) in young rats through kainic acid injections to generate rats exhibiting chronic TLE typified by SRS. (2...of status epilepticus (SE) via graded kainic acid injections, termination of acute seizures 2 hours after SE onset via diazepam injections and...injections to these rats to induce acute seizures or status epilepticus (SE) in 11 separate experimental sessions (n=8-12/session). These experiments

MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate.

PubMed

Huff, Courtney L; Morano, Rachel L; Herman, James P; Yamamoto, Bryan K; Gudelsky, Gary A

2016-12-01

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37-58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures. Copyright © 2016 Elsevier B.V. All rights reserved.

MDMA Decreases Gluatamic Acid Decarboxylase (GAD) 67-Immunoreactive Neurons in the Hippocampus and Increases Seizure Susceptibility: Role for Glutamate

PubMed Central

Huff, Courtney L.; Morano, Rachel L.; Herman, James P.; Yamamoto, Bryan K.; Gudelsky, Gary A.

2016-01-01

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37–58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30 days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures. PMID:27773601

The body comes to family therapy: Treatment of a school-aged boy with hyperventilation-induced non-epileptic seizures.

PubMed

Kozlowska, Kasia; Chudleigh, Catherine; Elliott, Bronwen; Landini, Andrea

2016-10-01

We present the case of a 10-year-old boy, Evan, where a knock to the head activated memories of past bullying, causing intense distress, activation of the body's stress-regulation systems and recurrent hospital presentations with hyperventilation-induced non-epileptic seizures. We describe the initial assessment session that enabled Evan and his family to understand the context for Evan's non-epileptic seizures, to engage with the therapeutic team and to collaborate in the implementation of a mind-body multimodal family-based intervention. Once the physical symptoms had been addressed therapeutically, we explored possible dangers within the family and school systems and we worked with Evan and his family to increase his ability to access comfort and protection from his parents. Our short hospital intervention highlighted the importance of ongoing therapeutic work with Evan and the family and laid the foundation stones for the next part of the family's therapeutic journey. © The Author(s) 2015.

Comparing maximum autonomic activity of psychogenic non-epileptic seizures and epileptic seizures using heart rate variability.

PubMed

Jeppesen, Jesper; Beniczky, Sándor; Johansen, Peter; Sidenius, Per; Fuglsang-Frederiksen, Anders

2016-04-01

The semiology of psychogenic non-epileptic seizures (PNES) can resemble epileptic seizures, and differentiation between epileptic seizures with no EEG-correlate and PNES can be challenging even for trained experts. Therefore, there has been a search for a quantitative measure, other than EEG and semiology that could distinguish PNES from epileptic seizures. We used ECG to measure heart rate variability (HRV) in order to compare maximum autonomic activity of epileptic seizures and PNES. These comparisons could potentially serve as biomarkers for distinguishing these types of clinical episodes. Forty-nine epileptic seizures from 17 patients and 24 PNES from 7 patients with analyzable ECG were recorded during long-term video-EEG monitoring. Moving windows of 100 R-R intervals throughout each seizure were used to find maximum values of Cardiac Sympathetic Index (CSI) (sympathetic tonus) and minimum values of Cardiac Vagal Index (CVI), Root-Mean-Square-of-Successive-Differences (RMSSD) and HF-power (parasympathetic tonus). In addition, non-seizure recordings of each patient were used to compare HRV-parameters between the groups. The maximum CSI for epilepsy seizures were higher than PNES (P=0.015). The minimum CVI, minimum RMSSD and HF-power did not show significant difference between epileptic seizures and PNES (P=0.762; P=0.152; P=0.818). There were no statistical difference of non-seizure HRV-parameters between the PNES and epilepsy patients. We found the maximum sympathetic activity accompanying the epileptic seizures to be higher, than that during the PNES. However, the great variation of autonomic response within both groups makes it difficult to use these HRV-measures as a sole measurement in distinguishing epileptic seizures from PNES. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Reflex epileptic mechanisms in humans: Lessons about natural ictogenesis.

PubMed

Wolf, Peter

2017-06-01

The definition of reflex epileptic seizures is that specific seizure types can be triggered by certain sensory or cognitive stimuli. Simple triggers are sensory (most often visual, more rarely tactile or proprioceptive; simple audiogenic triggers in humans are practically nonexistent) and act within seconds, whereas complex triggers like praxis, reading and talking, and music are mostly cognitive and work within minutes. The constant relation between a qualitatively, often even quantitatively, well-defined stimulus and a specific epileptic response provides unique possibilities to investigate seizure generation in natural human epilepsies. For several reflex epileptic mechanisms (REMs), this has been done. Reflex epileptic mechanisms have been reported less often in focal lesional epilepsies than in idiopathic "generalized" epilepsies (IGEs) which are primarily genetically determined. The key syndrome of IGE is juvenile myoclonic epilepsy (JME), where more than half of the patients present reflex epileptic traits (photosensitivity, eye closure sensitivity, praxis induction, and language-induced orofacial reflex myocloni). Findings with multimodal investigations of cerebral function concur to indicate that ictogenic mechanisms in IGEs largely (ab)use preexisting functional anatomic networks (CNS subsystems) normally serving highly complex physiological functions (e.g., deliberate complex actions and linguistic communication) which supports the concept of system epilepsy. Whereas REMs in IGEs, thus, are primarily function-related, in focal epilepsies, they are primarily localization-related. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". Copyright © 2015 Elsevier Inc. All rights reserved.

Knowledge and attitude of epilepsy among secondary schools students (epileptic and non-epileptic) in Assiut city Egypt.

PubMed

Shehata, Ghaydaa A; Mahran, Dalia G

2011-06-01

This study was designed to assess knowledge and attitude with respect to epilepsy among secondary school students (epileptic and none) in Assiut city, Egypt. A cross sectional study was applied among secondary school students in Assiut city, Egypt. A 13-item questionnaire was self administered by 2226 students who selected randomly. All students either epileptic or non-epileptic had been heard about epilepsy. Only 7.1% of epileptic students and 8.5% of non-epileptic students thought that the epilepsy is a brain disease. Out of 2198 non-epileptic students, 28.4% thought that person with epilepsy (PWE) should not marry and 92% of them refused to marry from PWE. The correct knowledge of epilepsy was significantly positive correlated with positive attitude towards PWE. However, students still feel persons with epilepsy are stigmatized and are different from others. Secondary school students in Egypt have a vague knowledge about the etiology of epilepsy. Misconceptions about and negative attitudes towards epilepsy are unexpectedly high among those students. Copyright © 2011 Elsevier B.V. All rights reserved.

[Video electroencephalographic diagnosis of epileptic and non-epileptic paroxysmal episodes in infants and children at the pre-school age].

PubMed

Pérez-Jiménez, Angeles; García-Fernández, Marta; Santiago, M del Mar; Fournier-Del Castillo, M Concepción

2012-05-21

The main usefulness of video electroencephalographic (video-EEG) monitoring lies in the fact that it allows proper classification of the type of epileptic seizure and epileptic syndrome, identification of minor seizures, location of the epileptogenic zone and differentiation between epileptic seizures and non-epileptic paroxysmal manifestations (NEPM). In infants and pre-school age children, the clinical signs with which epileptic seizures are expressed differ to those of older children, seizures with bilateral motor signs such as epileptic spasms, tonic and myoclonic seizures predominate, and seizures with interruption of activity or hypomotor seizures, and no prominent automatisms are observed. In children with focal epilepsies, focal and generalised signs are often superposed, both clinically and in the EEG. NEPM may be benign transitory disorders or they can be episodic symptoms of different neurological or psychopathological disorders. NEPM are often observed in children with mental retardation, neurological compromise or autism spectrum disorders, who present epileptic seizures and epileptiform abnormalities in the baseline EEG. It then becomes necessary to determine which episodes correspond to epileptic seizures and which do not. The NEPM that are most frequently registered in the video-EEG in infants and pre-school age children are unexpected sudden motor contractions ('spasms'), introspective tendencies, motor stereotypic movements and paroxysmal sleep disorders.

The Anticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms.

PubMed

Zhang, Yifan; Xu, Jingwei; Zhang, Kun; Yang, Wei; Li, Bingjin

2018-01-01

Epilepsy is a syndrome of brain dysfunction induced by the aberrant excitability of certain neurons. Despite advances in surgical technique and anti-epileptic drug in recent years, recurrent epileptic seizures remain intractable and lead to a serious morbidity in the world. The ketogenic diet refers to a high-fat, low-carbohydrate and adequate-protein diet. Currently, its beneficial effects on epileptic seizure reduction have been well established. However, the detailed mechanisms underlying the anti-epileptic effects of ketogenic diet are still poorly understood. In this article, the possible roles of ketogenic diet on epilepsy were discussed. Data was obtained from the websites including Web of Science, Medline, Pubmed, Scopus, based on these keywords: "Ketogenic diet" and "epilepsy". As shown in both clinical and basic studies, the therapeutic effects of ketogenic diet might involve neuronal metabolism, neurotransmitter function, neuronal membrane potential and neuron protection against ROS. In this review, we systematically reviewed the effects and possible mechanisms of ketogenic diet on epilepsy, which may optimize the therapeutic strategies against epilepsy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Magnetic resonance features of the feline hippocampus in epileptic and non-epileptic cats: a blinded, retrospective, multi-observer study.

PubMed

Claßen, Anne Christine; Kneissl, Sibylle; Lang, Johann; Tichy, Alexander; Pakozdy, Akos

2016-08-11

Hippocampal necrosis in cats has been reported to be associated with epileptic seizures. Magnetic resonance imaging (MRI) features of temporal lobe (TL) abnormalities in epileptic cats have been described but MR images from epileptic and non-epileptic individuals have not yet been systematically compared. TL abnormalities are highly variable in shape, size and signal, and therefore may lead to varying evaluations by different specialists. The aim of this study was to investigate whether there were differences in the appearance of the TL between epileptic and non-epileptic cats, and whether there were any relationships between TL abnormalities and seizure semiologies or other clinical findings. We also investigated interobserver agreement among three specialists. The MR images of 46 cats were reviewed independently by three observers, who were blinded to patient data, examination findings and the review of the other observers. Images were evaluated using a multiparametric scoring system developed for this study. Mann-Whitney U-tests and chi-square were used to analyse the differences between observers' evaluations. The kappa coefficient (k) and Fleiss' kappa coefficient were used to quantify interobserver agreement. The overall interobserver agreement was moderate to good (k =0.405 to 0.615). The MR scores between epileptic and non-epileptic cats did not differ significantly. However, there was a significant difference between the MR scores of epileptic cats with and without orofacial involvement according to all three observers. Likewise, MR scores of cats with cluster seizures were higher than those of cats without clusters. Cats presenting with recurrent epileptic seizures with orofacial involvement are more likely to have hippocampal pathologies, which suggests that TL abnormalities are not merely unspecific epileptic findings, but are associated with a certain type of epilepsy. TL signal alterations are more likely to be detected on FLAIR sequences. In contrast

Effect of hydroalcoholic extract of ginger on the liver of epileptic female rats treated with lamotrigine

PubMed Central

Poorrostami, Ameneh; Farokhi, Farah; Heidari, Reza

2014-01-01

Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each. Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy. Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control. Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity. PMID:25068142

Upregulation of GH, but not IGF1, in the hippocampus of the lactating dam after kainic acid injury

PubMed Central

Arellanes-Licea, Elvira C; Ávila-Mendoza, José; Ramírez-Martínez, Elizabeth C; Ramos, Eugenia; Uribe-González, Nancy; Arámburo, Carlos

2018-01-01

Lactation embodies a natural model of morphological, neurochemical, and functional brain plasticity. In this reproductive stage, the hippocampus of the female is less sensitive to excitotoxins in contrast to nulliparity. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) are known to be neuroprotective in several experimental models of brain lesion. Here, activation of the GH–IGF1 pituitary–brain axis following kainic acid (7.5 mg/kg i.p. KA) lesion was studied in lactating and nulliparous rats. Serum concentrations of GH and IGF1 were uncoupled in lactation. Compared to virgin rats, the basal concentration of GH increased up to 40% but IGF1 decreased 58% in dams, and only GH increased further after KA treatment. In the hippocampus, basal expression of GH mRNA was higher (2.8-fold) in lactating rats than in virgin rats. GH mRNA expression in lactating rats increased further after KA administration in the hippocampus and in the hypothalamus, in parallel to GH protein concentration in the hippocampus of KA-treated lactating rats (43% vs lactating control), as detected by Western blot and immunofluorescence. Except for the significantly lower mRNA concentration in the liver of lactating rats, IGF1 expression was not altered by the reproductive condition or by KA treatment in the hippocampus and hypothalamus. Present results indicate upregulation of GH expression in the hippocampus after an excitotoxic lesion, suggesting paracrine/autocrine actions of GH as a factor underlying neuroprotection in the brain of the lactating dam. Since no induction of IGF1 was detected, present data suggest a direct action of GH. PMID:29321175

Genetics Home Reference: early infantile epileptic encephalopathy 1

MedlinePlus

... infantile epileptic encephalopathy 1 Early infantile epileptic encephalopathy 1 Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Early infantile epileptic encephalopathy 1 (EIEE1) is ...

Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A.

PubMed

Mathew, Jobin; Balakrishnan, Savitha; Antony, Sherin; Abraham, Pretty Mary; Paulose, C S

2012-02-24

Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.

Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes.

PubMed

Patel, Jaina; Mercimek-Mahmutoglu, Saadet

2016-10-01

Epilepsy is one of the most common neurological disorders in childhood. Epilepsy associated with global developmental delay and cognitive dysfunction is defined as epileptic encephalopathy. Certain inherited metabolic disorders presenting with epileptic encephalopathy can be treated with disease specific diet, vitamin, amino acid or cofactor supplementations. In those disorders, disease specific therapy is successful to achieve good seizure control and improve long-term neurodevelopmental outcome. For this reason, intractable epilepsy with global developmental delay or history of developmental regression warrants detailed metabolic investigations for the possibility of an underlying treatable inherited metabolic disorder, which should be undertaken as first line investigations. An underlying genetic etiology in epileptic encephalopathy has been supported by recent studies such as array comparative genomic hybridization, targeted next generation sequencing panels, whole exome and whole genome sequencing. These studies report a diagnostic yield up to 70%, depending on the applied genetic testing as well as number of patients enrolled. In patients with epileptic encephalopathy, a stepwise approach for diagnostic work-up will help to diagnose treatable inherited metabolic disorders quickly. Application of detailed genetic investigations such as targeted next generation sequencing as second line and whole exome sequencing as third line testing will diagnose underlying genetic disease which will help for genetic counseling as well as guide for prenatal diagnosis. Knowledge of underlying genetic cause will provide novel insights into the pathogenesis of epileptic encephalopathy and pave the ground towards the development of targeted neuroprotective treatment strategies to improve the health outcome of children with epileptic encephalopathy.

Recurrent epileptic Wernicke aphasia.

PubMed

Sahaya, Kinshuk; Dhand, Upinder K; Goyal, Munish K; Soni, Chetan R; Sahota, Pradeep K

2010-04-15

We report a patient with recurrent epileptic Wernicke aphasia who prior to this presentation, had been misdiagnosed as transient ischemic attacks for several years. This case report emphasizes the consideration of epileptic nature of aphasia when a clear alternate etiology is unavailable, even when EEG fails to show a clear ictal pattern. We also present a brief discussion of previously reported ictal aphasias. Copyright 2010 Elsevier B.V. All rights reserved.

Neuroprotective actions of the synthetic estrogen 17alpha-ethynylestradiol in the hippocampus.

PubMed

Picazo, Ofir; Becerril-Montes, Adriana; Huidobro-Perez, Delia; Garcia-Segura, Luis M

2010-07-01

17alpha-ethynylestradiol (EE2), a major constituent of many oral contraceptives, is similar in structure to 17beta-estradiol, which has neuroprotective properties in several animal models. This study explored the potential neuroprotective actions of EE2 against kainic and quinolinic acid toxicity in the hippocampus of adult ovariectomized Wistar rats. A decrease in the number of Nissl-stained neurons and the induction of vimentin immunoreactivity in astrocytes was observed in the hilus of the dentate gyrus of the hippocampus after the administration of either kainic acid or quinolinic acid. EE2 prevented the neuronal loss and the induction of vimentin immunoreactivity induced by kainic acid at low (1 microg/rat) and high (10-100 microg/rat) doses and exerted a protection against quinolinic acid toxicity at a low dose (1 microg/rat) only. These observations demonstrate that EE2 exerts neuroprotective actions against excitotoxic insults. This finding is relevant for the design of new neuroprotective estrogenic compounds.

[Research advances in circadian rhythm of epileptic seizures].

PubMed

Yang, Wen-Qi; Li, Hong

2017-01-01

The time phase of epileptic seizures has attracted more and more attention. Epileptic seizures have their own circadian rhythm. The same type of epilepsy has different seizure frequencies in different time periods and states (such as sleeping/awakening state and natural day/night cycle). The circadian rhythm of epileptic seizures has complex molecular and endocrine mechanisms, and currently there are several hypotheses. Clarification of the circadian rhythm of epileptic seizures and prevention and administration according to such circadian rhythm can effectively control seizures and reduce the adverse effects of drugs. The research on the circadian rhythm of epileptic seizures provides a new idea for the treatment of epilepsy.

The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

PubMed

Löscher, Wolfgang

2017-07-01

Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with

A new epileptic seizure classification based exclusively on ictal semiology.

PubMed

Lüders, H; Acharya, J; Baumgartner, C; Benbadis, S; Bleasel, A; Burgess, R; Dinner, D S; Ebner, A; Foldvary, N; Geller, E; Hamer, H; Holthausen, H; Kotagal, P; Morris, H; Meencke, H J; Noachtar, S; Rosenow, F; Sakamoto, A; Steinhoff, B J; Tuxhorn, I; Wyllie, E

1999-03-01

Historically, seizure semiology was the main feature in the differential diagnosis of epileptic syndromes. With the development of clinical EEG, the definition of electroclinical complexes became an essential tool to define epileptic syndromes, particularly focal epileptic syndromes. Modern advances in diagnostic technology, particularly in neuroimaging and molecular biology, now permit better definitions of epileptic syndromes. At the same time detailed studies showed that there does not necessarily exist a one-to-one relationship between epileptic seizures or electroclinical complexes and epileptic syndromes. These developments call for the reintroduction of an epileptic seizure classification based exclusively on clinical semiology, similar to the seizure classifications which were used by neurologists before the introduction of the modern diagnostic methods. This classification of epileptic seizures should always be complemented by an epileptic syndrome classification based on all the available clinical information (clinical history, neurological exam, ictal semiology, EEG, anatomical and functional neuroimaging, etc.). Such an approach is more consistent with mainstream clinical neurology and would avoid the current confusion between the classification of epileptic seizures (which in the International Seizure Classification is actually a classification of electroclinical complexes) and the classification of epileptic syndromes.

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

PubMed Central

Palma, E.; Ragozzino, D. A.; Di Angelantonio, S.; Spinelli, G.; Trettel, F.; Martinez-Torres, A.; Torchia, G.; Arcella, A.; Di Gennaro, G.; Quarato, P. P.; Esposito, V.; Cantore, G.; Miledi, R.; Eusebi, F.

2004-01-01

The properties of γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABAA receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat α1β2γ2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABAA receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABAA receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABAA-receptor β1, β2, β3, and γ2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABAA receptors. Blockage of phosphatases stabilizes the TLE GABAA receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy. PMID:15218107

[Clinical analysis of 322 cases of non-epileptic cerebral palsy].

PubMed

Zhu, Deng-Na; Wang, Jun; Jia, Yan-Jie; Niu, Guo-Hui; Sun, Li; Xiong, Hua-Chun; Zhai, Hong-Yin; Chen, Hai; Li, Lin-Chen

2010-12-01

To study the clinical features of non-epileptic seizures associated with cerebral palsy (CP) in children. A total of 1 198 children with CP (age: 9 months to 6 years) were enrolled. The children with paroxysmal events were monitored by 24 hrs video-EEG (VEEG) to make sure the seizures were epileptic or non-epileptic. The symptoms, age, CP types and EEG features were observed in children with non-epileptic CP. Five hundred and seventy-eight children (48.24%) presented paroxysmal events. The seizures were epileptic in 231 children (19.28%) and non-epileptic in 322 cases (26.88%). In the 322 cases of non-epileptic CP, the paroxysmal events were of various kinds, including non-epileptic seizure tonic, seizure shake head, shrug shoulder or head hypsokinesis, cry or scream, panic attacks, sleep myoclonic and stereotyped movement. One hundred and fifty-eight (49.1%) out of the 322 children demonstrated nonspecific EEG abnormalities. One hundred and eleven children (34.5%) were misdiagnosed as epilepsy in primary hospitals. The CP children less than one year old showed higher frequency of non-epileptic seizures than the age groups over 1 year and 3 to 6 years. The frequency of non-epileptic seizures was the highest in children with spastic CP (168 cases, 52.2%), followed by dyskinetic CP (69 cases, 21.4%) and mixed type CP (65 cases, 20.2%). The paroxysmal events in children with CP partially are non-epileptic seizures and it is important to differentiate non-epileptic from epileptic seizures. The frequencies of non-epileptic seizures may be associated with a child's age and CP type.

Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

PubMed Central

2012-01-01

Abstact Background Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management. PMID:22364254

Clinical review of genetic epileptic encephalopathies

PubMed Central

Noh, Grace J.; Asher, Y. Jane Tavyev; Graham, John M.

2012-01-01

Seizures are a frequently encountered finding in patients seen for clinical genetics evaluations. The differential diagnosis for the cause of seizures is quite diverse and complex, and more than half of all epilepsies have been attributed to a genetic cause. Given the complexity of such evaluations, we highlight the more common causes of genetic epileptic encephalopathies and emphasize the usefulness of recent technological advances. The purpose of this review is to serve as a practical guide for clinical geneticists in the evaluation and counseling of patients with genetic epileptic encephalopathies. Common syndromes will be discussed, in addition to specific seizure phenotypes, many of which are refractory to anti-epileptic agents. Divided by etiology, we overview the more common causes of infantile epileptic encephalopathies, channelopathies, syndromic, metabolic, and chromosomal entities. For each condition, we will outline the diagnostic evaluation and discuss effective treatment strategies that should be considered. PMID:22342633

Occurrence and clinical features of epileptic and non-epileptic paroxysmal events in five children with Pallister–Killian syndrome

PubMed Central

Filloux, Francis M.; Carey, John C.; Krantz, Ian D.; Ekstrand, Jeffrey J.; Candee, Meghan S.

2013-01-01

Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder caused by tetrasomy 12p mosaicism associated with a supernumerary isochromosome. Craniofacial dysmorphism, learning impairment and seizures are considered characteristic. However, little is known of the seizure and epilepsy patterns seen in PKS. To better define the occurrence and nature of epileptic and non-epileptic paroxysmal events in PKS, we describe our experience with 5 patients and compare their features with data from a larger cohort of PKS patients ascertained via a web-based parental questionnaire. Three of the 5 patients have had definite epileptic seizures, and one other has had paroxysmal events as yet not clarified. Four of the 5 have also had either non-epileptic paroxysmal events or episodes of uncertain nature. In those with epilepsy, all have had some period of relatively refractory seizures, all have required more than one antiepileptic drug, but none experienced status epilepticus. Only one of the patients with epilepsy (the oldest) has gone into remission. In two of the four with non-epileptic events, video-electroencephalographic monitoring has been valuable in clarifying the nature of the events. EEG characteristics include a slow dominant frequency as well as generalized and focal epileptiform features. Brain MRI findings can be normal but are variable. These specific findings correspond well to information reported by parents in a larger cohort of 51 individuals with PKS. Better understanding of the nature of epileptic and non-epileptic events in PKS will result from a more detailed analysis of objective data obtained from this larger cohort, and from deeper understanding of the molecular impact of 12p tetrasomy in selected cell lines. PMID:22349688

[Unusual dreams in epileptics].

PubMed

Boldyrev, A I

1984-01-01

The author discusses bizarre dreams characteristic of epileptics and never occurring in normal subjects which have an important practical implication especially for early detection of epilepsy and the prevention of severe forms of the disease. This group of dreams includes vivid nightmares with vital fear, dreams not infrequently transforming into pro-dream states; persistently repeated stereotyped dreams and dreams with invariably the same unpleasant sensations representing an isolated aura of subsequent epileptic attacks. Diagnostically important may also be dreams with the symptoms of derealization and depersonalization, vague dream images and the deja vu phenomenon.

Altered expression of the voltage-gated calcium channel subunit α2δ-1: A comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain

PubMed Central

Nieto-Rostro, M.; Sandhu, G.; Bauer, C.S.; Jiruska, P.; Jefferys, J.G.R.; Dolphin, A.C.

2014-01-01

The auxiliary α2δ-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The α2δ-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, α2δ-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies. In this study we therefore examined whether the level or distribution of α2δ-1 was altered in the hippocampus following experimental induction of epileptic seizures in rats, using both the kainic acid model of human temporal lobe epilepsy, in which status epilepticus is induced, and the tetanus toxin model in which status epilepticus is not involved. The main finding of this study is that we did not identify somatic overexpression of α2δ-1 in hippocampal neurons in either of the epilepsy models, unlike the upregulation of α2δ-1 that occurs following peripheral nerve damage to both somatosensory and motor neurons. However, we did observe local reorganization of α2δ-1 immunostaining in the hippocampus only in the kainic acid model, where it was associated with areas of neuronal cell loss, as indicated by absence of NeuN immunostaining, dendritic loss, as identified by areas where microtubule-associated protein-2 immunostaining was missing, and reactive gliosis, determined by regions of strong OX42 staining. PMID:24641886

Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging.

PubMed

van Vliet, Erwin A; Otte, Willem M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

2016-01-01

The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced magnetic resonance imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis. Imaging was repeatedly performed until 6 weeks after kainic acid-induced status epilepticus in rapamycin (6 mg/kg for 6 weeks starting 4 h after SE) and vehicle-treated rats, using gadobutrol as contrast agent. Seizures were detected using video monitoring in the week following the last imaging session. Gadobutrol leakage was widespread and extensive in both rapamycin and vehicle-treated epileptic rats during the acute phase, with the piriform cortex and amygdala as the most affected regions. Gadobutrol leakage was higher in rapamycin-treated rats 4 and 8 days after status epilepticus compared to vehicle-treated rats. However, during the chronic epileptic phase, gadobutrol leakage was lower in rapamycin-treated epileptic rats along with a decreased seizure frequency. This was confirmed by local fluorescein staining in the brains of the same rats. Total brain volume was reduced by this rapamycin treatment regimen. The initial slow recovery of BBB function in rapamycin-treated epileptic rats indicates that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. The reduced BBB leakage during the chronic phase, however, could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Multimodality localization of epileptic foci

NASA Astrophysics Data System (ADS)

Desco, Manuel; Pascau, Javier; Pozo, M. A.; Santos, Andres; Reig, Santiago; Gispert, Juan D.; Garcia-Barreno, Pedro

2001-05-01

This paper presents a multimodality approach for the localization of epileptic foci using PET, MRI and EEG combined without the need of external markers. Mutual Information algorithm is used for MRI-PET registration. Dipole coordinates (provided by BESA software) are projected onto the MRI using a specifically developed algorithm. The four anatomical references used for electrode positioning (nasion, inion and two preauricular points) are located on the MRI using a triplanar viewer combined with a surface-rendering tool. Geometric transformation using deformation of the ideal sphere used for dipole calculations is then applied to match the patient's brain size and shape. Eight treatment-refractory epileptic patients have been studied. The combination of the anatomical information from the MRI, hipoperfusion areas in PET and dipole position and orientation helped the physician in the diagnosis of epileptic focus location. Neurosurgery was not indicated for patients where PET and dipole results were inconsistent; in two cases it was clinically indicated despite the mismatch, showing a negative follow up. The multimodality approach presented does not require external markers for dipole projection onto the MRI, this being the main difference with previous methods. The proposed method may play an important role in the indication of surgery for treatment- refractory epileptic patients.

How Sleep Activates Epileptic Networks?

PubMed Central

Halász, Peter

2013-01-01

Background. The relationship between sleep and epilepsy has been long ago studied, and several excellent reviews are available. However, recent development in sleep research, the network concept in epilepsy, and the recognition of high frequency oscillations in epilepsy and more new results may put this matter in a new light. Aim. The review address the multifold interrelationships between sleep and epilepsy networks and with networks of cognitive functions. Material and Methods. The work is a conceptual update of the available clinical data and relevant studies. Results and Conclusions. Studies exploring dynamic microstructure of sleep have found important gating mechanisms for epileptic activation. As a general rule interictal epileptic manifestations seem to be linked to the slow oscillations of sleep and especially to the reactive delta bouts characterized by A1 subtype in the CAP system. Important link between epilepsy and sleep is the interference of epileptiform discharges with the plastic functions in NREM sleep. This is the main reason of cognitive impairment in different forms of early epileptic encephalopathies affecting the brain in a special developmental window. The impairment of cognitive functions via sleep is present especially in epileptic networks involving the thalamocortical system and the hippocampocortical memory encoding system. PMID:24159386

HOMEOSTATIC REGULATION OF KCC2 ACTIVITY BY THE ZINC RECEPTOR mZnR/GPR39 DURING SEIZURES

PubMed Central

Gilad, David; Shorer, Sharon; Ketzef, Maya; Friedman, Alon; Sekler, Israel; Aizenman, Elias; Hershfinkel, Michal

2015-01-01

The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K+/Cl− co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn2+ chelation. Importantly, kainate-induced synaptic Zn2+ release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity. PMID:25562657

Impact of cognitive stimulation on ripples within human epileptic and non-epileptic hippocampus.

PubMed

Brázdil, Milan; Cimbálník, Jan; Roman, Robert; Shaw, Daniel J; Stead, Matt M; Daniel, Pavel; Jurák, Pavel; Halámek, Josef

2015-07-25

Until now there has been no way of distinguishing between physiological and epileptic hippocampal ripples in intracranial recordings. In the present study we addressed this by investigating the effect of cognitive stimulation on interictal high frequency oscillations in the ripple range (80-250 Hz) within epileptic (EH) and non-epileptic hippocampus (NH). We analyzed depth EEG recordings in 10 patients with intractable epilepsy, in whom hippocampal activity was recorded initially during quiet wakefulness and subsequently during a simple cognitive task. Using automated detection of ripples based on amplitude of the power envelope, we analyzed ripple rate (RR) in the cognitive and resting period, within EH and NH. Compared to quiet wakefulness we observed a significant reduction of RR during cognitive stimulation in EH, while it remained statistically marginal in NH. Further, we investigated the direct impact of cognitive stimuli on ripples (i.e. immediately post-stimulus), which showed a transient statistically significant suppression of ripples in the first second after stimuli onset in NH only. Our results point to a differential reactivity of ripples within EH and NH to cognitive stimulation.

Combined Effects of Feedforward Inhibition and Excitation in Thalamocortical Circuit on the Transitions of Epileptic Seizures

PubMed Central

Fan, Denggui; Duan, Lixia; Wang, Qian; Luan, Guoming

2017-01-01

The mechanisms underlying electrophysiologically observed two-way transitions between absence and tonic-clonic epileptic seizures in cerebral cortex remain unknown. The interplay within thalamocortical network is believed to give rise to these epileptic multiple modes of activity and transitions between them. In particular, it is thought that in some areas of cortex there exists feedforward inhibition from specific relay nucleus of thalamus (TC) to inhibitory neuronal population (IN) which has even more stronger functions on cortical activities than the known feedforward excitation from TC to excitatory neuronal population (EX). Inspired by this, we proposed a modified computational model by introducing feedforward inhibitory connectivity within thalamocortical circuit, to systematically investigate the combined effects of feedforward inhibition and excitation on transitions of epileptic seizures. We first found that the feedforward excitation can induce the transition from tonic oscillation to spike and wave discharges (SWD) in cortex, i.e., the epileptic tonic-absence seizures, with the fixed weak feedforward inhibition. Thereinto, the phase of absence seizures corresponding to strong feedforward excitation can be further transformed into the clonic oscillations with the increasing of feedforward inhibition, representing the epileptic absence-clonic seizures. We also observed the other fascinating dynamical states, such as periodic 2/3/4-spike and wave discharges, reversed SWD and clonic oscillations, as well as saturated firings. More importantly, we can identify the stable parameter regions representing the tonic-clonic oscillations and SWD discharges of epileptic seizures on the 2-D plane composed of feedforward inhibition and excitation, where the physiologically plausible transition pathways between tonic-clonic and absence seizures can be figured out. These results indicate the functional role of feedforward pathways in controlling epileptic seizures and

The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

PubMed

Orr, J M; Farrell, K; Abbott, F S; Ferguson, S; Godolphin, W J

1983-01-01

The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

Epileptic peri-ictal psychosis, a reversible cause of psychosis.

PubMed

González Mingot, C; Gil Villar, M P; Calvo Medel, D; Corbalán Sevilla, T; Martínez Martínez, L; Iñiguez Martínez, C; Santos Lasaosa, S; Mauri Llerda, J A

2013-03-01

Epileptic psychoses are categorised as peri-ictal and interictal according to their relationship with the occurrence of seizures. There is a close temporal relationship between peri-ictal psychosis and seizures, and psychosis may present before (preictal), during (ictal) or after seizures (postictal). Epileptic psychoses usually have acute initial and final phases, with a short symptom duration and complete remission with a risk of recurrence. There is no temporal relationship between interictal or chronic psychosis and epileptic seizures. Another type of epileptic psychosis is related to the response to epilepsy treatment: epileptic psychosis caused by the phenomenon of forced normalisation (alternative psychosis), which includes epileptic psychosis secondary to epilepsy surgery. Although combination treatment with antiepileptic and neuroleptic drugs is now widely used to manage this condition, there are no standard treatment guidelines for epileptic psychosis. We present 5 cases of peri-ictal epileptic psychosis in which we observed an excellent response to treatment with levetiracetam. Good control was achieved over both seizures and psychotic episodes. Levetiracetam was used in association with neuroleptic drugs with no adverse effects, and our patients did not require high doses of the latter. Categorising psychotic states associated with epilepsy according to their temporal relationship with seizures is clinically and prognostically useful because it provides important information regarding disease treatment and progression. The treatment of peri-ictal or acute mental disorders is based on epileptic seizure control, while the treatment of interictal or chronic disorders has more in common with managing disorders which are purely psychiatric in origin. In addition to improving the patient's quality of life and reducing disability, achieving strict control over seizures may also prevent the development of interictal psychosis. For this reason, we believe that

Effect of the non-NMDA receptor antagonist GYKI 52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia.

PubMed

Arvin, B; Lekieffre, D; Graham, J L; Moncada, C; Chapman, A G; Meldrum, B S

1994-04-01

The effect of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) on ischaemia-induced changes in the microdialysate and tissue concentrations of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was studied in rats. Twenty minutes of four-vessel occlusion resulted in a transient increase in microdialysate levels of glutamate, aspartate, and GABA in striatum, cortex, and hippocampus. Administration of GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min intravenously starting 20 min before onset of ischaemia) inhibited ischaemia-induced increases in microdialysate glutamate and GABA in striatum without affecting the increases in hippocampus or cortex. Twenty minutes of four-vessel occlusion resulted in immediate small decreases and larger delayed (72 h) decreases in tissue levels of glutamate and aspartate. Transient increases in tissue levels of GABA were shown in all three structures at the end of the ischaemic period. At 72 h, after the ischaemic period, significantly reduced GABA levels were observed in striatum and hippocampus. GYKI 52466, given under identical conditions as above, augmented the ischaemia-induced decrease in striatal tissue levels of glutamate and aspartate, without significantly affecting the decreases in hippocampus and cortex. Twenty minutes of ischaemia resulted in a large increase in microdialysate dopamine in striatum. GYKI 52466 failed to inhibit this increase. Kainic acid (500 microM infused through the probe for 20 min) caused increases in microdialysate glutamate and aspartate in the striatum. GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min) completely inhibited the kainic acid-induced glutamate release. In conclusion, the action of the non-NMDA antagonist, GYKI 52466, in the striatum is different from that in the cortex and hippocampus. The inhibition by GYKI 52466 of ischaemia-induced and kainate-induced increases in microdialysate

Spread of epileptic activity in human brain

NASA Astrophysics Data System (ADS)

Milton, John

1997-03-01

For many patients with medically refractory epilepsy surgical resection of the site of seizure onset (epileptic focus) offers the best hope for cure. Determination of the nature of seizure propagation should lead to improved methods for locating the epileptic focus (and hence reduce patient morbidity) and possibly to new treatment modalities directed at blocking seizure spread. Theoretical studies of neural networks emphasize the role of traveling waves for the propagation of activity. However, the nature of seizure propagation in human brain remains poorly characterized. The spread of epileptic activity in patients undergoing presurgical evaluation for epilepsy surgery was measured by placing subdural grids of electrodes (interelectrode spacings of 3-10 mm) over the frontal and temporal lobes. The exact location of each electrode relative to the surface of the brain was determined using 3--D MRI imaging techniques. Thus it is possible to monitor the spread of epileptic activity in both space and time. The observations are discussed in light of models for seizure propagation.

Study on localization of epileptic focus based on causality analysis

NASA Astrophysics Data System (ADS)

Shan, Shaojie; Li, Hanjun; Tang, Xiaoying

2018-05-01

In this paper, we considered that the ECoG signal contain abundant pathological information, which can be used for the localization of epileptic focus before epileptic seizures in 1-2 mins. In order to validate this hypothesis, cutting the ECoG into three stages: before seizure, seizure and after seizure, then through using Granger causality algorithm, PSI causality algorithm, Transfer Entropy causality algorithm at different stages of epilepsy ECoG, we were able to do the causality analysis of ECoG data. The results have shown that there is significant difference with the causality value of the epileptic focus area in before seizure, seizure and after seizure. An increase is in the causality value of each channel during epileptic seizure. After epileptic seizure, the causality between the channels showed a downward trend, but the difference was not obvious. The difference of the causality provides a reliable technical method to assist the clinical diagnosis of epileptic focus.

Changes in /sup 3/H-substance P receptor binding in the rat brain after kainic acid lesion of the corpus striatum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mantyh, P.W.; Hunt, S.P.

1986-06-01

Previous studies have indicated that the substantia nigra contains the highest concentration of substance P-like immunoreactivity (SPLI) in the brain. Paradoxically, it also appears to contain one of the lowest concentrations of substance P receptors in the brain. One possibility is that the massive amount of SPLI blocks the binding of the radioligand to the substance P receptor and/or down-regulates the number of substance P receptors present in this structure. Since greater than 95% of the SPLI within the substantia nigra originates from the corpus striatum, we have lesioned this area and measured the changes in substance P receptor concentrationmore » in the substantia nigra and other corpus striatal projection areas. A semiquantitative autoradiographic technique for measuring the binding of /sup 3/H-substance P to substance P receptors was used in conjunction with tritium-sensitive film. 3H-substance P binding was measured in both the corpus striatum and its projection areas after kainic acid lesion of the corpus striatum. At either 4 or 21 d after the lesion there was approximately a 90% loss of substance P receptors in the rostral striatum, a 74% loss in the globus pallidus, a 57% increase in receptor number in lamina I and II of the ipsilateral somatosensory cortex, and no apparent change in the number of receptors in the substantia nigra pars reticulata, superior colliculus, and central gray. These findings suggest that the low concentration of substance P receptors found within the substantia nigra is not due the massive SPLI innervation, since removal of greater than 95% of the SPLI had no measurable effect on the concentration of substance P receptors.« less

Ethosuximide: liver enzyme induction and D-glucaric acid excretion.

PubMed

Gilbert, J C; Scott, A K; Galloway, D B; Petrie, J C

1974-06-01

1 A study has been carried out to determine if ethosuximide induces liver enzymes. 2 Ethosuximide did not affect the urinary excretion of D-glucaric acid by healthy adult subjects nor was the mean daily D-glucaric acid excretion of three epileptic children on long term ethosuximide therapy different from that of three matched controls. 3 Ethosuximide (10 mg/kg or 50 mg/kg daily) did not influence D-glucaric acid excretion or liver microsomal protein and cytochrome P450 contents of guinea pigs but at a dose of 100 mg/kg daily in rats it increased liver microsomal protein and cytochrome P450 without altering D-glucaric acid excretion. 4 These results suggest that at anticonvulsant doses ethosuximide is unlikely to induce liver enzymes. The precise relationship between D-glucaric acid excretion and liver enzyme induction remains in doubt.

Daytime encopresis associated with gland mal epileptic seizures: case report.

PubMed

Oyatsi, D P

2005-08-01

Sphincteric incontinence of stool and urine are not unusual features of generalised epileptic seizures. Isolated secondary encopresis as a manifestation of an epileptic seizure is unusual. This report is of, a four year old boy, with daytime secondary non-retentive encopresis. The onset of encopresis was preceded by several episodes of nocturnal generalised tonic clonic epileptic seizures. An electroencephalogram showed features consistent with complex partial seizures. He was commenced on anti-epileptic treatment with phenytoin sodium, and by the third day of treatment, the patient had achieved stool control.

Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice

PubMed Central

Washington, James; Kumar, Udaya; Medel-Matus, Jesus-Servando; Shin, Don; Sankar, Raman; Mazarati, Andrey

2015-01-01

Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1β (IL-1β) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus offering an explanation for autism-epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1β combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)- induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6+IL-1β, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57bl/6j mice received daily injections of IL-6, IL-1β or IL-6+IL-1β combination. At postnatal day 40, male offspring was examined for the presence of social behavioral deficit and status epilepticus was induced by intrahippocampal KA injection. After six weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6+IL-1β offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1β exacerbated the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6+IL-1β mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy, and that the nature of these relationships depends on components of MIA involved. PMID:26103532

Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation.

PubMed

Mao, J; Coghill, R C; Kellstein, D E; Frenk, H; Mayer, D J

1992-03-06

The present study examined the effects of intrathecal (i.t.) injection of calcitonin gene-related peptide (CGRP) on caudally directed biting and scratching induced by i.t. substance P (SP), bombesin (BBS), strychnine (STR), and kainic acid (KA). CGRP alone (5.25, 10.5 and 21 nmol) had no effect on these behaviors, but CGRP pretreatment produced a dose-related enhancement of behaviors induced by SP or BBS, but not by KA or STR. 2-Amino-5-phosphonovaleric acid (APV, 25 nmol), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, did not block the CGRP potentiation of SP and BBS induced behaviors. CGRP, however, failed to enhance scratching and biting induced by a SP analogue [pGlu5-Mephe8-MeGly9]SP(5-11) (Dime-C7) that is resistant to enzymatic degradation by SP endopeptidase. These findings demonstrate that CGRP potentiates SP induced behavioral responses via inhibition of neuropeptide degradation and that this mechanism may serve as a physiological mechanism of SP modulation.

De novo mutations in HCN1 cause early infantile epileptic encephalopathy.

PubMed

Nava, Caroline; Dalle, Carine; Rastetter, Agnès; Striano, Pasquale; de Kovel, Carolien G F; Nabbout, Rima; Cancès, Claude; Ville, Dorothée; Brilstra, Eva H; Gobbi, Giuseppe; Raffo, Emmanuel; Bouteiller, Delphine; Marie, Yannick; Trouillard, Oriane; Robbiano, Angela; Keren, Boris; Agher, Dahbia; Roze, Emmanuel; Lesage, Suzanne; Nicolas, Aude; Brice, Alexis; Baulac, Michel; Vogt, Cornelia; El Hajj, Nady; Schneider, Eberhard; Suls, Arvid; Weckhuysen, Sarah; Gormley, Padhraig; Lehesjoki, Anna-Elina; De Jonghe, Peter; Helbig, Ingo; Baulac, Stéphanie; Zara, Federico; Koeleman, Bobby P C; Haaf, Thomas; LeGuern, Eric; Depienne, Christel

2014-06-01

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

miRNA Expression Profile after Status Epilepticus and Hippocampal Neuroprotection by Targeting miR-132

PubMed Central

Jimenez-Mateos, Eva M.; Bray, Isabella; Sanz-Rodriguez, Amaya; Engel, Tobias; McKiernan, Ross C.; Mouri, Genshin; Tanaka, Katsuhiro; Sano, Takanori; Saugstad, Julie A.; Simon, Roger P.; Stallings, Raymond L.; Henshall, David C.

2011-01-01

When an otherwise harmful insult to the brain is preceded by a brief, noninjurious stimulus, the brain becomes tolerant, and the resulting damage is reduced. Epileptic tolerance develops when brief seizures precede an episode of prolonged seizures (status epilepticus). MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators of gene expression. We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice. The miRNA was extracted from the ipsilateral CA3 subfield 24 hours after focal-onset status epilepticus in animals that had previously received either seizure preconditioning (tolerance) or no preconditioning (injury), and mature miRNA levels were measured using TaqMan low-density arrays. Expression of 21 miRNAs was increased, relative to control, after status epilepticus alone, and expression of 12 miRNAs was decreased. Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death. PMID:21945804

Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

PubMed

Krogsgaard-Larsen, Niels; Delgar, Claudia G; Koch, Karina; Brown, Patricia M G E; Møller, Charlotte; Han, Liwei; Huynh, Tri H V; Hansen, Stinne W; Nielsen, Birgitte; Bowie, Derek; Pickering, Darryl S; Kastrup, Jette Sandholm; Frydenvang, Karla; Bunch, Lennart

2017-01-12

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K i = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC 50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

Epileptic Seizures Prediction Using Machine Learning Methods

PubMed Central

Usman, Syed Muhammad

2017-01-01

Epileptic seizures occur due to disorder in brain functionality which can affect patient's health. Prediction of epileptic seizures before the beginning of the onset is quite useful for preventing the seizure by medication. Machine learning techniques and computational methods are used for predicting epileptic seizures from Electroencephalograms (EEG) signals. However, preprocessing of EEG signals for noise removal and features extraction are two major issues that have an adverse effect on both anticipation time and true positive prediction rate. Therefore, we propose a model that provides reliable methods of both preprocessing and feature extraction. Our model predicts epileptic seizures' sufficient time before the onset of seizure starts and provides a better true positive rate. We have applied empirical mode decomposition (EMD) for preprocessing and have extracted time and frequency domain features for training a prediction model. The proposed model detects the start of the preictal state, which is the state that starts few minutes before the onset of the seizure, with a higher true positive rate compared to traditional methods, 92.23%, and maximum anticipation time of 33 minutes and average prediction time of 23.6 minutes on scalp EEG CHB-MIT dataset of 22 subjects. PMID:29410700

Nocturnal acute laryngospasm in children: a possible epileptic phenomenon.

PubMed

Cohen, H A; Ashkenazi, A; Barzilai, A; Lahat, E

2000-03-01

Respiratory difficulties are not uncommon during epileptic activity in all age groups. Laryngospasm, as an isolated manifestation of epileptic disorder, is a rare phenomenon described previously in only two patients. We report our experience with five children in whom nocturnal laryngospasm was the only clinical manifestation of their epileptic disorder. All children underwent extensive workup and the diagnosis was made by sleep-deprived electroencephalography (two cases) and sleep study (three cases). All patients were treated with carbamezapine with prompt resolution of their laryngospasm.

Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.

PubMed

Orr, J M; Abbott, F S; Farrell, K; Ferguson, S; Sheppard, I; Godolphin, W

1982-05-01

In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.

Seizure-mediated neuronal activation induces DREAM gene expression in the mouse brain.

PubMed

Matsu-ura, Toru; Konishi, Yoshiyuki; Aoki, Tsutomu; Naranjo, Jose R; Mikoshiba, Katsuhiko; Tamura, Taka-aki

2002-12-30

Various transcriptional activators are induced in neurons concomitantly with long-lasting neural activity, whereas only a few transcription factors are known to act as neural activity-inducible transcription repressors. In this study, mRNA of DREAM (DRE-antagonizing modulator), a Ca(2+)-modulated transcriptional repressor, was demonstrated to accumulate in the mouse brain after pentylenetetrazol (PTZ)-induced seizures. Accumulation in the mouse hippocampus reached maximal level in the late phase (at 7-8 h) after PTZ injection. Kainic acid induced the same response. Interestingly, the late induction of DREAM expression required new protein synthesis and was blocked by MK801 suggesting that Ca(2+)-influx via NMDA receptors is necessary for the PTZ-mediated DREAM expression. In situ hybridization revealed that PTZ-induced DREAM mRNA accumulation was observed particularly in the dentate gyrus, cerebral cortex, and piriform cortex. The results of the present study demonstrate that DREAM is a neural activity-stimulated late gene and suggest its involvement in adaptation to long-lasting neuronal activity.

Is there anything distinctive about epileptic deja vu?

PubMed

Warren-Gash, Charlotte; Zeman, Adam

2014-02-01

Déjà vu can occur as an aura of temporal lobe epilepsy and in some psychiatric conditions but is also common in the general population. It is unclear whether any clinical features distinguish pathological and physiological forms of déjà vu. 50 epileptic patients with ictal déjà vu, 50 non-epileptic patients attending general neurology clinics and 50 medical students at Edinburgh University were recruited. Data were collected on demographic factors, the experience of déjà vu using a questionnaire based on Sno's Inventory for Déjà Vu Experiences Assessment, symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale as well as seizure characteristics, anti-epileptic medications, handedness, EEG and neuroimaging findings for epileptic patients. 73.5% of neurology patients, 88% of students and (by definition) all epilepsy patients had experienced déjà vu. The experience of déjà vu itself was similar in the three groups. Epileptic déjà vu occurred more frequently and lasted somewhat longer than physiological déjà vu. Epilepsy patients were more likely to report prior fatigue and concentrated activity, associated derealisation, olfactory and gustatory hallucinations, physical symptoms such as headaches, abdominal sensations and fear. After controlling for study group, anxiety and depression scores were not associated with déjà vu frequency. Déjà vu is common and qualitatively similar whether it occurs as an epileptic aura or normal phenomenon. However ictal déjà vu occurs more frequently and is accompanied by several distinctive features. It is distinguished primarily by 'the company it keeps'.

Concepts of Connectivity and Human Epileptic Activity

PubMed Central

Lemieux, Louis; Daunizeau, Jean; Walker, Matthew C.

2011-01-01

This review attempts to place the concept of connectivity from increasingly sophisticated neuroimaging data analysis methodologies within the field of epilepsy research. We introduce the more principled connectivity terminology developed recently in neuroimaging and review some of the key concepts related to the characterization of propagation of epileptic activity using what may be called traditional correlation-based studies based on EEG. We then show how essentially similar methodologies, and more recently models addressing causality, have been used to characterize whole-brain and regional networks using functional MRI data. Following a discussion of our current understanding of the neuronal system aspects of the onset and propagation of epileptic discharges and seizures, we discuss the most advanced and ambitious framework to attempt to fully characterize epileptic networks based on neuroimaging data. PMID:21472027

Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies.

PubMed

Suleiman, Jehan; Brenner, Tanja; Gill, Deepak; Troedson, Christopher; Sinclair, Adriane J; Brilot, Fabienne; Vincent, Angela; Lang, Bethan; Dale, Russell C

2011-11-01

Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normal<100), but extended antibody testing, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), was negative. The patient showed a partial response to steroid treatment, which was started late in the disease course. On review at 13 months of age, her development was consistent with an age of 5 to 6 months. These results suggest that VGKC-complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Mouse neuroblastoma cell-based model and the effect of epileptic events on calcium oscillations and neural spikes

NASA Astrophysics Data System (ADS)

Kim, Suhwan; Jung, Unsang; Baek, Juyoung; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

2013-01-01

Recently, mouse neuroblastoma cells have been considered as an attractive model for the study of human neurological and prion diseases, and they have been intensively used as a model system in different areas. For example, the differentiation of neuro2a (N2A) cells, receptor-mediated ion current, and glutamate-induced physiological responses have been actively investigated with these cells. These mouse neuroblastoma N2A cells are of interest because they grow faster than other cells of neural origin and have a number of other advantages. The calcium oscillations and neural spikes of mouse neuroblastoma N2A cells in epileptic conditions are evaluated. Based on our observations of neural spikes in these cells with our proposed imaging modality, we reported that they can be an important model in epileptic activity studies. We concluded that mouse neuroblastoma N2A cells produce epileptic spikes in vitro in the same way as those produced by neurons or astrocytes. This evidence suggests that increased levels of neurotransmitter release due to the enhancement of free calcium from 4-aminopyridine causes the mouse neuroblastoma N2A cells to produce epileptic spikes and calcium oscillations.

The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients.

PubMed

Eldin, Essam Eldin Mohamed Nour; Elshebiny, Hosam Abdel-Fattah; Mohamed, Tarek Mostafa; Abdel-Aziz, Mohamed Abdel-Azim; El-Readi, Mahmoud Zaki

2016-01-01

Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency.

Patient-specific connectivity pattern of epileptic network in frontal lobe epilepsy

PubMed Central

Luo, Cheng; An, Dongmei; Yao, Dezhong; Gotman, Jean

2014-01-01

There is evidence that focal epilepsy may involve the dysfunction of a brain network in addition to the focal region. To delineate the characteristics of this epileptic network, we collected EEG/fMRI data from 23 patients with frontal lobe epilepsy. For each patient, EEG/fMRI analysis was first performed to determine the BOLD response to epileptic spikes. The maximum activation cluster in the frontal lobe was then chosen as the seed to identify the epileptic network in fMRI data. Functional connectivity analysis seeded at the same region was also performed in 63 healthy control subjects. Nine features were used to evaluate the differences of epileptic network patterns in three connection levels between patients and controls. Compared with control subjects, patients showed overall more functional connections between the epileptogenic region and the rest of the brain and higher laterality. However, the significantly increased connections were located in the neighborhood of the seed, but the connections between the seed and remote regions actually decreased. Comparing fMRI runs with interictal epileptic discharges (IEDs) and without IEDs, the patient-specific connectivity pattern was not changed significantly. These findings regarding patient-specific connectivity patterns of epileptic networks in FLE reflect local high connectivity and connections with distant regions differing from those of healthy controls. Moreover, the difference between the two groups in most features was observed in the strictest of the three connection levels. The abnormally high connectivity might reflect a predominant attribute of the epileptic network, which may facilitate propagation of epileptic activity among regions in the network. PMID:24936418

Immunomodulatory effect of Celecoxib on HMGB1/TLR4 pathway in a recurrent seizures model in immature rats.

PubMed

Morales-Sosa, Mariana; Orozco-Suárez, Sandra; Vega-García, Angélica; Caballero-Chacón, Sara; Feria-Romero, Iris A

2018-07-01

Epileptic seizures constitute an important problem in pediatric neurology during the developmental period. The frequency and nosological significance of seizures, as well as their association with epileptogenesis, may be related to underlying mechanisms such as neuroinflammation. Those mechanisms of response activate inflammatory molecules induced in the neurons, activated glial cells and endothelial cells via the key HMGB1/TLR4 pathway. In this study, the drug celecoxib (CCX) was used as a blocker of the cyclooxygenase 2 (COX-2) and HMGB1/TLR-4 pathways. The experimental model was implemented in 10-day-old neonatal Sprague Dawley rats to induce recurrent seizures with kainic acid (KA, 1.4 mg/kg). Data were evaluated at early (14 PND) and late (30 PND) time points. The results showed that the CCX and CCX + pentobarbital (PB) groups exhibited a protective effect by significantly increasing the time latency of seizures compared to the KA group at both early (p < 0.01) and late (p < 0.001) times. When the CCX group was compared to the KA group, there was also a significant decrease in the number of HMGB1 and TLR-4 transcripts (p < 0.05) and in COX-2 protein expression (p < 0.05) in the most important areas for seizure generation (the hippocampus and cortex) at both the early and late time points. These results demonstrated that CCX treatment after epileptic seizures has a neuroprotective effect due to the inhibition of proinflammatory proteins and associated signaling pathways and reduces seizure susceptibility. Additionally, the timely intervention of inflammatory pathways will reduce the risk of developing epilepsy in adulthood. Copyright © 2018 Elsevier Inc. All rights reserved.

Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo.

PubMed

Arias, Clorinda; Montiel, Teresa; Peña, Fernando; Ferrera, Patricia; Tapia, Ricardo

2002-09-01

Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours after okadaic acid a marked destruction of hippocampal CA1 region was observed, which was not prevented by the receptor antagonists. These findings suggest that hyperphosphorylation of glutamate receptors in vivo may result in an increased sensitivity to the endogenous transmitter and therefore induce neuronal hyperexcitability and epilepsy.

A Novel Dynamic Update Framework for Epileptic Seizure Prediction

PubMed Central

Wang, Minghui; Hong, Xiaojun; Han, Jie

2014-01-01

Epileptic seizure prediction is a difficult problem in clinical applications, and it has the potential to significantly improve the patients' daily lives whose seizures cannot be controlled by either drugs or surgery. However, most current studies of epileptic seizure prediction focus on high sensitivity and low false-positive rate only and lack the flexibility for a variety of epileptic seizures and patients' physical conditions. Therefore, a novel dynamic update framework for epileptic seizure prediction is proposed in this paper. In this framework, two basic sample pools are constructed and updated dynamically. Furthermore, the prediction model can be updated to be the most appropriate one for the prediction of seizures' arrival. Mahalanobis distance is introduced in this part to solve the problem of side information, measuring the distance between two data sets. In addition, a multichannel feature extraction method based on Hilbert-Huang transform and extreme learning machine is utilized to extract the features of a patient's preseizure state against the normal state. At last, a dynamic update epileptic seizure prediction system is built up. Simulations on Freiburg database show that the proposed system has a better performance than the one without update. The research of this paper is significantly helpful for clinical applications, especially for the exploitation of online portable devices. PMID:25050381

A novel dynamic update framework for epileptic seizure prediction.

PubMed

Han, Min; Ge, Sunan; Wang, Minghui; Hong, Xiaojun; Han, Jie

2014-01-01

Epileptic seizure prediction is a difficult problem in clinical applications, and it has the potential to significantly improve the patients' daily lives whose seizures cannot be controlled by either drugs or surgery. However, most current studies of epileptic seizure prediction focus on high sensitivity and low false-positive rate only and lack the flexibility for a variety of epileptic seizures and patients' physical conditions. Therefore, a novel dynamic update framework for epileptic seizure prediction is proposed in this paper. In this framework, two basic sample pools are constructed and updated dynamically. Furthermore, the prediction model can be updated to be the most appropriate one for the prediction of seizures' arrival. Mahalanobis distance is introduced in this part to solve the problem of side information, measuring the distance between two data sets. In addition, a multichannel feature extraction method based on Hilbert-Huang transform and extreme learning machine is utilized to extract the features of a patient's preseizure state against the normal state. At last, a dynamic update epileptic seizure prediction system is built up. Simulations on Freiburg database show that the proposed system has a better performance than the one without update. The research of this paper is significantly helpful for clinical applications, especially for the exploitation of online portable devices.

Genetic epileptic encephalopathies: is all written into the DNA?

PubMed

Striano, Pasquale; de Jonghe, Peter; Zara, Federico

2013-11-01

Epileptic encephalopathy is a condition in which epileptic activity, clinical or subclinical, is thought to be responsible for any disturbance of cognition, behavior, or motor control. However, experimental evidence supporting this clinical observation are still poor and the causal relationship between pharmacoresistant seizures and cognitive outcome is controversial. In the past two decades, genetic studies shed new light onto complex mechanisms underlying different severe epileptic conditions associated with intellectual disability and behavioral abnormalities, thereby providing important clues on the relationship between seizures and cognitive outcome. Dravet syndrome is a childhood disorder associated with loss-of-function mutations in SCN1A and is characterized by frequent seizures and severe cognitive impairment, thus well illustrating the concept of epileptic encephalopathy. However, it is difficult to determine the causative role of the underlying sodium channel dysfunction and that of the consequent seizures in influencing cognitive outcome in these children. It is also difficult to demonstrate whether a recognizable profile of cognitive impairment or a definite behavioral phenotype exists. Data from the laboratory and the clinics may provide greater insight into the degree to which epileptic activity may contribute to cognitive impairment in individual syndromes. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy.

PubMed

Wang, Ping; Yin, Tao; Ma, Hong-ying; Liu, Dan-Qi; Sheng, Yangh-ao; Zhou, Bo-Ting

2015-01-01

Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.

[Subacute encephalopathy with epileptic seizures in an alcoholic patient].

PubMed

Kozian, R; Otto, F G

2000-09-01

We introduce a case of a 66 year-old male with chronic alcoholism who suffered from confusion, Wernicke-aphasia and epileptic seizures. Several EEG revealed periodic lateralized epileptiform discharges. The patient's case resembles the symptoms of a subacute encephalopathy with epileptic seizures which can occur in alcoholics.

An effective assessment of valproate sodium-induced hepatotoxicity with UPLC-MS and (1)HNMR-based metabonomics approach.

PubMed

Huo, Taoguang; Chen, Xi; Lu, Xiumei; Qu, Lianyue; Liu, Yang; Cai, Shuang

2014-10-15

Valproate sodium is one of the most prescribed antiepileptic drugs. However, valproate sodium has various side effects, especially its toxicity on liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods for toxicity evaluation are desired. To evaluate the toxicity of valproate sodium on liver, we performed both UPLC-MS and (1)HNMR-based metabonomics analysis of serum samples from 34 epileptic patients (age: 42.0±18.6, 18 male/16 female) after valproate sodium treatment. Compared to conventional markers, the serum metabolic profiles provided clear distinction of the valproate sodium induced normal liver function and abnormal liver function in epileptic patients. Through multivariate statistical analysis, we identified marker metabolites associated with the hepatotoxicity induced by valproate sodium, such as glucose, lactate, acetoacetate, VLDL/LDL, lysophosphatidylcholines, phosphatidylcholines, choline, creatine, amino acids, N-acetyl glycoprotein, pyruvate and uric acid. This metabonomics approach may provide effective way to evaluate the valproate sodium-induced toxicity in a manner that can complement current measures. This approach is expected to find broader application in other drug-induced toxicity assessment. Copyright © 2014 Elsevier B.V. All rights reserved.

Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling.

PubMed

Sugaya, Yuki; Kano, Masanobu

2018-05-08

Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy. Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis.

BDNF restores the expression of Jun and Fos inducible transcription factors in the rat brain following repetitive electroconvulsive seizures.

PubMed

Hsieh, T F; Simler, S; Vergnes, M; Gass, P; Marescaux, C; Wiegand, S J; Zimmermann, M; Herdegen, T

1998-01-01

The expression of inducible transcription factors was studied following repetitive electroconvulsive seizures (ECS), c-Fos, c-Jun, JunB, and JunD immunoreactivities were investigated following a single (1 x ECS) or repetitive ECS evoked once per day for 4, 5, or 10 days (4 x ECS, 5 x ECS, or 10 x ECS). Animals were killed 3 or 12 h following the last ECS. Three hours after 1 x ECS, c-Fos was expressed throughout the cortex and hippocampus. After 5 x ECS and 10 x ECS, c-Fos was reexpressed in the CA4 area, but was completely absent in the other hippocampal areas and cortex. In these areas, c-Fos became only reinducible when the time lag between two ECS stimuli was 5 days. In contrast to c-Fos, intense JunB expression was inducible in the cortex and hippocampus, but not CA4 subfield, after 1 x ECS, 5 x ECS, and 10 x ECS. Repetitive ECS did not effect c-Jun and JunD expression. In a second model of systemic excitation of the brain, repetitive daily injection of kainic acid for 4 days completely failed to express c-Fos, c-Jun, and JunB after the last application whereas injection of kainic acid once per week did not alter the strong expressions compared to a single application of kainic acid. In order to study the maintenance of c-Fos expression during repetitive seizures, brain-derived neurotrophic factor (BDNF) was applied in parallel for 5 or 10 days via miniosmotic pumps and permanent cannula targeted at the hippocampus or the parietal cortex. Infusion of BDNF completely reinduced c-Fos expression during 5 x ECS or 10 x ECS in the cortex ipsilaterally to the cannula and, to a less extent, also increased the expression of c-Jun and JunB when compared to saline-treated controls. BDNF had no effect on the expression patterns in the hippocampus. ECS with or without BDNF infusion did not change the expression patterns of the constitutive transcription factors ATF-2, CREB, and SRF. These data demonstrate that various transcription factors substantially differ in their

Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

NASA Astrophysics Data System (ADS)

Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

2013-05-01

Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

Etomidate accurately localizes the epileptic area in patients with temporal lobe epilepsy.

PubMed

Pastor, Jesús; Wix, Rybel; Meilán, María Luisa; Martínez-Chacón, José Luís; de Dios, Eva; Domínguez-Gadea, Luis; Herrera-Peco, Iván; Sola, Rafael G

2010-04-01

A variety of drugs have been used to activate and identify the epileptogenic area in patients during presurgical evaluation. We have evaluated the safety and usefulness of etomidate in identifying the epileptic zone by measuring bioelectrical brain activity and cerebral blood flow (CBF). We studied 13 men and 9 women under presurgical evaluation for temporal lobe epilepsy. We applied etomidate (0.1 mg/kg) while patients were monitored by video-electroencephalography (VEEG) with foramen ovale electrodes. In a subset of 15 patients, we also measured CBF with single photon emission computed tomography (SPECT). (1) Etomidate induced seizures in 2 of 22 patients. (2) The main side-effects observed were myoclonus (14 of 20) and moderate pain (3 of 20). (3) No changes in capillary oxygen saturation, respiration, or heart rate were observed. (4) Irritative activity specifically increased in the temporal mesial and lateral areas. No spikes were observed in other areas, aside from those observed under baseline conditions. (5) Irritative activity induced by etomidate correctly lateralized the ictal onset zone in 19 of 20 patients. In addition, the two etomidate-induced seizures appeared in the same regions as spontaneous ones. (6) The kinetics of pharmacologically induced activity was higher in the region of the ictal-onset zone. (7) Etomidate increased the CBF in the basal ganglia and especially in the posterior hippocampus of the temporal mesial region contralateral to the ictal-onset zone. Etomidate activation is a safe, specific, and quick test that can be used to identify the epileptic region in patients evaluated as candidates for temporal lobe epilepsy surgery.

Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

PubMed

Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

2017-08-01

The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

PubMed Central

Carter, Dawn S.; Harrison, Anne J.; Falenski, Katherine W.; Blair, Robert E.; DeLorenzo, Robert J.

2010-01-01

Summary Acquired epilepsy (AE) is characterized by spontaneous recurrent seizures and long-term changes that occur in surviving neurons following an injury such as status epilepticus (SE). Long-lasting alterations in hippocampal Ca2+ homeostasis have been observed in both in vivo and in vitro models of AE. One major regulator of Ca2+ homeostasis is the neuronal calcium binding protein, calbindin-D28k that serves to buffer and transport Ca2+ ions. This study evaluated the expression of hippocampal calbindin levels in the rat pilocarpine model of AE. Calbindin protein expression was reduced over 50% in the hippocampus in epileptic animals. This decrease was observed in the pyramidal layer of CA1, stratum lucidum of CA3, hilus, and stratum granulosum and stratum moleculare of the dentate gyrus when corrected for cell loss. Furthermore, calbindin levels in individual neurons were also significantly reduced. In addition, the expression of calbindin mRNA was decreased in epileptic animals. Time course studies demonstrated that decreased calbindin expression was initially present 1 month following pilocarpine-induced SE and lasted for up to 2 years after the initial episode of SE. The results indicate that calbindin is essentially permanently decreased in the hippocampus in AE. This decrease in hippocampal calbindin may be a major contributing factor underlying some of the plasticity changes that occur in epileptogenesis and contribute to the alterations in Ca2+ homeostasis associated with AE. PMID:18394865

Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES).

PubMed

Illingworth, Marjorie A; Hanrahan, Donncha; Anderson, Claire E; O'Kane, Kathryn; Anderson, Jennifer; Casey, Maureen; de Sousa, Carlos; Cross, J Helen; Wright, Sukvhir; Dale, Russell C; Vincent, Angela; Kurian, Manju A

2011-11-01

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Activity-induced and developmental downregulation of the Nogo receptor.

PubMed

Josephson, Anna; Trifunovski, Alexandra; Schéele, Camilla; Widenfalk, Johan; Wahlestedt, Claes; Brené, Stefan; Olson, Lars; Spenger, Christian

2003-03-01

The three axon growth inhibitory proteins, myelin associated glycoprotein, oligodendrocyte-myelin glycoprotein and Nogo-A, can all bind to the Nogo-66 receptor (NgR). This receptor is expressed by neurons with high amounts in regions of high plasticity where Nogo expression is also high. We hypothesized that simultaneous presence of high levels of Nogo and its receptor in neurons confers a locked state to hippocampal and cortical microcircuitry and that one or both of these proteins must be effectively and temporarily downregulated to permit plastic structural changes underlying formation of long-term memory. Hence, we subjected rats to kainic acid treatment and exposed rats to running wheels and measured NgR mRNA levels by quantitative in situ hybridization at different time points. We also studied spinal cord injuries and quantified NgR mRNA levels in spinal cord and ganglia during a critical postnatal period using real-time PCR. Strikingly, kainic acid led to a strong transient downregulation of NgR mRNA levels in gyrus dentatus, hippocampus, and neocortex during a time when BDNF mRNA was upregulated instead. Animals exposed to running wheels for 3 and 7, but not 1 or 21, days showed a significant downregulation of NgR mRNA in cortex, hippocampus and the dentate gyrus. NgR mRNA levels decreased from high to low expression in spinal cord and ganglia during the first week of life. No robust regulation of NgR was observed in the spinal cord following spinal cord injury. Together, our data show that NgR levels in developing and adult neurons are regulated in vivo under different conditions. Strong, rapid and transient downregulation of NgR mRNA in response to kainic acid and after wheel running in cortex and hippocampus suggests a role for NgR and Nogo-A in plasticity, learning and memory.

Wavelet analysis of epileptic spikes

NASA Astrophysics Data System (ADS)

Latka, Miroslaw; Was, Ziemowit; Kozik, Andrzej; West, Bruce J.

2003-05-01

Interictal spikes and sharp waves in human EEG are characteristic signatures of epilepsy. These potentials originate as a result of synchronous pathological discharge of many neurons. The reliable detection of such potentials has been the long standing problem in EEG analysis, especially after long-term monitoring became common in investigation of epileptic patients. The traditional definition of a spike is based on its amplitude, duration, sharpness, and emergence from its background. However, spike detection systems built solely around this definition are not reliable due to the presence of numerous transients and artifacts. We use wavelet transform to analyze the properties of EEG manifestations of epilepsy. We demonstrate that the behavior of wavelet transform of epileptic spikes across scales can constitute the foundation of a relatively simple yet effective detection algorithm.

Electroencephalography and phenytoin toxicity in mentally retarded epileptic patients.

PubMed Central

Iivanainen, M; Viukari, M; Seppäläinen, A M; Helle, E P

1978-01-01

There were significantly more diffuse and focal electroencephalographic abnormalities in 127 mentally retarded epileptic patients treated with phenytoin than in 68 epileptics without phenytoin. Phenytoin intoxication made the difference still more pronounced. Monitoring drug levels and electroencephalograms appears to be the method of choice for ensuring safe and effective medication in intractable epilepsy. PMID:632825

Behavioral deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats: effect of Bacopa monnieri and bacoside A.

PubMed

Mathew, Jobin; Peeyush Kumar, T; Khan, Reas S; Paulose, C S

2010-04-01

In the present study, the effects of Bacopa monnieri and its active component, bacoside A, on motor deficit and alterations of GABA receptor functional regulation in the cerebellum of epileptic rats were investigated. Scatchard analysis of [(3)H]GABA and [(3)H]bicuculline in the cerebellum of epileptic rats revealed a significant decrease in B(max) compared with control. Real-time polymerase chain reaction amplification of GABA(A) receptor subunits-GABA(Aalpha1), GABA(Aalpha5,) and GABA(Adelta)-was downregulated (P<0.001) in the cerebellum of epileptic rats compared with control rats. Epileptic rats exhibit deficits in radial arm and Y-maze performance. Treatment with B. monnieri and bacoside A reversed these changes to near-control levels. Our results suggest that changes in GABAergic activity, motor learning, and memory deficit are induced by the occurrence of repetitive seizures. Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity, motor learning, and memory deficit. Copyright (c) 2010 Elsevier Inc. All rights reserved.

The contribution of raised intraneuronal chloride to epileptic network activity.

PubMed

Alfonsa, Hannah; Merricks, Edward M; Codadu, Neela K; Cunningham, Mark O; Deisseroth, Karl; Racca, Claudia; Trevelyan, Andrew J

2015-05-20

Altered inhibitory function is an important facet of epileptic pathology. A key concept is that GABAergic activity can become excitatory if intraneuronal chloride rises. However, it has proved difficult to separate the role of raised chloride from other contributory factors in complex network phenomena, such as epileptic pathology. Therefore, we asked what patterns of activity are associated with chloride dysregulation by making novel use of Halorhodopsin to load clusters of mouse pyramidal cells artificially with Cl(-). Brief (1-10 s) activation of Halorhodopsin caused substantial positive shifts in the GABAergic reversal potential that were proportional to the charge transfer during the illumination and in adult neocortical pyramidal neurons decayed with a time constant of τ = 8.0 ± 2.8s. At the network level, these positive shifts in EGABA produced a transient rise in network excitability, with many distinctive features of epileptic foci, including high-frequency oscillations with evidence of out-of-phase firing (Ibarz et al., 2010). We show how such firing patterns can arise from quite small shifts in the mean intracellular Cl(-) level, within heterogeneous neuronal populations. Notably, however, chloride loading by itself did not trigger full ictal events, even with additional electrical stimulation to the underlying white matter. In contrast, when performed in combination with low, subepileptic levels of 4-aminopyridine, Halorhodopsin activation rapidly induced full ictal activity. These results suggest that chloride loading has at most an adjunctive role in ictogenesis. Our simulations also show how chloride loading can affect the jitter of action potential timing associated with imminent recruitment to an ictal event (Netoff and Schiff, 2002). Copyright © 2015 Alfonsa et al.

Recording epileptic activity with MEG in a light-weight magnetic shield.

PubMed

De Tiège, Xavier; Op de Beeck, Marc; Funke, Michael; Legros, Benjamin; Parkkonen, Lauri; Goldman, Serge; Van Bogaert, Patrick

2008-12-01

Ten patients with focal epilepsy were studied with magnetoencephalography (MEG) to determine if a new light-weight magnetically shielded room (lMSR) provides sufficient attenuation of magnetic interference to detect and localize the magnetic correlates of epileptic activity. Interictal MEG epileptic events co-localizing with the presumed location of the epileptogenic zone were found in all patients. MEG measurements performed in the lMSR provide an adequate signal-to-noise ratio for non-invasive localization of epileptic foci.

Behavioral deficit and decreased GABA receptor functional regulation in the hippocampus of epileptic rats: effect of Bacopa monnieri.

PubMed

Mathew, Jobin; Gangadharan, Gireesh; Kuruvilla, Korah P; Paulose, C S

2011-01-01

In the present study, alterations of the General GABA and GABA(A) receptors in the hippocampus of pilocarpine-induced temporal lobe epileptic rats and the therapeutic application of Bacopa monnieri and its active component Bacoside-A were investigated. Bacopa monnieri (Linn.) is a herbaceous plant belonging to the family Scrophulariaceae. Hippocampus is the major region of the brain belonging to the limbic system and plays an important role in epileptogenesis, memory and learning. Scatchard analysis of [³H]GABA and [³H]bicuculline in the hippocampus of the epileptic rat showed significant decrease in B(max) (P < 0.001) compared to control. Real Time PCR amplification of GABA(A) receptor sub-units such as GABA(Aά₁), GABA(Aά₅) GABA(Aδ), and GAD were down regulated (P < 0.001) in the hippocampus of the epileptic rats compared to control. GABA(Aγ) subunit was up regulated. Epileptic rats have deficit in the radial arm and Y maze performance. Bacopa monnieri and Bacoside-A treatment reverses all these changes near to control. Our results suggest that decreased GABA receptors in the hippocampus have an important role in epilepsy associated behavioral deficit, Bacopa monnieri and Bacoside-A have clinical significance in the management of epilepsy.

miRNA Expression profile after status epilepticus and hippocampal neuroprotection by targeting miR-132.

PubMed

Jimenez-Mateos, Eva M; Bray, Isabella; Sanz-Rodriguez, Amaya; Engel, Tobias; McKiernan, Ross C; Mouri, Genshin; Tanaka, Katsuhiro; Sano, Takanori; Saugstad, Julie A; Simon, Roger P; Stallings, Raymond L; Henshall, David C

2011-11-01

When an otherwise harmful insult to the brain is preceded by a brief, noninjurious stimulus, the brain becomes tolerant, and the resulting damage is reduced. Epileptic tolerance develops when brief seizures precede an episode of prolonged seizures (status epilepticus). MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators of gene expression. We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice. The miRNA was extracted from the ipsilateral CA3 subfield 24 hours after focal-onset status epilepticus in animals that had previously received either seizure preconditioning (tolerance) or no preconditioning (injury), and mature miRNA levels were measured using TaqMan low-density arrays. Expression of 21 miRNAs was increased, relative to control, after status epilepticus alone, and expression of 12 miRNAs was decreased. Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

GABAergic transmission facilitates ictogenesis and synchrony between CA3, hilus, and dentate gyrus in slices from epileptic rats

PubMed Central

Gafurov, Boris

2013-01-01

The impact of regional hippocampal interactions and GABAergic transmission on ictogenesis remain unclear. Cortico-hippocampal slices from pilocarpine-treated epileptic rats were compared with controls to investigate associations between seizurelike events (SLE), GABAergic transmission, and neuronal synchrony within and between cortico-hippocampal regions. Multielectrode array recordings revealed more prevalent hippocampal SLE in epileptic tissue when excitatory transmission was enhanced and GABAergic transmission was intact [removal of Mg2+ (0Mg)] than when GABAergic transmission was blocked [removal of Mg2+ + bicuculline methiodide (0Mg+BMI)]. When activity within individual regions was analyzed, spectral and temporal slow oscillation/SLE correlations and cross-correlations were highest within the hilus of epileptic tissue during SLE but were similar in 0Mg and 0Mg+BMI. GABAergic facilitation of spectral “slow” oscillation and ripple correlations was most prominent within CA3 of epileptic tissue during SLE. When activity between regions was analyzed, slow oscillation and ripple coherence was highest between the hilus and dentate gyrus as well as between the hilus and CA3 of epileptic tissue during SLE and was significantly higher in 0Mg than 0Mg+BMI. High 0Mg-induced SLE cross-correlations between the hilus and dentate gyrus as well as between the hilus and CA3 were reduced or abolished in 0Mg+BMI. SLE cross-correlation lag measurements provided evidence for a monosynaptic connection from the hilus to the dentate gyrus during SLE. Findings implicate the hilus as an oscillation generator, whose impact on other cortico-hippocampal regions is mediated by GABAergic transmission. Data also suggest that GABAA receptor-mediated transmission facilitates back-propagation from CA3/hilus to the dentate gyrus and that this back-propagation augments SLE in epileptic hippocampus. PMID:23615549

Effects of cell phone radiation on lipid peroxidation, glutathione and nitric oxide levels in mouse brain during epileptic seizure.

PubMed

Esmekaya, Meric Arda; Tuysuz, Mehmet Zahid; Tomruk, Arın; Canseven, Ayse G; Yücel, Engin; Aktuna, Zuhal; Keskil, Semih; Seyhan, Nesrin

2016-09-01

The objective of the this study was to evaluate the effects of cellular phone radiation on oxidative stress parameters and oxide levels in mouse brain during pentylenetetrazole (PTZ) induced epileptic seizure. Eight weeks old mice were used in the study. Animals were distributed in the following groups: Group I: Control group treated with PTZ, Group II: 15min cellular phone radiation+PTZ treatment+30min cellular phone radiation, Group III: 30min cellular phone radiation+PTZ treatment+30min cellular phone radiation. The RF radiation was produced by a 900MHz cellular phone. Lipid peroxidation, which is the indicator of oxidative stress was quantified by measuring the formation of thiobarbituric acid reactive substances (TBARS). The glutathione (GSH) levels were determined by the Ellman method. Tissue total nitric oxide (NOx) levels were obtained using the Griess assay. Lipid peroxidation and NOx levels of brain tissue increased significantly in group II and III compared to group I. On the contrary, GSH levels were significantly lower in group II and III than group I. However, no statistically significant alterations in any of the endpoints were noted between group II and Group III. Overall, the experimental findings demonstrated that cellular phone radiation may increase the oxidative damage and NOx level during epileptic activity in mouse brain. Copyright © 2016 Elsevier B.V. All rights reserved.

Clonazepam oral droplets for the treatment of acute epileptic seizures.

PubMed

Sakata, Osamu; Onishi, Hiraku; Machida, Yoshiharu

2008-12-01

Oral droplet formulations of clonazepam (CZ) were developed to examine their potentials as an alternative to i.v. administration for the treatment of acute epileptic seizures. Propylene glycol containing 2.5% (wt/wt) CZ with or without 5.0% (wt/wt) oleic acid (OA) was prepared as a solution by heating at 90 degrees C and subsequently lowering the temperature to 30 degrees C. The droplet (20 microL) was administered to the oral cavity between the lower gum and bottom lip before CZ precipitation started. With a droplet of propylene glycol loaded with 2.5% (wt/wt) CZ and 5.0% (wt/wt) OA, the plasma concentration reached 20 ng/mL (minimal effective concentration) within 10 min and was maintained between 20 and 60 ng/mL, less than a toxic level, for a period of 60 min. For a droplet of propylene glycol loaded only with CZ at 2.5% (wt/wt), it took more than 15 min for the plasma concentration to reach 20 ng/mL. It is suggested that a droplet of CZ/OA/propylene glycol (2.5:5.0:92.5, wt/wt) might be useful as an alternative to i.v. injection of CZ for the treatment of acute epileptic seizures.

Multifractal and wavelet analysis of epileptic seizures

NASA Astrophysics Data System (ADS)

Dick, Olga E.; Mochovikova, Irina A.

The aim of the study is to develop quantitative parameters of human electroencephalographic (EEG) recordings with epileptic seizures. We used long-lasting recordings from subjects with epilepsy obtained as part of their clinical investigation. The continuous wavelet transform of the EEG segments and the wavelet-transform modulus maxima method enable us to evaluate the energy spectra of the segments, to fin lines of local maximums, to gain the scaling exponents and to construct the singularity spectra. We have shown that the significant increase of the global energy with respect to background and the redistribution of the energy over the frequency range are observed in the patterns involving the epileptic activity. The singularity spectra expand so that the degree of inhomogenety and multifractality of the patterns enhances. Comparing the results gained for the patterns during different functional probes such as open and closed eyes or hyperventilation we demonstrate the high sensitivity of the analyzed parameters (the maximal global energy, the width and asymmetry of the singularity spectrum) for detecting the epileptic patterns.

Consciousness in Non-Epileptic Attack Disorder

PubMed Central

Reuber, M.; Kurthen, M.

2011-01-01

Non-epileptic attack disorder (NEAD) is one of the most important differential diagnoses of epilepsy. Impairment of consciousness is the key feature of non-epileptic attacks (NEAs). The first half of this review summarises the clinical research literature featuring observations relating to consciousness in NEAD. The second half places this evidence in the wider context of the recent discourse on consciousness in neuroscience and the philosophy of mind. We argue that studies of consciousness should not only distinguish between the ‘level’ and ‘content’ of consciousness but also between ‘phenomenal consciousness’ (consciousness of states it somehow “feels to be like”) and ‘access consciousness’ (having certain ‘higher’ cognitive processes at one’s disposal). The existing evidence shows that there is a great intra- and interindividual variability of NEA experience. However, in most NEAs phenomenal experience – and, as a precondition for that experience, vigilance or wakefulness – is reduced to a lesser degree than in those epileptic seizures involving impairment of consciousness. In fact, complete loss of “consciousness” is the exception rather than the rule in NEAs. Patients, as well as external observers, may have a tendency to overestimate impairments of consciousness during the seizures. PMID:21447903

Decreased GABA receptor in the striatum and spatial recognition memory deficit in epileptic rats: effect of Bacopa monnieri and bacoside-A.

PubMed

Mathew, Jobin; Soman, Smijin; Sadanandan, Jayanarayanan; Paulose, Cheramadathikudyil Skaria

2010-07-20

Gamma-aminobutyric acid A receptors are the principal mediators of synaptic inhibition in striatal neurons and play an important role in preventing the spreading of seizures through the striatum. In the present study, effect of Bacopa monnieri (L.) Pennel and its active component bacoside-A on spatial recognition memory deficit and alterations of GABA receptor in the striatum of epileptic rats were investigated. Total GABA and GABA(A) receptor numbers in the control and epileptic rats were evaluated using [(3)H]GABA and [(3)H]bicuculline binding. GABA(Aalpha1,) GABA(Aalpha5,) GABA(Agamma3) and GABA(Adelta) gene expressions were studied. Behavioral performance was assed using Y-maze. Scatchard analysis of [(3)H]GABA and [(3)H]bicuculline in the striatum of epileptic rats showed significant decrease in B(max) compared to control. Real-Time PCR amplification of GABA(A) receptor subunits such as GABA(Aalpha1,) GABA(Aalpha5) and GABA(Adelta), were down regulated (p<0.001) in the striatum of epileptic rats compared to control. Epileptic rats have deficit in Y-maze performance. Bacopa monnieri and bacoside-A treatment reversed these changes to near control. Our results suggest that decreased GABA receptors in the striatum have an important role in epilepsy associated motor learning deficits and Bacopa monnieri and bacoside-A has a beneficial effect in the management of epilepsy. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Potentiation of tonic GABAergic inhibition by activation of postsynaptic kainate receptors.

PubMed

Jiang, L; Kang, D; Kang, J

2015-07-09

Presynaptic kainate-type glutamate ionotropic receptors (KARs) that mediate either the depression or the facilitation of GABA release have been intensively studied. Little attention has been given to the modulation of GABAA receptors (GABAARs) by postsynaptic KARs. Recent studies suggest that two GABAAR populations, synaptic (sGABAAR) and extrasynaptic (eGABAAR) GABAARs, mediate phasic and tonic forms of inhibition, respectively. Tonic inhibition plays an important role in the excitability of neuronal circuits and the occurrence of epileptic seizures. For this study, we are the first to report that the activation of postsynaptic KARs by the KAR agonist, Kainic acid (KA, 5 μM), enhanced tonic inhibition by potentiating eGABAARs. KA enhanced THIP-induced eGABAAR currents and prolonged the rise and decay time of muscimol-induced sGABAAR/eGABAAR currents, but also depressed the amplitude of evoked inhibitory postsynaptic currents (IPSCs), unitary IPSCs (uIPSCs), and muscimol-induced sGABAAR/eGABAAR currents. The PKC inhibitor, staurosporine (1 μM), in the patch pipette solution fully blocked the KA-induced potentiation of tonic inhibition, suggesting the involvement of an intracellular PKC pathway. Our study suggests that the activation of postsynaptic KARs potentiates eGABAARs but depresses sGABAARs. By activating postsynaptic KARs, synaptically released glutamate depresses phasic inhibition to facilitate neuronal plasticity, but potentiates tonic inhibition to protect neurons from over-excitation. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Chronic deficit in the expression of voltage-gated potassium channel Kv3.4 subunit in the hippocampus of pilocarpine-treated epileptic rats

PubMed Central

Pacheco Otalora, Luis F.; Skinner, Frank; Oliveira, Mauro S.; Dotson, Bianca Farrel; Arshadmansab, Massoud F.; Pandari, Tarun; Garcia, Ileana; Robles, Leslie; Rosas, Gerardo; Mello, Carlos F.; Ermolinsky, Boris S.; Garrido-Sanabria, Emilio R.

2010-01-01

Voltage gated K+ channels (Kv) are a highly diverse group of channels critical in determining neuronal excitability. Deficits of Kv channel subunit expression and function have been implicated in the pathogenesis of epilepsy. In this study, we investigate whether the expression of the specific subunit Kv3.4 is affected during epileptogenesis following pilocarpine-induced status epilepticus. For this purpose, we used immunohistochemistry, Western blotting assays and comparative analysis of gene expression using TaqMan-based probes and delta-delta cycle threshold (Δ ΔCT) method of quantitative real-time polymerase chain reaction (qPCR) technique in samples obtained from age-matched control and epileptic rats. A marked down-regulation of Kv3.4 immunoreactivity was detected in the stratum lucidum and hilus of dentate gyrus in areas corresponding to the mossy fiber system of chronically epileptic rats. Correspondingly, a 20% reduction of Kv3.4 protein levels was detected in the hippocampus of chronic epileptic rats. Real-time quantitative PCR analysis of gene expression revealed that a significant 33% reduction of transcripts for Kv3.4 (gene Kcnc4) occurred after 1 month of pilocarpine-induced status epilepticus and persisted during the chronic phase of the model. These data indicate a reduced expression of Kv3.4 channels at protein and transcript levels in the epileptic hippocampus. Down-regulation of Kv3.4 in mossy fibers may contribute to enhanced presynaptic excitability leading to recurrent seizures in the pilocarpine model of temporal lobe epilepsy. PMID:20971086

Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures

PubMed Central

Kaminski, Rafal M.; Shippenberg, Toni S.; Witkin, Jeffrey M.; Rocha, Beatriz A.

2005-01-01

Norepinephrine (NE) has been reported to modulate neuronal excitability and act as endogenous anticonvulsant. In the present study we used NE transporter knock-out mice (NET-KO), which are characterized by high levels of extracellular NE, to investigate the role of endogenous NE in seizure susceptibility. Seizure thresholds for cocaine (i.p.), pentylenetetrazol (i.v.) and kainic acid (i.v.) were compared in NET-KO, heterozygous (NET-HT) and wild type (NET-WT) female mice. The dose-response curve for cocaine-induced convulsions was significantly shifted to the right in NET-KO mice, indicating higher seizure thresholds. The threshold doses of pentylenetetrazol that induced clonic and tonic seizures were also significantly higher in NET-KO when compared to NET-WT mice. Similarly, NET-KO mice displayed higher resistance to convulsions engendered by kainic acid. For all drugs tested, the response of NET-HT mice was always intermediate. These data provide further support for a role of endogenous NE in the control of seizure susceptibility. PMID:15911120

Surgical Treatment of Pediatric Epileptic Encephalopathies

PubMed Central

Fridley, J.; Reddy, G.; Curry, D.; Agadi, S.

2013-01-01

Pediatric epileptiform encephalopathies are a group of neurologically devastating disorders related to uncontrolled ictal and interictal epileptic activity, with a poor prognosis. Despite the number of pharmacological options for treatment of epilepsy, many of these patients are drug resistant. For these patients with uncontrolled epilepsy, motor and/or neuropsychological deterioration is common. To prevent these secondary consequences, surgery is often considered as either a curative or a palliative option. Magnetic resonance imaging to look for epileptic lesions that may be surgically treated is an essential part of the workup for these patients. Many surgical procedures for the treatment of epileptiform encephalopathies have been reported in the literature. In this paper the evidence for these procedures for the treatment of pediatric epileptiform encephalopathies is reviewed. PMID:24288601

Global Interactions Analysis of Epileptic ECoG Data

NASA Astrophysics Data System (ADS)

Ortega, Guillermo J.; Sola, Rafael G.; Pastor, Jesús

2007-05-01

Localization of the epileptogenic zone is an important issue in epileptology, even though there is not a unique definition of the epileptic focus. The objective of the present study is to test ultrametric analysis to uncover cortical interactions in human epileptic data. Correlation analysis has been carried out over intraoperative Electro-Corticography (ECoG) data in 2 patients suffering from temporal lobe epilepsy (TLE). Recordings were obtained using a grid of 20 electrodes (5×4) covering the lateral temporal lobe and a strip of either 4 or 8 electrodes at the mesial temporal lobe. Ultrametric analysis was performed in the averaged final correlation matrices. By using the matrix of linear correlation coefficients and the appropriate metric distance between pairs of electrodes time series, we were able to construct Minimum Spanning Trees (MST). The topological connectivity displayed by these trees gives useful and valuable information regarding physiological and pathological information in the temporal lobe of epileptic patients.

Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.

PubMed

Ihara, Yukiko; Tomonoh, Yuko; Deshimaru, Masanobu; Zhang, Bo; Uchida, Taku; Ishii, Atsushi; Hirose, Shinichi

2016-01-01

The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63-100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine's scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats

PubMed Central

Garrido-Sanabria, Emilio R.; Otalora, Luis F. Pacheco; Arshadmansab, Massoud F.; Herrera, Berenice; Francisco, Sebastian; Ermolinsky, Boris

2008-01-01

Group II metabotropic (mGlu II) receptor subtypes mGlu2 and mGlu3 are important modulators of synaptic plasticity and glutamate release in the brain. Accordingly, several pharmacological ligands have been designed to target these receptors for the treatment of neurological disorders characterized by anomalous glutamate regulation including epilepsy. In this study, we examine whether the expression level and function of mGlu2 and mGlu3 are altered in experimental epilepsy by using immunohistochemistry, Western blot analysis, RT-PCR and extracellular recordings. A down-regulation of mGlu2/3 protein expression at the mossy fiber pathway was associated with a significant reduction in mGlu2/3 protein expression in the hippocampus and cortex of chronically epileptic rats. Moreover, a reduction in mGlu2 and mGlu3 transcripts levels was noticed as early as 24h after pilocarpine-induced status epilepticus (SE) and persisted during subsequent “latent” and chronic periods. In addition, a significant impairment of mGlu II-mediated depression of field excitatory postsynaptic potentials at mossy fiber-CA3 synapses was detected in chronically epileptic rats. Application of mGlu II agonists (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) induced a significant reduction of the fEPSP amplitude in control rats, but not in chronic epileptic rats. These data indicate a long-lasting impairment of mGlu2/3 expression that may contribute to abnormal presynaptic plasticity, exaggerate glutamate release and hyperexcitability in temporal lobe epilepsy. PMID:18804094

Pancytopenia associated with levetiracetam in an epileptic woman.

PubMed

García Carretero, Rafael; Romero Brugera, Marta; Olid-Velilla, Monica; Salamanca-Ramirez, Inmaculada

2016-12-07

Haematological toxicity due to antiepileptic drugs is uncommon, but the increased risk of aplastic anaemia has been reported. Few case reports have been published regarding pancytopenia associated with levetiracetam treatment, and its intrinsic pathogenesis is still unknown. We describe the case of a woman aged 77 years who presented with abdominal pain and loss of appetite. She had been taking valproic acid, due to a previous episode of epileptic seizures, and presented with drowsiness and dizziness. Valproate was discontinued and therapy with levetiracetam was initiated. 2 days later, we observed severe anaemia, leucopenia and thrombocytopenia, which were attributed to levetiracetam. Although she recovered soon after the treatment was discontinued, it took 2 weeks for cell counts to return to normal. 2016 BMJ Publishing Group Ltd.

Models for discovery of targeted therapy in genetic epileptic encephalopathies.

PubMed

Maljevic, Snezana; Reid, Christopher A; Petrou, Steven

2017-10-01

Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies. © 2017 International Society for Neurochemistry.

Aminocaproic Acid and Tranexamic Acid Fail to Reverse Dabigatran-Induced Coagulopathy.

PubMed

Levine, Michael; Huang, Margaret; Henderson, Sean O; Carmelli, Guy; Thomas, Stephen H

In recent years, dabigatran has emerged as a popular alternative to warfarin for treatment of atrial fibrillation. If rapid reversal is required, however, no reversal agent has clearly been established. The primary purpose of this manuscript was to evaluate the efficacy of tranexamic acid and aminocaproic acid as agents to reverse dabigatran-induced coagulopathy. Rats were randomly assigned to 6 groups. Each rat received either dabigatran or oral placebo, followed by saline, tranexamic acid, or aminocaproic acid. An activated clotting test was used to measure the coagulopathy. Neither tranexamic acid nor aminocaproic acid successfully reversed dabigatran-induced coagulopathy. In this rodent model of dabigatran-induced coagulopathy, neither tranexamic acid nor aminocaproic acid were able to reverse the coagulopathy.

Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures.

PubMed

Töllner, Kathrin; Twele, Friederike; Löscher, Wolfgang

2016-04-01

Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Psychogenic Non-epileptic Seizures: An Updated Primer.

PubMed

Baslet, Gaston; Seshadri, Ashok; Bermeo-Ovalle, Adriana; Willment, Kim; Myers, Lorna

2016-01-01

Psychogenic non-epileptic seizures are the most common paroxysmal event misdiagnosed as epilepsy. They significantly affect quality of life, functional status, and use of medical resources. The goal of this review is to provide guidance to psychiatrists and other mental health professionals in the understanding and practical management of this condition. An abundance of new reports on the pathogenesis and effective treatments have become available over the last decade, yet specific barriers impede the fluid transition to treatment and remain an important challenge in the management of patients with psychogenic non-epileptic seizures. In the context of these difficulties, we initially present background information on psychogenic non-epileptic seizures covering their historic context, epidemiology, etiologic factors (including psychiatric, neuromedical, and neuropsychological factors), and current neurobiological models. Updated evidence-based treatments are discussed along with data on long-term outcomes. We also provide practical tools to help clinicians navigate differential diagnoses, establish their interdisciplinary roles, communicate the diagnosis, deliver treatment, and sort out commonly encountered challenges in the management of this condition. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus

PubMed Central

Chali, Farah; Djelti, Fathia; Eugene, Emmanuel; Valderrama, Mario; Marquer, Catherine; Aubourg, Patrick; Duykaerts, Charles; Miles, Richard; Cartier, Nathalie; Navarro, Vincent

2015-01-01

Elevations in neuronal cholesterol have been associated with several degenerative diseases. An enhanced excitability and synchronous firing in surviving neurons are among the sequels of neuronal death in these diseases and also in some epileptic syndromes. Here, we attempted to increase neuronal cholesterol levels, using a short hairpin RNA (shRNA) to suppress expression of the enzyme CYP46A1. This protein hydroxylates cholesterol and so facilitates trans-membrane extrusion. A sh-RNA CYP46A1construction coupled to an adeno-associated virus (AAV5) was injected focally and unilaterally into mouse hippocampus. It was selectively expressed first in neurons of the CA3a region. Cytoplasmic and membrane cholesterol increased, neuronal soma volume increased and then decreased before pyramidal cells died. As CA3a pyramidal cells died, inter-ictal EEG events occurred during exploration and non-REM sleep. With time, neuronal death spread to involve pyramidal cells and interneurons of the CA1 region. CA1 neuronal death was correlated with a delayed local expression of phosphorylated tau. Astrocytes were activated throughout the hippocampus and microglial activation was specific to regions of neuronal death. CA1 neuronal death was correlated with distinct aberrant EEG activity. During exploratory behaviour and rapid eye movement sleep, EEG oscillations at 7-10 Hz (theta) could accelerate to 14-21 Hz (beta) waves. They were accompanied by low amplitude, high-frequency oscillations of peak power at ~300Hz and a range of 250-350 Hz. While episodes of EEG acceleration were not correlated with changes in exploratory behaviour, they were followed in some animals by structured seizure-like discharges. These data strengthen links between increased cholesterol, neuronal sclerosis and epileptic behavior PMID:25847620

[Pharmacology of glutamate sensitive synapses (I). Glutamate agonists (author's transl)].

PubMed

Shinozaki, H

1982-04-01

The actions of kainic acid, quisqualic acid, and ibotenic acid on the crayfish neuromuscular junction were described, and it was particularly interesting that the discrepancy between glutamate responses and EJPs was revealed by the use of kainic acid. On the other hand, there is increasing evidence showing that glutamate is an excitatory transmitter at the crayfish neuromuscular junction. At this stage, we are unable as yet to definitively support or reject glutamate's candidacy as the excitatory transmitter at the crayfish neuromuscular junction. The discrepancy revealed by the use of kainic acid may bring up some questions. Certainly, the differential action of kainic acid on the glutamate current and the excitatory synaptic current opens to doubt the transmitter role of glutamate. In the case of the study on a transmitter role for a substance of doubt status, the value of pharmacological studies seems to be greater in disproving than in asserting such the role. However, we have to consider the matter of the extra-junctional receptor postulated on the crayfish postsynaptic membrane as one of the major problems for pharmacological identification.

Psycho-Social Aspects of Educating Epileptic Children: Roles for School Psychologists.

ERIC Educational Resources Information Center

Frank, Brenda B.

1985-01-01

Epileptic children may have physical and emotional needs which can interfere with learning and socialization. Current prevalence estimates, definitions, and classifications of epilepsy are surveyed. Factors affecting the epileptic child's school performance and specific learning problems are addressed. Specific roles are presented for school…

Loss of Hippocampal Neurons after Kainate Treatment Correlates with Behavioral Deficits

PubMed Central

Maia, Gisela H.; Quesado, José L.; Soares, Joana I.; do Carmo, Joana M.; Andrade, Pedro A.; Andrade, José P.; Lukoyanov, Nikolai V.

2014-01-01

Treating rats with kainic acid induces status epilepticus (SE) and leads to the development of behavioral deficits and spontaneous recurrent seizures later in life. However, in a subset of rats, kainic acid treatment does not induce overt behaviorally obvious acute SE. The goal of this study was to compare the neuroanatomical and behavioral changes induced by kainate in rats that developed convulsive SE to those who did not. Adult male Wistar rats were treated with kainic acid and tested behaviorally 5 months later. Rats that had experienced convulsive SE showed impaired performance on the spatial water maze and passive avoidance tasks, and on the context and tone retention tests following fear conditioning. In addition, they exhibited less anxiety-like behaviors than controls on the open-field and elevated plus-maze tests. Histologically, convulsive SE was associated with marked neuron loss in the hippocampal CA3 and CA1 fields, and in the dentate hilus. Rats that had not experienced convulsive SE after kainate treatment showed less severe, but significant impairments on the spatial water maze and passive avoidance tasks. These rats had fewer neurons than control rats in the dentate hilus, but not in the hippocampal CA3 and CA1 fields. Correlational analyses revealed significant relationships between spatial memory indices of rats and neuronal numbers in the dentate hilus and CA3 pyramidal field. These results show that a part of the animals that do not display intense behavioral seizures (convulsive SE) immediately after an epileptogenic treatment, later in life, they may still have noticeable structural and functional changes in the brain. PMID:24409306

Effect of epileptic seizures on the cerebrospinal fluid--A systematic retrospective analysis.

PubMed

Tumani, Hayrettin; Jobs, Catherine; Brettschneider, Johannes; Hoppner, Anselm C; Kerling, Frank; Fauser, Susanne

2015-08-01

Analyses of the cerebrospinal fluid (CSF) are obligatory when epileptic seizures manifest for the first time in order to exclude life-threatening causes or treatable diseases such as acute infections or autoimmune encephalitis. However, there are only few systematic investigations on the effect of seizures themselves on CSF parameters and the significance of these parameters in differential diagnosis. CSF samples of 309 patients with epileptic and 10 with psychogenic seizures were retrospectively analyzed. CSF samples were collected between 1999 and 2008. Cell counts, the albumin quotient, lactate and Tau-protein levels were determined. Findings were correlated with seizure types, seizure etiology (symptomatic, cryptogenic, occasional seizure), and seizure duration. Pathological findings were only observed in patients with epileptic but not with psychogenic seizures. The lactate concentration was elevated in 14%, the albumin quotient in 34%, and the Tau protein level in 36% of CSF samples. Cell counts were only slightly elevated in 6% of patients. Different seizure types influenced all parameters except for the cell count: In status epilepticus highest, in simple partial seizures lowest values were seen. Symptomatic partial and generalized epileptic seizures had significantly higher Tau-protein levels than cryptogenic partial seizures. In patients with repetitive and occasional epileptic seizures, higher Tau-protein levels were seen than in those with psychogenic seizures. Duration of epileptic seizures was positively correlated with the albumin quotient, lactate and Tau-protein levels. High variability of investigated CSF parameters within each subgroup rendered a clear separation between epileptic and psychogenic seizures impossible. Elevated cell counts are infrequently observed in patients with epileptic seizures and should therefore not uncritically be interpreted as a postictal phenomenon. However, blood-CSF barrier disruption, increased glucose metabolism

Epileptic Seizure Prediction Using a New Similarity Index for Chaotic Signals

NASA Astrophysics Data System (ADS)

Niknazar, Hamid; Nasrabadi, Ali Motie

Epileptic seizures are generated by abnormal activity of neurons. The prediction of epileptic seizures is an important issue in the field of neurology, since it may improve the quality of life of patients suffering from drug resistant epilepsy. In this study a new similarity index based on symbolic dynamic techniques which can be used for extracting behavior of chaotic time series is presented. Using Freiburg EEG dataset, it is found that the method is able to detect the behavioral changes of the neural activity prior to epileptic seizures, so it can be used for prediction of epileptic seizure. A sensitivity of 63.75% with 0.33 false positive rate (FPR) in all 21 patients and sensitivity of 96.66% with 0.33 FPR in eight patients were achieved using the proposed method. Moreover, the method was evaluated by applying on Logistic and Tent map with different parameters to demonstrate its robustness and ability in determining similarity between two time series with the same chaotic characterization.

Complementary treatment of psychotic and epileptic patients in malaysia.

PubMed

Razali, Salleh Mohd; Yassin, Azhar Mohd

2008-09-01

The objective of this article is to describe and compare the use of traditional/complementary medicine (T/CM) among psychotic (schizophrenia and schizophreniform disorder) and epileptic Malay patients in peninsular Malaysia. There were 60 patients in each group. T/CM consultation was uniformly spread across all levels of education and social status. We could not find a single over-riding factor that influenced the decision to seek T/CM treatment because the decision to seek such treatment was complex and the majority of decisions were made by others. Fifty-three patients (44.2%), consisting of 37 (61.7%) psychotic and 16 (26.7%) epileptic patients had consulted Malay traditional healers (bomoh) and/or homeopathic practitioners in addition to modern treatment; of these, only three had consulted bomoh and homeopathic practitioners at the same time. The use of T/CM was significantly higher in psychotic than in epileptic Malay patients.

The ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies.

PubMed

Ville, Dorothée; Chiron, Catherine; Laschet, Jacques; Dulac, Olivier

2015-07-01

Hormonal therapy or ketogenic diet often permits overcoming the challenging periods of many epileptic encephalopathies (West and Lennox-Gastaut syndromes and encephalopathy with continuous spike-waves in slow sleep), but relapse affects over 20% of patients. We report here a monocenter pilot series of 42 consecutive patients in whom we combined oral steroids with the ketogenic diet for corticosteroid-resistant or -dependent epileptic encephalopathy. We retrospectively evaluated the effect on seizure frequency, interictal spike activity, neuropsychological course, and steroid treatment course. Twenty-three patients had West syndrome (WS), 13 had encephalopathy with continuous spike-waves in slow sleep (CSWS), and six others had miscellaneous epileptic encephalopathies. All patients succeeded to reach 0.8 to 1.6g/l ketone bodies in the urine following the usual KD regimen. For at least 6 months, 14/42 responded to the addition of the ketogenic diet: 4/23 with WS, 8/13 with CSWS, and 2/6 with miscellaneous epileptic encephalopathies. The addition of the KD allowed withdrawing steroids in all responders. Among them, 10/15 had been patients with steroid-dependent epileptic encephalopathy and 4/27 patients with steroid-resistant epileptic encephalopathy. Therefore, the ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. Patients presenting with steroid-dependent CSWS seem to be the best candidates. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparative study of nonlinear properties of EEG signals of normal persons and epileptic patients

PubMed Central

2009-01-01

Background Investigation of the functioning of the brain in living systems has been a major effort amongst scientists and medical practitioners. Amongst the various disorder of the brain, epilepsy has drawn the most attention because this disorder can affect the quality of life of a person. In this paper we have reinvestigated the EEGs for normal and epileptic patients using surrogate analysis, probability distribution function and Hurst exponent. Results Using random shuffled surrogate analysis, we have obtained some of the nonlinear features that was obtained by Andrzejak et al. [Phys Rev E 2001, 64:061907], for the epileptic patients during seizure. Probability distribution function shows that the activity of an epileptic brain is nongaussian in nature. Hurst exponent has been shown to be useful to characterize a normal and an epileptic brain and it shows that the epileptic brain is long term anticorrelated whereas, the normal brain is more or less stochastic. Among all the techniques, used here, Hurst exponent is found very useful for characterization different cases. Conclusion In this article, differences in characteristics for normal subjects with eyes open and closed, epileptic subjects during seizure and seizure free intervals have been shown mainly using Hurst exponent. The H shows that the brain activity of a normal man is uncorrelated in nature whereas, epileptic brain activity shows long range anticorrelation. PMID:19619290

The functional organization of human epileptic hippocampus

PubMed Central

Klimes, Petr; Duque, Juliano J.; Brinkmann, Ben; Van Gompel, Jamie; Stead, Matt; St. Louis, Erik K.; Halamek, Josef; Jurak, Pavel

2016-01-01

The function and connectivity of human brain is disrupted in epilepsy. We previously reported that the region of epileptic brain generating focal seizures, i.e., the seizure onset zone (SOZ), is functionally isolated from surrounding brain regions in focal neocortical epilepsy. The modulatory effect of behavioral state on the spatial and spectral scales over which the reduced functional connectivity occurs, however, is unclear. Here we use simultaneous sleep staging from scalp EEG with intracranial EEG recordings from medial temporal lobe to investigate how behavioral state modulates the spatial and spectral scales of local field potential synchrony in focal epileptic hippocampus. The local field spectral power and linear correlation between adjacent electrodes provide measures of neuronal population synchrony at different spatial scales, ∼1 and 10 mm, respectively. Our results show increased connectivity inside the SOZ and low connectivity between electrodes in SOZ and outside the SOZ. During slow-wave sleep, we observed decreased connectivity for ripple and fast ripple frequency bands within the SOZ at the 10 mm spatial scale, while the local synchrony remained high at the 1 mm spatial scale. Further study of these phenomena may prove useful for SOZ localization and help understand seizure generation, and the functional deficits seen in epileptic eloquent cortex. PMID:27030735

The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats.

PubMed

Osgood, Doreen B; Harrington, William F; Kenney, Elizabeth V; Harrington, J Frederick

2013-01-01

The authors have previously demonstrated that human herniated disc material contains high concentrations of free glutamate. In an experimental model, elevated epidural glutamate concentrations in the lumbar spine can cause a focal hyperesthetic state. Rats underwent epidural glutamate infusion in the lumbar spine by a miniosmotic pump over a 72-hour period. Some rats underwent coinfusion with glutamate and ionotropic glutamate antagonists. Nociception was assessed by von Frey fibers and by assessment of glutamate receptor expression in the corresponding dorsal horn of the spinal cord. The kainic acid antagonist, UBP 301, decreased epidural glutamate-based hyperesthesia in a dose dependent manner. Concordant with these findings, there was significant decrease in kainate receptor expression in the dorsal horn. The N-Methyl-4-isoxazoleproionic acid (NMDA) antagonist Norketamine also significantly diminished hyperesthesia and decreased receptor expression in the dorsal horn. Both UBP 301, the kainic acid receptor antagonist and Norketamine, an NMDA receptor antagonist, dampened epidural glutamate-based nociception. Focal epidural injections of Kainate or NMDA receptor antagonists could be effective treatments for disc herniation-based lumbar radiculopathy.

Patterns of human local cerebral glucose metabolism during epileptic seizures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Engel, J. Jr.; Kuhl, D.E.; Phelps, M.E.

1982-10-01

Ictal patterns of local cerebral metabolic rate have been studied in epileptic patients by positron computed tomography with /sup 18/F-labeled 2-fluoro-2-deoxy-D-glucose. Partial seizures were associated with activation of anatomic structures unique to each patient studied. Ictal increases and decreases in local cerebral metabolism were observed. Scans performed during generalized convulsions induced by electroshock demonstrated a diffuse ictal increase and postictal decrease in cerebral metabolism. Petit mal absences were associated with a diffuse increase in cerebral metabolic rate. The ictal fluorodeoxyglucose patterns obtained from patients do not resemble autoradiographic patterns obtained from common experimental animal models of epilepsy.

Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy.

PubMed

Zhao, Junli; Wang, Yi; Xu, Cenglin; Liu, Keyue; Wang, Ying; Chen, Liying; Wu, Xiaohua; Gao, Feng; Guo, Yi; Zhu, Junming; Wang, Shuang; Nishibori, Masahiro; Chen, Zhong

2017-08-01

Brain inflammation is a major factor in epilepsy, and the high mobility group box-1 (HMGB1) protein is known to contribute significantly to the generation of seizures. Here, we investigated the therapeutic potential of an anti-HMGB1 monoclonal antibody (mAb) in epilepsy. anti-HMGB1 mAb attenuated both acute seizure models (maximal electroshock seizure, pentylenetetrazole-induced and kindling-induced), and chronic epilepsy model (kainic acid-induced) in a dose-dependent manner. Meanwhile, the anti-HMGB1 mAb also attenuated seizure activities of human brain slices obtained from surgical resection from drug-resistant epilepsy patients. The mAb showed an anti-seizure effect with a long-term manner and appeared to be minimal side effects at even very high dose (no disrupted physical EEG rhythm and no impaired basic physical functions, such as body growth rate and thermoregulation). This anti-seizure effect of mAb results from its inhibition of translocated HMGB1 from nuclei following seizures, and the anti-seizure effect was absent in toll-like receptor 4 knockout (TLR4 -/- ) mice. Interestingly, the anti-HMGB1 mAb also showed a disease-modifying anti-epileptogenetic effect on epileptogenesis after status epileptics, which is indicated by reducing seizure frequency and improving the impaired cognitive function. These results indicate that the anti-HMGB1 mAb should be viewed as a very promising approach for the development of novel therapies to treat refractory epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuroprotective Mechanisms Activated in Non-seizing Rats Exposed to Sarin

DTIC Science & Technology

2015-06-04

after kainic acid-induced seizures. Brain Res. 1424, 1–8. Johnson, E.A., Kan, R.K., 2010. The acute phase response and soman-induced status epilepticus ...2011. Comparison of status epilepticus models induced by pilocarpine and nerve agents – a systematic review of the underlying aetiology and adopted...2007) Nqo2 Loss of Nqo1 and Nqo2 leads to altered intracellular redox status , decreased expression and activation of NF-κB, and altered

Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

PubMed

Muzaffar, Suhail; Chattoo, Bharat B

2017-03-01

Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

Epileptic spasms are a feature of DEPDC5 mTORopathy

PubMed Central

Carvill, Gemma L.; Crompton, Douglas E.; Regan, Brigid M.; McMahon, Jacinta M.; Saykally, Julia; Zemel, Matthew; Schneider, Amy L.; Dibbens, Leanne; Howell, Katherine B.; Mandelstam, Simone; Leventer, Richard J.; Harvey, A. Simon; Mullen, Saul A.; Berkovic, Samuel F.; Sullivan, Joseph; Scheffer, Ingrid E.

2015-01-01

Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. Results: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies. PMID:27066554

Kainate-induced network activity in the anterior cingulate cortex.

PubMed

Shinozaki, R; Hojo, Y; Mukai, H; Hashizume, M; Murakoshi, T

2016-06-14

Anterior cingulate cortex (ACC) plays a pivotal role in higher order processing of cognition, attention and emotion. The network oscillation is considered an essential means for integration of these CNS functions. The oscillation power and coherence among related areas are often dis-regulated in several psychiatric and pathological conditions with a hemispheric asymmetric manner. Here we describe the network-based activity of field potentials recorded from the superficial layer of the mouse ACC in vitro using submerged type recordings. A short activation by kainic acid administration to the preparation induced populational activities ranging over several frequency bands including theta (3-8Hz), alpha (8-12Hz), beta (13-30Hz), low gamma (30-50Hz) and high gamma (50-80Hz). These responses were repeatable and totally abolished by tetrodotoxin, and greatly diminished by inhibitors of ionotropic and metabotropic glutamate receptors, GABAA receptor or gap-junctions. These observations suggest that the kainate-induced network activity can be a useful model of the network oscillation in the ACC circuit. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Guanosine may increase absence epileptic activity by means of A2A adenosine receptors in Wistar Albino Glaxo Rijswijk rats.

PubMed

Lakatos, Renáta Krisztina; Dobolyi, Árpád; Todorov, Mihail Ivilinov; Kékesi, Katalin A; Juhász, Gábor; Aleksza, Magdolna; Kovács, Zsolt

2016-06-01

The non-adenosine nucleoside guanosine (Guo) was demonstrated to decrease quinolinic acid(QA)-induced seizures, spontaneously emerged absence epileptic seizures and lipopolysaccharide(LPS)-evoked induction of absence epileptic seizures suggesting its antiepileptic potential. It was also described previously that intraperitoneal (i.p.) injection of 20 and 50mg/kg Guo decreased the number of spike-wave discharges (SWDs) in a well investigated model of human absence epilepsy, the Wistar Albino Glaxo Rijswijk (WAG/Rij) rats during 4th (20mg/kg Guo) and 3rd as well as 4th (50mg/kg Guo) measuring hours. Guanosine can potentially decrease SWD number by means of its putative receptors but absence epileptic activity changing effects of Guo by means of increased extracellular adenosine (Ado) cannot be excluded. An increase in the dose of i.p. injected Guo is limited by its low solubility in saline, therefore, we addressed in the present study whether higher doses of Guo, diluted in sodium hydroxide (NaOH) solution, have more potent antiepileptic effect in WAG/Rij rats. We confirmed that i.p. 50mg/kg Guo decreased but, surprisingly, i.p. 100mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5mg/kg) or a selective Ado A2A receptor (A2AR) antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) (1mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10mg/kg) with 100mg/kg Guo decreased the SWD number compared to i.p. 100mg/kg Guo alone. The results suggest that i.p. 100mg/kg Guo can increase SWD number by means of the adenosinergic system. Copyright © 2016 Elsevier Inc. All rights reserved.

Syndrome of Electrical Status Epilepticus During Sleep: Epileptic Encephalopathy Related to Brain Development.

PubMed

Chen, Xiao-Qiao; Zhang, Wei-Na; Hu, Lin-Yan; Liu, Meng-Jia; Zou, Li-Ping

2016-03-01

Epileptic encephalopathy with electrical status epilepticus during sleep is an age-related and self-limited disorder. The present study analyzed the etiology, demographics, and pathogenesis of patients with electrical status epilepticus during sleep to provide information on the diagnosis and therapy of this syndrome. The etiologies of epileptic encephalopathy with electrical status epilepticus during sleep in patients admitted in Chinese People's Liberation Army General Hospital from 2009 to 2014 were retrospectively analyzed. Patients were classified into the genetic, structural-metabolic, and unknown groups according to the etiology. Demographics and clinical characteristics of all the patients were then analyzed and compared among groups. The etiologies of epileptic encephalopathy with electrical status epilepticus during sleep in 75 patients mainly included benign childhood epilepsy with centrotemporal spikes, Landau-Kleffner syndrome, polymicrogyria, and migration disorders. Age at onset of epilepsy did not show a specific pattern, but age at onset of epileptic encephalopathy with electrical status epilepticus during sleep was concentrated at age 6-9 years. The mean age at onset of epilepsy in the genetic group was significantly older than that in the structural-metabolic group (P < 0.05). Age at onset of epileptic encephalopathy with electrical status epilepticus during sleep did not significantly differ between the two groups. Electrical status epilepticus during sleep is an epileptic encephalopathy related to brain development and presents an age-dependent occurrence. Copyright © 2016 Elsevier Inc. All rights reserved.

Ketogenic diet efficacy in the treatment of intractable epileptic spasms.

PubMed

Kayyali, Husam R; Gustafson, Megan; Myers, Tara; Thompson, Lindsey; Williams, Michelle; Abdelmoity, Ahmad

2014-03-01

To determine the efficacy of the ketogenic diet in controlling epileptic spasms after failing traditional antiepileptic medication therapy. This is a prospective, case-based study of all infants with epileptic spasms who were referred for treatment with the ketogenic diet at our hospital between 2009 and 2012. All subjects continued to have epileptic spasms with evidence of hypsarrhythmia or severe epileptic encephalopathy on electroencephalography despite appropriate medication treatments. The diet efficacy was assessed through clinic visits, phone communications, and electroencephalography. Quality of life improvement was charted based on the caregiver's perspective. Twenty infants (15 males) were included in the study. The mean age at seizure onset was 4.5 months. Age at ketogenic diet initiation was 0.3 to 2.9 years (mean 1.20, standard deviation 0.78). Fifteen patients had epileptic spasms of unknown etiology; three had perinatal hypoxic ischemic encephalopathy, one had lissencephaly, and one had STXBP1 mutation. Fifteen infants failed to respond to adrenocorticotropin hormone and/or vigabatrin before going on the ketogenic diet. Three months after starting the diet, >50% seizure reduction was achieved in 70% of patients (95% CI 48-86). These results were maintained at 6- and 12-month intervals. All eight of the patients followed for 24 months had >50% seizure reduction (95% CI 63-100). At least 90% seizure reduction was reported in 20% of patients at 3 months (95% CI 7-42), 22% (95% CI 8-46) at 6 months, and 35% (95% CI 17-59) at 12 months. The majority of patients (63%) achieved improvement of their spasms within 1 month after starting the diet. Sixty percent of patients had electroencephalographic improvement. All caregivers reported improvement of the quality of life at the 3-month visit (95% confidence interval 81-100). This ratio was 94% at 6 months (95% CI 72-99) and 82% at 12 months (95% CI 58-95). The ketogenic diet is a safe and potentially

Neuronal activity-induced regulation of Lingo-1.

PubMed

Trifunovski, Alexandra; Josephson, Anna; Ringman, Andreas; Brené, Stefan; Spenger, Christian; Olson, Lars

2004-10-25

Axonal regeneration after injury can be limited in the adult CNS by the presence of inhibitory proteins such as Nogo. Nogo binds to a receptor complex that consists of Nogo receptor (NgR), p75NTR, and Lingo-1. Nogo binding activates RhoA, which inhibits axonal outgrowth. Here we assessed Lingo-1 and NgR mRNA levels after delivery of BDNF into the rat hippocampal formation, Lingo-1 mRNA levels in rats subjected to kainic acid (KA) and running in running wheels. Lingo-1 mRNA was not changed by running. However, we found that Lingo-1 mRNA was strongly up-regulated while NgR mRNA was down-regulated in the dentate gyrus in both the BDNF and the KA experiments. Our data demonstrate inverse regulation of NgR and Lingo-1 in these situations, suggesting that Lingo-1 up-regulation is one characteristic of activity-induced neural plasticity responses.

Intra-hippocampal microinjection of oxytocin produced antiepileptic effect on the pentylenetetrazol-induced epilepsy in rats.

PubMed

Erfanparast, Amir; Tamaddonfard, Esmaeal; Henareh-Chareh, Farzin

2017-08-01

In addition to its role as a circulating hormone, oxytocin can also act as a neurotransmitter and a neuromodulator within the brain. In this study, we investigated the intra-hippocampal effect of oxytocin on an experimental seizure model induced by pentylenetetrazole (PTZ) in rats. We also used atosiban (oxytocin antagonist), diazepam and flumazenil (gamma-aminobutyric acid or GABA-benzodiazepine receptor agonist and antagonist, respectively) to clarify the involved mechanism. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Epileptic behaviors were induced by intraperitoneal (ip) injection of PTZ (60mg/kg), and the latency time to onset of first myoclonic jerk, and the duration of epileptic seizures were determined for 30min. Intra-hippocampal microinjections of oxytocin at doses of 10 and 20ng/site, diazepam (100 and 200ng/site) and co-administration of their ineffective doses significantly (p<0.01) increased the onset of first myoclonic jerk and decreased duration of epileptic seizure. Antiepileptic effects of oxytocin (20ng/site) were inhibited by atosiban (20 and 40ng/site) and flumazenil (100 and 200ng/site) pretreatments. On the other hand, prior administration of flumazenil (100 and 200ng/site) and atosiban (20 and 40ng/site) prevented the antiepileptic effects induced by diazepam (100 and 200ng/site). The results of the present study showed that at the level of the hippocampus oxytocin suppressed the severity of epileptic behaviors. A hippocampal GABA-benzodiazepine receptor mechanism may be involved in antiepileptic effect of oxytocin. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Effects of valproate on the carotid artery intima-media thickness in epileptics.

PubMed

Luo, Xinming; Zhang, Ming; Deng, Liying; Zhao, Jing

2015-01-01

The objective was to explore the effects of valproate (VPA) on the carotid artery intima-media thickness (CA-IMT) in epileptics. A total of 30 epileptic patients treated with VPA was included as disease group, while 33 healthy people who matched general basic demographic details were the control group. The IMTs of the left and right carotids of the both groups were measured, and the average CA-IMT was calculated. The IMT-related risk factors were acquired for the univariate and multivariate analysis. The bilateral carotid and average CA-IMTs of the disease group were significantly higher than the control group (P < 0.001). The multivariant gradual regressive analysis screened out two CA-IMT-related factors, namely the disease duration and the drug administration duration were positively correlated with the average CA-IMT. The epileptic patients with disease course of more than 3 years had much higher average CA-IMT than that of the epileptics with ≤3 years disease (P < 0.001). The average CA-IMT of the patients with VPA-administration duration >1 year was also higher than that of the patients with VPA-administration duration <1 year, while the difference was not statistically significant (P = 0.196). The average CA-IMT of the epileptic patients treated with VPA was higher than that of healthy people.

Relations between epileptic seizures and headaches.

PubMed

Gameleira, Fernando Tenório; Ataíde, Luiz; Raposo, Maria Cristina Falcão

2013-10-01

To describe headaches in patients with epilepsy and try to identify relations between epileptic seizures and headaches. Cross-sectional study, with 304 patients from the epilepsy out-patient section of University Hospital of Federal University of Alagoas (Brazil) between February 2007 and February 2008. The presence of headaches and their relationships with the epileptic seizures were analyzed. Frequent seizures were associated with a greater tendency of occurrence of headaches (odds ratio=1.6 times, p=0.077). Headaches occurred in 66.1% of the cases. The highest occurrence was of migraine (32.9% of the patients), followed by tension-type headaches (9.2%). Two syndromes with a continuum epilepsy-migraine in the same seizure are worth mentioning: migralepsy in 6.6% and epilepgraine in 10.2% of the patients with epilepsy. A high prevalence of headaches in patients with epilepsy was observed, with emphasis on hybrid crises of epilepsy and migraine. Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Long-term variability of global statistical properties of epileptic brain networks

NASA Astrophysics Data System (ADS)

Kuhnert, Marie-Therese; Elger, Christian E.; Lehnertz, Klaus

2010-12-01

We investigate the influence of various pathophysiologic and physiologic processes on global statistical properties of epileptic brain networks. We construct binary functional networks from long-term, multichannel electroencephalographic data recorded from 13 epilepsy patients, and the average shortest path length and the clustering coefficient serve as global statistical network characteristics. For time-resolved estimates of these characteristics we observe large fluctuations over time, however, with some periodic temporal structure. These fluctuations can—to a large extent—be attributed to daily rhythms while relevant aspects of the epileptic process contribute only marginally. Particularly, we could not observe clear cut changes in network states that can be regarded as predictive of an impending seizure. Our findings are of particular relevance for studies aiming at an improved understanding of the epileptic process with graph-theoretical approaches.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals.

PubMed

Singh, Tanveer; Bagga, Neetu; Kaur, Anureet; Kaur, Navjot; Gawande, Dinesh Yugraj; Goel, Rajesh Kumar

2017-08-01

Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits. The animals were made epileptic employing pentylenetetrazole (35mg/kg i.p. every 48±2h) kindling model of epilepsy and subsequently were treated with vehicle, valproic acid (300mg/kg/day i.p.) and agmatine (2.5, 5, and 10mg/kg)/day/i.p. for 15days. Except naïve, all the groups were challenged with same pentylenetetrazole dose as employed during kindling on days 5, 10, and 15 to evaluate seizure severity. Two hours after seizure severity test, tail suspension test and passive shock avoidance paradigm was employed to evaluate depression and cognitive behavior respectively. Results suggested that epileptic animals were significantly associated with depression and cognitive impairment. Chronic valproate treatment significantly reduced seizure severity, but was found unable to mitigate depression and cognitive deficits. However, agmatine treatment dose dependently ameliorated seizure severity as well as associated depression and cognitive deficits. On 15th day, animals were euthanized and pertinent neurochemical estimations were carried out in cortical and hippocampal areas of the mice brain. Thus, study concluded that agmatine ameliorated seizure severity, depression and cognitive impairment in epileptic animals, possibly via restoring glutamate-GABA neurotransmission and serotonin synthesis with decreased nitrosative stress. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Neuroscience. Stout guards of the central nervous system.

PubMed

Mechoulam, R; Lichtman, A H

2003-10-03

Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. In their Perspective, Mechoulam and Lichtman discuss new work (Marsicano et al.) showing that activation of the cannabinoid receptor CB1 by the endocannabinoid anandamide protects against excitotoxic damage in a mouse model of kainic acid-induced epilepsy.

A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5.

PubMed

Saitsu, Hirotomo; Osaka, Hitoshi; Nishiyama, Kiyomi; Tsurusaki, Yoshinori; Doi, Hiroshi; Miyake, Noriko; Matsumoto, Naomichi

2012-05-01

Recent studies have shown that aberrations of CDKL5 in female patients cause early-onset intractable seizures, severe developmental delay or regression, and Rett syndrome-like features. We report on a Japanese girl with early-onset epileptic encephalopathy, hypotonia, developmental regression, and Rett syndrome-like features. The patient showed generalized tonic seizures, and later, massive myoclonus induced by phone and light stimuli. Brain magnetic resonance imaging showed no structural brain anomalies but cerebral atrophy. Electroencephalogram showed frontal dominant diffuse poly spikes and waves. Through copy number analysis by genomic microarray, we found a microdeletion at Xp22.13. A de novo 137-kb deletion, involving exons 5-21 of CDKL5, RS1, and part of PPEF1 gene, was confirmed by quantitative PCR and breakpoint specific PCR analyses. Our report suggests that the clinical features associated with CDKL5 deletions could be implicated in Japanese patients, and that genetic testing of CDKL5, including both sequencing and deletion analyses, should be considered in girls with early-onset epileptic encephalopathy and RTT-like features. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PubMed

Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

2015-02-01

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

2D Raman study of the healthy and epileptic rat cerebellar cortex tissue

NASA Astrophysics Data System (ADS)

Sacharz, Julia; Wesełucha-Birczyńska, Aleksandra; Zięba-Palus, Janina; Lewandowski, Marian H.; Palus-Chramiec, Katarzyna; Chrobok, Łukasz; Moskal, Paulina; Birczyńska, Malwina; Sozańska, Agnieszka

2018-07-01

The aim of this study was to determine what changes in the Cerebellar cortex (Cc) of the rat's brain tissue can be observed by Raman spectroscopy comparing epileptic (WAG/Rij) and control (Wistar) rats. Experiments were performed on the brain slices obtained from male rats (2-3 weeks old). WAG/Rij rats, used in this study, represent the well-established model of epilepsy. The Raman spectra of the fresh, not additionally preserved brain scraps, kept in artificial cerebrospinal fluid, were collected using a 442 nm, 514.5 nm, 785 nm and 1064 nm laser lines as an excitation source. 2D correlation analysis was used to create two-dimensional (2D) spectra and wavelength of the excitation laser was regarded as an external stimulus. Differences in the 2D spectra of two investigated groups of rats were observed. Analysis of the intensity ratios of the respective marker Raman bands indicated close packing between the lipid chains in a healthy Cerebellar cortex tissue. In asynchronous maps of healthy tissue the cross-peaks of Trp and Tyr vibration, that are neurotransmitters' precursors, are recognized. In the epileptic tissue, the amino acids glutamate (Glu) and aspartate (Asp), excitatory neurotransmitters, initiate changes observed in the asynchronous map.

Laboratory findings in neurosyphilis patients with epileptic seizures alone as the initial presenting symptom.

PubMed

Tong, Man-Li; Liu, Li-Li; Zeng, Yan-Li; Zhang, Hui-Lin; Liu, Gui-Li; Zheng, Wei-Hong; Dong, Jie; Wu, Jing-Yi; Su, Yuan-Hui; Lin, Li-Rong; Yang, Tian-Ci

2013-04-01

A retrospective chart review was performed to characterize the clinical presentation, the characteristic combination of serologic and cerebrospinal fluid (CSF) abnormalities, and the neuroimaging findings of neurosyphilis (NS) patients who had epileptic seizures alone as an initial presenting symptom. In a 6.75-year period, 169 inpatients with NS were identified at Zhongshan Hospital (from June 2005 to February 2012). We demonstrated that 13 (7.7%) of the 169 NS patients had epileptic seizures alone as an initial presenting feature. Epileptic seizures occurred in NS patients with syphilitic meningitis (2 cases), meningovascular NS (5 cases), and general paresis (6 cases). The types of epileptic seizures included simple partial, complex partial with secondary generalization (including status epilepticus), and generalized seizures (no focal onset reported). Nine of NS patients with only epileptic seizures as primary symptom were misdiagnosed, and the original misdiagnosis was 69.23% (9/13). Ten (10/13, 76.9%) patients had an abnormal magnetic resonance imaging, and 7 (7/13 53.8%) patients had abnormal electroencephalogram recordings. In addition, the sera rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) from all 13 patients were positive. The overall positive rates of the CSF-RPR and CSF-TPPA were 61.5% and 69.2%, respectively. Three patients demonstrated CSF pleocytosis, and 9 patients exhibited elevated CSF protein levels. Therefore, NS with only epileptic seizures at the initial presentation exhibits a lack of specificity. It is recommended that every patient with clinically evident symptoms of epileptic seizures should have a blood test performed for syphilis. When the serology results are positive, all of the patients should undergo a CSF examination to diagnose NS. Copyright © 2013 Elsevier Inc. All rights reserved.

Recurrent occurrences of CDKL5 mutations in patients with epileptic encephalopathy.

PubMed

Yamamoto, Toshiyuki; Shimojima, Keiko; Kimura, Nobusuke; Mogami, Yukiko; Usui, Daisuke; Takayama, Rumiko; Ikeda, Hiroko; Imai, Katsumi

2015-01-01

The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration.

Domoic acid excretion in dungeness crabs, razor clams and mussels.

PubMed

Schultz, Irvin R; Skillman, Ann; Woodruff, Dana

2008-07-01

Domoic acid (DA) is a neurotoxic amino acid produced by several marine algal species of the Pseudo-nitzschia (PN) genus. We studied the elimination of DA from hemolymph after intravascular (IV) injection in razor clams (Siliqua patula), mussels (Mytilus edulis) and Dungeness crabs (Cancer magister). Crabs were also injected with two other organic acids, dichloroacetic acid (DCAA) and kainic acid (KA). For IV dosing, hemolymph was repetitively sampled and DA concentrations measured by HPLC-UV. Toxicokinetic analysis of DA in crabs suggested most of the injected dose remained within hemolymph compartment with little extravascular distribution. This observation is in sharp contrast to results obtained from clams and mussels which exhibited similarly large apparent volumes of distribution despite large differences in overall clearance. These findings suggest fundamentally different storage and elimination processes are occurring for DA between bivalves and crabs.

Detection of Epileptic Seizure Event and Onset Using EEG

PubMed Central

Ahammad, Nabeel; Fathima, Thasneem; Joseph, Paul

2014-01-01

This study proposes a method of automatic detection of epileptic seizure event and onset using wavelet based features and certain statistical features without wavelet decomposition. Normal and epileptic EEG signals were classified using linear classifier. For seizure event detection, Bonn University EEG database has been used. Three types of EEG signals (EEG signal recorded from healthy volunteer with eye open, epilepsy patients in the epileptogenic zone during a seizure-free interval, and epilepsy patients during epileptic seizures) were classified. Important features such as energy, entropy, standard deviation, maximum, minimum, and mean at different subbands were computed and classification was done using linear classifier. The performance of classifier was determined in terms of specificity, sensitivity, and accuracy. The overall accuracy was 84.2%. In the case of seizure onset detection, the database used is CHB-MIT scalp EEG database. Along with wavelet based features, interquartile range (IQR) and mean absolute deviation (MAD) without wavelet decomposition were extracted. Latency was used to study the performance of seizure onset detection. Classifier gave a sensitivity of 98.5% with an average latency of 1.76 seconds. PMID:24616892

Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves

PubMed Central

von Ellenrieder, Nicolás; Ferrari-Marinho, Taissa; Avoli, Massimo; Dubeau, François; Gotman, Jean

2015-01-01

Epileptic discharges in focal epilepsy are frequently activated during non-rapid eye movement sleep. Sleep slow waves are present during this stage and have been shown to include a deactivated (‘down’, hyperpolarized) and an activated state (‘up’, depolarized). The ‘up’ state enhances physiological rhythms, and we hypothesize that sleep slow waves and particularly the ‘up’ state are the specific components of non-rapid eye movement sleep that mediate the activation of epileptic activity. We investigated eight patients with pharmaco-resistant focal epilepsies who underwent combined scalp-intracerebral electroencephalography for diagnostic evaluation. We analysed 259 frontal electroencephalographic channels, and manually marked 442 epileptic spikes and 8487 high frequency oscillations during high amplitude widespread slow waves, and during matched control segments with low amplitude widespread slow waves, non-widespread slow waves or no slow waves selected during the same sleep stages (total duration of slow wave and control segments: 49 min each). During the slow waves, spikes and high frequency oscillations were more frequent than during control segments (79% of spikes during slow waves and 65% of high frequency oscillations, both P ∼ 0). The spike and high frequency oscillation density also increased for higher amplitude slow waves. We compared the density of spikes and high frequency oscillations between the ‘up’ and ‘down’ states. Spike and high frequency oscillation density was highest during the transition from the ‘up’ to the ‘down’ state. Interestingly, high frequency oscillations in channels with normal activity expressed a different peak at the transition from the ‘down’ to the ‘up’ state. These results show that the apparent activation of epileptic discharges by non-rapid eye movement sleep is not a state-dependent phenomenon but is predominantly associated with specific events, the high amplitude widespread slow

Transient epileptic amnesia: clinical report of a cohort of patients.

PubMed

Lapenta, Leonardo; Brunetti, Valerio; Losurdo, Anna; Testani, Elisa; Giannantoni, Nadia Mariagrazia; Quaranta, Davide; Di Lazzaro, Vincenzo; Della Marca, Giacomo

2014-07-01

Transient epileptic amnesia is a seizure disorder, usually with onset in the middle-elderly and good response to low dosages of antiepileptic drugs. We describe the clinical, electroencephalography (EEG), and neuroimaging features of 11 patients with a temporal lobe epilepsy characterized by amnesic seizures as the sole or the main symptom. We outline the relevance of a detailed clinical history to recognize amnesic seizures and to avoid the more frequent misdiagnoses. Moreover, the response to monotherapy was usually good, although the epileptic disorder was symptomatic of acquired lesions in the majority of patients.

Seroepidemiological study of Toxoplasma gondii infection in a population of Iranian epileptic patients.

PubMed

Babaie, Jalal; Sayyah, Mohammad; Gharagozli, Kourosh; Mostafavi, Ehsan; Golkar, Majid

2017-01-01

Epilepsy is one of the most common neurologic disorders. Underlying cause of epilepsy is unknown in 60 % of the patients. Toxoplasma gondii is an intracellular parasite which is capable of forming tissue cysts in brain of chronically infected hosts including humans. Some epidemiological studies suggested an association between toxoplasmosis and acquisition of epilepsy. In this study we determined seroprevalence of latent Toxoplasma infection in a population of Iranian epileptic patients. Participants were classified in three groups as Iranian epileptic patients (IEP, n = 414), non-epileptic patients who had other neurologic disorders (NEP, n = 150), and healthy people without any neurologic disorders (HP, n = 63). The presence of anti- Toxoplasma IgG antibodies and IgG titer in the sera were determined by ELISA method. Anti- T. gondii IgG seroprevalence obtained 35.3 %, 34.7 % and 38.1 % in IEP, NEP and HP, respectively. The seroprevalence rate was not significantly different among the three groups (P = 0.88). Anti- T. gondii IgG titer was 55.7 ± 78, 52.4 ± 74 and 69.7 ± 92 IU/ml in IEP, NEP and HP, respectively. There was not any statistically significant difference in the antibody titer between the study groups (P = 0.32). The rate of T. gondii infection in epileptic patients was not higher than non-epileptic patients and healthy people in the Iranian population.

Monoamine metabolites, iron induced seizures, and the anticonvulsant effect of tannins.

PubMed

Kabuto, H; Yokoi, I; Mori, A

1992-06-01

Intracortical injections of iron ions have been shown to induce recurrent seizures and epileptic discharges in the EEG. (-)-Epigallocatechin (EGC) and (-)-epigallocatechin-3-O-gallate (EGCG), isolated from green tea leaves, have been reported to prevent or diminish the occurrence of epileptic discharges induced by iron ions, and to inhibit catechol-O-methyltransferase. Iron ions significantly increased DOPAC and HVA levels in the intrastriatal perfusate 140 and 180 minutes, respectively, after injection. EGC and EGCG inhibited the increases induced by iron ions. Furthermore, EGCG decreased the HVA level in the perfusate 200 minutes after injection whether or not iron ions were injected. Iron ions had no effect on the 5-HIAA level, and EGC and EGCG raised it. These results suggest that formation of an epileptic focus induced by iron ions might be accompanied by activation of dopaminergic neurons, and that EGC and EGCG inhibit that hyperactivity.

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

PubMed Central

Johnson, Michael R.; Rossetti, Tiziana; Speed, Doug; Srivastava, Prashant K.; Chadeau-Hyam, Marc; Hajji, Nabil; Dabrowska, Aleksandra; Rotival, Maxime; Razzaghi, Banafsheh; Kovac, Stjepana; Wanisch, Klaus; Grillo, Federico W.; Slaviero, Anna; Langley, Sarah R.; Shkura, Kirill; Roncon, Paolo; De, Tisham; Mattheisen, Manuel; Niehusmann, Pitt; O’Brien, Terence J.; Petrovski, Slave; von Lehe, Marec; Hoffmann, Per; Eriksson, Johan; Coffey, Alison J.; Cichon, Sven; Walker, Matthew; Simonato, Michele; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Schoch, Susanne; De Paola, Vincenzo; Kaminski, Rafal M.; Cunliffe, Vincent T.; Becker, Albert J.; Petretto, Enrico

2015-01-01

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo. PMID:25615886

Recurrent occurrences of CDKL5 mutations in patients with epileptic encephalopathy

PubMed Central

Yamamoto, Toshiyuki; Shimojima, Keiko; Kimura, Nobusuke; Mogami, Yukiko; Usui, Daisuke; Takayama, Rumiko; Ikeda, Hiroko; Imai, Katsumi

2015-01-01

The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration. PMID:27081548

Seizure tests distinguish intermittent fasting from the ketogenic diet

PubMed Central

Hartman, Adam L.; Zheng, Xiangrong; Bergbower, Emily; Kennedy, Michiko; Hardwick, J. Marie

2010-01-01

Summary Purpose Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests. Methods Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ~ 12 days, starting at 3–4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol. Results The ketogenic and calorie-restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz–induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol. Discussion In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption. PMID:20477852

Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities.

PubMed

Morimoto, Masahito; Satomura, Shigeko; Hashimoto, Toshiaki; Ito, Etsuro; Kyotani, Shojiro

2016-06-01

The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d-ROMs ratio were noted. These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID.

[Portable Epileptic Seizure Monitoring Intelligent System Based on Android System].

PubMed

Liang, Zhenhu; Wu, Shufeng; Yang, Chunlin; Jiang, Zhenzhou; Yu, Tao; Lu, Chengbiao; Li, Xiaoli

2016-02-01

The clinical electroencephalogram (EEG) monitoring systems based on personal computer system can not meet the requirements of portability and home usage. The epilepsy patients have to be monitored in hospital for an extended period of time, which imposes a heavy burden on hospitals. In the present study, we designed a portable 16-lead networked monitoring system based on the Android smart phone. The system uses some technologies including the active electrode, the WiFi wireless transmission, the multi-scale permutation entropy (MPE) algorithm, the back-propagation (BP) neural network algorithm, etc. Moreover, the software of Android mobile application can realize the processing and analysis of EEG data, the display of EEG waveform and the alarm of epileptic seizure. The system has been tested on the mobile phones with Android 2. 3 operating system or higher version and the results showed that this software ran accurately and steadily in the detection of epileptic seizure. In conclusion, this paper provides a portable and reliable solution for epileptic seizure monitoring in clinical and home applications.

Manganese intoxication: the cause of an inexplicable epileptic syndrome in a 3 year old child.

PubMed

Herrero Hernandez, Elena; Discalzi, Gianluigi; Dassi, Patrizia; Jarre, Laura; Pira, Enrico

2003-08-01

Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have reported epileptic syndromes related to manganese intoxication. We describe an epileptic syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was elevated, but no other abnormal values or toxic substances were found in blood or urine. The electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to remove excess manganese and promptly succeeded in reverting epileptic symptoms. Concurrently, manganese blood levels and electroencephalogram progressively normalized. Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in excellent conditions without any treatment.

High-Definition transcranial direct current stimulation in early onset epileptic encephalopathy: a case study.

PubMed

Meiron, Oded; Gale, Rena; Namestnic, Julia; Bennet-Back, Odeya; David, Jonathan; Gebodh, Nigel; Adair, Devin; Esmaeilpour, Zeinab; Bikson, Marom

2018-01-01

Early onset epileptic encephalopathy is characterized by high daily seizure-frequency, multifocal epileptic discharges, severe psychomotor retardation, and death at infancy. Currently, there are no effective treatments to alleviate seizure frequency and high-voltage epileptic discharges in these catastrophic epilepsy cases. The current study examined the safety and feasibility of High-Definition transcranial direct current stimulation (HD-tDCS) in reducing epileptiform activity in a 30-month-old child suffering from early onset epileptic encephalopathy. HD-tDCS was administered over 10 intervention days spanning two weeks including pre- and post-intervention video-EEG monitoring. There were no serious adverse events or side effects related to the HD-tDCS intervention. Frequency of clinical seizures was not significantly reduced. However, interictal sharp wave amplitudes were significantly lower during the post-intervention period versus baseline. Vital signs and blood biochemistry remained stable throughout the entire study. These exploratory findings support the safety and feasibility of 4 × 1 HD-tDCS in early onset epileptic encephalopathy and provide the first evidence of HD-tDCS effects on paroxysmal EEG features in electroclinical cases under the age of 36 months. Extending HD-tDCS treatment may enhance electrographic findings and clinical effects.

Transplantation of bone marrow mononuclear cells modulates hippocampal expression of growth factors in chronically epileptic animals.

PubMed

Zanirati, Gabriele; Azevedo, Pamella Nunes; Marinowic, Daniel Rodrigo; Rodrigues, Felipe; de Oliveira Dias, Ana Christina; Venturin, Gianina Teribele; Greggio, Samuel; Simão, Fabrício; DaCosta, Jaderson Costa

2015-05-01

In previous studies, transplantation of bone marrow mononuclear cells (BMMCs) in epileptic animals has been found to be neuroprotective. However, the mechanism by which the BMMCs act remains unclear. We hypothesize that BMMCs may provide neuroprotection to the epileptic brain through trophic support. To test our hypothesis, we studied the temporal expression of neurotrophins after BMMC transplantation in the epileptic rat hippocampus. Chronically epileptic rats were intravenously transplanted with 1 × 10(7) BMMCs isolated from GFP transgenic mice. Expression levels of BDNF, GDNF, NGF, VEGF, and TGF-β1, and their receptors, were evaluated by ELISA and/or qRT-PCR analysis. Our data revealed increased protein expression of BDNF, GDNF, NGF, and VEGF and reduced levels of TGF-β1 in the hippocampus of transplanted epileptic animals. Additionally, an increase in the mRNA expression of BDNF, GDNF, and VEGF, a reduction in TGF-β1, and a decrease in mRNA levels of the TrkA and TGFR-β1 receptors were also observed. The gain provided by transplanted BMMCs in the epileptic brain may be related to the ability of these cells in modulating the network of neurotrophins and angiogenic signals. © 2015 John Wiley & Sons Ltd.

Mediation of the neuroprotective action of R-phenylisopropyl-adenosine through a centrally located adenosine A1 receptor.

PubMed Central

MacGregor, D. G.; Miller, W. J.; Stone, T. W.

1993-01-01

1. Systemic injections of kainic acid, 10 mg kg-1, into adult rats resulted in lesions in the hippocampus, as assessed by peripheral benzodiazepine ligand binding. Co-administration of clonazepam at 1 mg kg-1 or 0.2 mg kg-1 prevented major seizures associated with kainate injections, but did not alter significantly the production of hippocampal damage. 2. The co-administration of the adenosine A1 agonist R-phenylisopropyladenosine (R-PIA, 25 micrograms kg-1, i.p.) abolished the lesions induced by kainic acid. 3. The presence of the selective A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (250 or 50 micrograms kg-1, i.p.) abolished the R-PIA neuroprotective action. 4. The A1/A2 antagonist, 8-(p-sulphophenyl)theophylline (20 mg kg-1, i.p.) which cannot cross the blood brain barrier, did not alter significantly the neuroprotective action of R-PIA, indicating that the neuroprotective action of the purine may be predominantly central. 5. The time course of the neuroprotection was also examined. R-PIA was effective when administered 2 h before or after kainate administration. 6. The results emphasise the potential utility of systemically active adenosine A1 receptor ligands in reducing CNS gliosis induced by the activation of excitatory amino acid receptors. PMID:8220909

Localizing epileptic seizure onsets with Granger causality

NASA Astrophysics Data System (ADS)

Adhikari, Bhim M.; Epstein, Charles M.; Dhamala, Mukesh

2013-09-01

Accurate localization of the epileptic seizure onset zones (SOZs) is crucial for successful surgery, which usually depends on the information obtained from intracranial electroencephalography (IEEG) recordings. The visual criteria and univariate methods of analyzing IEEG recordings have not always produced clarity on the SOZs for resection and ultimate seizure freedom for patients. Here, to contribute to improving the localization of the SOZs and to understanding the mechanism of seizure propagation over the brain, we applied spectral interdependency methods to IEEG time series recorded from patients during seizures. We found that the high-frequency (>80 Hz) Granger causality (GC) occurs before the onset of any visible ictal activity and causal relationships involve the recording electrodes where clinically identifiable seizures later develop. These results suggest that high-frequency oscillatory network activities precede and underlie epileptic seizures, and that GC spectral measures derived from IEEG can assist in precise delineation of seizure onset times and SOZs.

ALA-induced PpIX fluorescence in epileptogenic tissue

NASA Astrophysics Data System (ADS)

Kleen, Jonathan K.; Valdes, Pablo A.; Harris, Brent T.; Holmes, Gregory L.; Paulsen, Keith D.; Roberts, David W.

2011-03-01

Astrogliotic tissue displays markedly increased levels of ALA-induced PpIX fluorescence, making it useful for fluorescence-guided resection in glioma surgery. In patients with temporal lobe epilepsy (TLE) and corresponding animal models, there are areas of astrogliosis that often co-localize with the epileptic focus, which can be resected to eliminate seizures in the majority of treated patients. If this epileptogenic tissue can exhibit PpIX fluorescence that is sufficiently localized, it could potentially help identify margins in epilepsy surgery. We tested the hypothesis that ALA-induced PpIX fluorescence could visually accentuate epileptogenic tissue, using an established animal model of chronic TLE. An acute dose of pilocarpine was used to induce chronic seizure activity in a rat. This rat and a normal control were given ALA, euthanized, and brains examined post-mortem for PpIX fluorescence and neuropathology. Preliminary evidence indicates increased PpIX fluorescence in areas associated with chronic epileptic changes and seizure generation in TLE, including the hippocampus and parahippocampal areas. In addition, strong PpIX fluorescence was clearly observed in layer II of the piriform cortex, a region known for epileptic reorganization and involvement in the generation of seizures in animal studies. We are further investigating whether ALA-induced PpIX fluorescence can consistently identify epileptogenic zones, which could warrant the extension of this technique to clinical studies for use as an adjuvant guidance technology in the resection of epileptic tissue.

Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities

PubMed Central

Morimoto, Masahito; Satomura, Shigeko; Hashimoto, Toshiaki; Ito, Etsuro; Kyotani, Shojiro

2016-01-01

Background The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. Methods Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. Results The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d-ROMs ratio were noted. Conclusions These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID. PMID:27222671

CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life.

PubMed

Melani, Federico; Mei, Davide; Pisano, Tiziana; Savasta, Salvatore; Franzoni, Emilio; Ferrari, Anna Rita; Marini, Carla; Guerrini, Renzo

2011-04-01

Cyclin-dependent kinase-like 5 (CDKL5) gene abnormalities cause an early-onset epileptic encephalopathy. We performed video-electroencephalography (video-EEG) monitoring early in the course of CDKL5-related epileptic encephalopathy in order to examine the early electroclinical characteristics of the condition. We used video-EEG to monitor six infants (five females, one male) with CDKL5-related epileptic encephalopathy (five mutations; one deletion), at ages 45 days to 12 months and followed them up to the ages of 14 months to 5 years (mean age 23 mo). We focused our analysis on the first year of life. The results were evaluated against those of a comparison group of nine infants (aged below 1y) with epileptic encephalography who had tested negative for CDKL5 mutations and deletions. One infant exhibited normal background activity, three exhibited moderate slowing, and two exhibited a suppression burst pattern. Two participants had epileptic spasms and four had a stereotyped complex seizure pattern, which we defined as a 'prolonged' generalized tonic-clonic event consisting of a tonic-tonic/vibratory contraction, followed by a clonic phase with series of spasms, gradually translating into repetitive distal myoclonic jerks. Seizure duration ranged from 2 to 4 minutes. The EEG correlate of each clinical phase included an initial electrodecremental event (tonic vibratory phase), irregular series of sharp waves and spike slow waves (clonic phase with series of spasms), and bilateral rhythmic sharp waves (time locked with myoclonus). Infants with CDKL5-related early epileptic encephalopathy can present in the first year of life with an unusual electroclinical pattern of 'prolonged' generalized tonic-clonic seizures. © The Authors. Journal compilation © Mac Keith Press 2011.

VEGF Receptor-2 (Flk-1) Overexpression in Mice Counteracts Focal Epileptic Seizures

PubMed Central

Nikitidou, Litsa; Kanter-Schlifke, Irene; Dhondt, Joke; Carmeliet, Peter; Lambrechts, Diether; Kokaia, Mérab

2012-01-01

Vascular endothelial growth factor (VEGF) was first described as an angiogenic agent, but has recently also been shown to exert various neurotrophic and neuroprotective effects in the nervous system. These effects of VEGF are mainly mediated by its receptor, VEGFR-2, which is also referred to as the fetal liver kinase receptor 1 (Flk-1). VEGF is up-regulated in neurons and glial cells after epileptic seizures and counteracts seizure-induced neurodegeneration. In vitro, VEGF administration suppresses ictal and interictal epileptiform activity caused by AP4 and 0 Mg2+ via Flk-1 receptor. We therefore explored whether increased VEGF signaling through Flk-1 overexpression may regulate epileptogenesis and ictogenesis in vivo. To this extent, we used transgenic mice overexpressing Flk-1 postnatally in neurons. Intriguingly, Flk-1 overexpressing mice were characterized by an elevated threshold for seizure induction and a decreased duration of focal afterdischarges, indicating anti-ictal action. On the other hand, the kindling progression in these mice was similar to wild-type controls. No significant effects on blood vessels or glia cells, as assessed by Glut1 and GFAP immunohistochemistry, were detected. These results suggest that increased VEGF signaling via overexpression of Flk-1 receptors may directly affect seizure activity even without altering angiogenesis. Thus, Flk-1 could be considered as a novel target for developing future gene therapy strategies against ictal epileptic activity. PMID:22808185

Cerebral perfusion alterations in epileptic patients during peri-ictal and post-ictal phase: PASL vs DSC-MRI.

PubMed

Pizzini, Francesca B; Farace, Paolo; Manganotti, Paolo; Zoccatelli, Giada; Bongiovanni, Luigi G; Golay, Xavier; Beltramello, Alberto; Osculati, Antonio; Bertini, Giuseppe; Fabene, Paolo F

2013-07-01

Non-invasive pulsed arterial spin labeling (PASL) MRI is a method to study brain perfusion that does not require the administration of a contrast agent, which makes it a valuable diagnostic tool as it reduces cost and side effects. The purpose of the present study was to establish the viability of PASL as an alternative to dynamic susceptibility contrast (DSC-MRI) and other perfusion imaging methods in characterizing changes in perfusion patterns caused by seizures in epileptic patients. We evaluated 19 patients with PASL. Of these, the 9 affected by high-frequency seizures were observed during the peri-ictal period (within 5hours since the last seizure), while the 10 patients affected by low-frequency seizures were observed in the post-ictal period. For comparison, 17/19 patients were also evaluated with DSC-MRI and CBF/CBV. PASL imaging showed focal vascular changes, which allowed the classification of patients in three categories: 8 patients characterized by increased perfusion, 4 patients with normal perfusion and 7 patients with decreased perfusion. PASL perfusion imaging findings were comparable to those obtained by DSC-MRI. Since PASL is a) sensitive to vascular alterations induced by epileptic seizures, b) comparable to DSC-MRI for detecting perfusion asymmetries, c) potentially capable of detecting time-related perfusion changes, it can be recommended for repeated evaluations, to identify the epileptic focus, and in follow-up and/or therapy-response assessment. Copyright © 2013 Elsevier Inc. All rights reserved.

Do seizures and epileptic activity worsen epilepsy and deteriorate cognitive function?

PubMed

Avanzini, Giuliano; Depaulis, Antoine; Tassinari, Alberto; de Curtis, Marco

2013-11-01

Relevant to the definition of epileptic encephalopathy (EE) is the concept that the epileptic activity itself may contribute to bad outcomes, both in terms of epilepsy and cognition, above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time. The review of the clinical and experimental evidence that seizures or interictal electroencephalography (EEG) discharges themselves can induce a progression toward more severe epilepsy and a regression of brain function leads to the following conclusions: The possibility of seizure-dependent worsening is by no means a general one but is limited to some types of epilepsy, namely mesial temporal lobe epilepsy (MTLE) and EEs. Clinical and experimental data concur in indicating that prolonged seizures/status epilepticus (SE) are a risky initial event that can set in motion an epileptogenic process leading to persistent, possibly drug-refractory epilepsies. The mechanisms for SE-related epileptogenic process are incompletely known; they seem to involve inflammation and/or glutamatergic transmission. The evidence of the role of recurrent individual seizures in sustaining epilepsy progression is ambiguous. The correlation between high seizure frequency and bad outcome does not necessarily demonstrate a cause-effect relationship, rather high seizure frequency and bad outcome can both depend on a particularly aggressive epileptogenic process. The results of EE studies challenge the idea of a common seizure-dependent mechanism for epilepsy progression/intellectual deterioration. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

CDKL5 alterations lead to early epileptic encephalopathy in both genders.

PubMed

Liang, Jao-Shwann; Shimojima, Keiko; Takayama, Rumiko; Natsume, Jun; Shichiji, Minobu; Hirasawa, Kyoko; Imai, Kaoru; Okanishi, Tohru; Mizuno, Seiji; Okumura, Akihisa; Sugawara, Midori; Ito, Tomoshiro; Ikeda, Hiroko; Takahashi, Yukitoshi; Oguni, Hirokazu; Imai, Katsumi; Osawa, Makiko; Yamamoto, Toshiyuki

2011-10-01

Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.

PubMed

Coughlin, Curtis R; Scharer, Gunter H; Friederich, Marisa W; Yu, Hung-Chun; Geiger, Elizabeth A; Creadon-Swindell, Geralyn; Collins, Abigail E; Vanlander, Arnaud V; Coster, Rudy Van; Powell, Christopher A; Swanson, Michael A; Minczuk, Michal; Van Hove, Johan L K; Shaikh, Tamim H

2015-08-01

Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy. We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl-tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology. Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling.

PubMed

Soriano, Jaymar; Kubo, Takatomi; Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu; Ikeda, Kazushi

2017-10-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain's normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling

PubMed Central

Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu

2017-01-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain’s normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is

Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children.

PubMed

Bayram, Ayşe Kaçar; Canpolat, Mehmet; Karacabey, Neslihan; Gumus, Hakan; Kumandas, Sefer; Doğanay, Selim; Arslan, Duran; Per, Hüseyin

2016-03-01

Gastroesophageal reflux disease (GERD) can mimic epileptic seizure, and may be misdiagnosed as epilepsy. On the other hand, GERD can be more commonly seen in children with neurological disorders such as cerebral palsy (CP); this co-incidence may complicate the management of patients by mimicking refractory seizures. The purpose of our study was to evaluate the clinical features, definite diagnoses and treatment approaches of the patients with clinically suspected GERD who were referred to the division of pediatric neurology with a suspected diagnosis of epileptic seizure. We also aimed to investigate the occurrence of GERD in children with epilepsy and/or CP. Fifty-seven children who had a final diagnosis of GERD but were initially suspected of having epileptic seizures were assessed prospectively. All patients were assigned to 3 groups according to definite diagnoses as follows: patients with only GERD who were misdiagnosed as having epileptic seizure (group 1: n=16; 28.1%), those with comorbidity of epilepsy and GERD (group 2: n=21; 36.8%), and those with the coexistence of GERD with epilepsy and CP (group 3: n=20; 35.1%). Five patients (8.8%) did not respond to anti-reflux treatment and laparoscopic reflux surgery was performed. The positive effect of GERD therapy on paroxysmal nonepileptic events was observed in 51/57 (89.5%) patients. GERD is one of the important causes of paroxysmal nonepileptic events. In addition, GERD must be kept in mind at the initial diagnosis and also in the long-term management of patients with neurological disorders such as epilepsy and CP. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Brain Graph Topology Changes Associated with Anti-Epileptic Drug Use

PubMed Central

Levin, Harvey S.; Chiang, Sharon

2015-01-01

Abstract Neuroimaging studies of functional connectivity using graph theory have furthered our understanding of the network structure in temporal lobe epilepsy (TLE). Brain network effects of anti-epileptic drugs could influence such studies, but have not been systematically studied. Resting-state functional MRI was analyzed in 25 patients with TLE using graph theory analysis. Patients were divided into two groups based on anti-epileptic medication use: those taking carbamazepine/oxcarbazepine (CBZ/OXC) (n=9) and those not taking CBZ/OXC (n=16) as a part of their medication regimen. The following graph topology metrics were analyzed: global efficiency, betweenness centrality (BC), clustering coefficient, and small-world index. Multiple linear regression was used to examine the association of CBZ/OXC with graph topology. The two groups did not differ from each other based on epilepsy characteristics. Use of CBZ/OXC was associated with a lower BC. Longer epilepsy duration was also associated with a lower BC. These findings can inform graph theory-based studies in patients with TLE. The changes observed are discussed in relation to the anti-epileptic mechanism of action and adverse effects of CBZ/OXC. PMID:25492633

Weather as a risk factor for epileptic seizures: A case-crossover study.

PubMed

Rakers, Florian; Walther, Mario; Schiffner, Rene; Rupprecht, Sven; Rasche, Marius; Kockler, Michael; Witte, Otto W; Schlattmann, Peter; Schwab, Matthias

2017-07-01

Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients' perception that weather is a risk factor for epileptic seizures. Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated. We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01-1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09-1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11-1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32-0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14-0.74). Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

The antiepileptic effect of Centella asiatica on the activities of Na+/K+, Mg2+ and Ca2+-ATPases in rat brain during pentylenetetrazol–induced epilepsy

PubMed Central

G., Visweswari; K., Siva Prasad; V., Lokanatha; Rajendra, W.

2010-01-01

Background: To study the anticonvulsant effect of different extracts of Centella asiatica (CA) in male albino rats with reference to Na+/K+, Mg2+ and Ca2+-ATPase activities. Materials and Methods: Male Wistar rats (150±25 g b.w.) were divided into seven groups of six each i.e. (a) control rats treated with saline, (b) pentylenetetrazol (PTZ)-induced epileptic group (60 mg/kg, i.p.), (c) epileptic group pretreated with n-hexane extract (n-HE), (d) epileptic group pretreated with chloroform extract (CE), (e) epileptic group pretreated with ethyl acetate extract (EAE), (f) epileptic group pretreated with n-butanol extract (n-BE), and (g) epileptic group pretreated with aqueous extract (AE). Results: The activities of three ATPases were decreased in different regions of brain during PTZ-induced epilepsy and were increased in epileptic rats pretreated with different extracts of CA except AE. Conclusion: The extracts of C. asiatica, except AE, possess anticonvulsant and neuroprotective activity and thus can be used for effective management in treatment of epileptic seizures. PMID:20711371

Acid mediates a prolonged antinociception via substance P signaling in acid-induced chronic widespread pain.

PubMed

Chen, Wei-Nan; Chen, Chih-Cheng

2014-05-21

Substance P is an important neuropeptide released from nociceptors to mediate pain signals. We recently revealed antinociceptive signaling by substance P in acid-sensing ion channel 3 (ASIC3)-expressing muscle nociceptors in a mouse model of acid-induced chronic widespread pain. However, methods to specifically trigger the substance P antinociception were still lacking. Here we show that acid could induce antinociceptive signaling via substance P release in muscle. We prevented the intramuscular acid-induced hyperalgesia by pharmacological inhibition of ASIC3 and transient receptor potential V1 (TRPV1). The antinociceptive effect of non-ASIC3, non-TRPV1 acid signaling lasted for 2 days. The non-ASIC3, non-TRPV1 acid antinociception was largely abolished in mice lacking substance P. Moreover, pretreatment with substance P in muscle mimicked the acid antinociceptive effect and prevented the hyperalgesia induced by next-day acid injection. Acid could mediate a prolonged antinociceptive signaling via the release of substance P from muscle afferent neurons in a non-ASIC3, non-TRPV1 manner.

Management of a high risk epileptic patient under conscious sedation: A multidisciplinary approach

PubMed Central

Chellathurai, Burnice Nalina Kumari; Thiagarajan, Ramakrishnan; Jayakumaran, SelvaKumar; Devadoss, Pradeep; Elavazhagan

2016-01-01

Epilepsy, characterized by the risk of recurrent seizures, is a chronic disease that afflicts about 5% of the world's population. The main dental problems associated with epileptic patients include gingival hyperplasia, minor oral injuries, tooth trauma, and prosthodontic problems, which require the dental treatment. Stress and fear are the most common triggering factors for the epilepsy in dental chair. Therefore, a more appropriate method of treating such epileptic patients may be warranted. Conscious sedation is a technique of providing good anesthesia and analgesia to patients, the main advantage of which is the patient's rapid return to presentation levels. Midazolam used as a sedative agent has anticonvulsant properties. This case report highlights a case requiring multiple dental procedures carried out in a high risk epileptic patient under conscious sedation. PMID:27041847

Long-term variability of importance of brain regions in evolving epileptic brain networks

NASA Astrophysics Data System (ADS)

Geier, Christian; Lehnertz, Klaus

2017-04-01

We investigate the temporal and spatial variability of the importance of brain regions in evolving epileptic brain networks. We construct these networks from multiday, multichannel electroencephalographic data recorded from 17 epilepsy patients and use centrality indices to assess the importance of brain regions. Time-resolved indications of highest importance fluctuate over time to a greater or lesser extent, however, with some periodic temporal structure that can mostly be attributed to phenomena unrelated to the disease. In contrast, relevant aspects of the epileptic process contribute only marginally. Indications of highest importance also exhibit pronounced alternations between various brain regions that are of relevance for studies aiming at an improved understanding of the epileptic process with graph-theoretical approaches. Nonetheless, these findings may guide new developments for individualized diagnosis, treatment, and control.

Effect of Naringenin (A naturally occurring flavanone) Against Pilocarpine-induced Status Epilepticus and Oxidative Stress in Mice

PubMed Central

Shakeel, Sheeba; Rehman, Muneeb U.; Tabassum, Nahida; Amin, Umar; Mir, Manzoor ur Rahman

2017-01-01

Background: Epilepsy is a disorder of the central nervous system characterized by recurrent seizures. It is a very common disease in which approximately 30% of patients do not respond favourably to treatment with anticonvulsants. Oxidative stress is associated with neuronal damage arising from epileptic seizures. The present study investigated the effects of naringenin in pilocarpine-induced epilepsy in mice. Naringenin, one of the most frequently occurring flavanone in citrus fruits, was evaluated for its shielding effect against the pilocarpine induced behavioural, oxidative and histopathological alterations in rodent model of epilepsy. Methodology: Epilepsy was induced by giving pilocarpine (300mg/kg) and sodium valproate (300mg/kg) was given as standard anti-epileptic drug Pilocarpine was administered (300 mg /kg body weight) intraperitoneally to the mice on 15th day while naringenin was administered orally (20 and 40 mg/kg body weight) for 15 days prior to administration of pilocarpine. Results: The intraperitoneal administration of pilocarpine enhanced lipid peroxidation, caused reduction in antioxidant enzymes, viz., catalase, superoxide dismutase and glutathione reductase. Treatment of mice orally with naringenin (20 mg/kg body weight and 40 mg/kg body weight) resulted in a significant decrease in lipid peroxidation. There was significant recovery of glutathione content and all the antioxidant enzymes studied. Also in case of behavioural parameters studied, naringenin showed decrease in seizure severity. All these changes were supported by histological observations, which revealed excellent improvement in neuronal damage. Conclusion: The higher dose of naringenin was more potent in our study and was comparable to the standard drug (sodium valproate) in effectiveness. SUMMARY Naringenin ameliorated the development of ROS formation in hippocamus.Naringenin helped in recovery of antioxidant enzymes.Naringenin decreased seizure severity.Naringenin treatment

Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

PubMed

Zwart, R; Sher, E; Ping, X; Jin, X; Sims, J R; Chappell, A S; Gleason, S D; Hahn, P J; Gardinier, K; Gernert, D L; Hobbs, J; Smith, J L; Valli, S N; Witkin, J M

2014-10-01

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients. Copyright © 2014 by The American Society for

Antiepileptic activity of total triterpenes isolated from Poria cocos is mediated by suppression of aspartic and glutamic acids in the brain.

PubMed

Gao, Yanqiong; Yan, Hua; Jin, Ruirui; Lei, Peng

2016-11-01

Triterpenes from Poria cocos Wolf (Polyporaceae) have been used to treat various diseases in traditional Chinese medicine. However, the antiepileptic effects and mechanism are not fully understood. The objective of this study is to investigate the antiepileptic properties of total triterpenes (TTP) from the whole P. cocos. The ethanol extract TTP was identified by HPLC fingerprint analysis. Male ICR mice were gavaged (i.g.) with TTP (5, 20, 80 or 160 mg/kg) or reference drugs twice a day for 7 d. Antiepileptic activities of TTP were evaluated by maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizures in mice for 30 and 60 min, respectively. Locomotor activity and Rota-rod tests were performed for 60 min and 5 min, respectively. The levels of glutamic acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA) and glycine (Gly) in convulsive mice were estimated. The chronic epileptic model of Wistar rats was built to measure expressions of glutamate decarboxylase 65 (GAD65) and GABA A in rat brain after TTP treatment. The LC 50 of TTP (i.g.) was above 6 g/kg. TTP (5-160 mg/kg) protected mice against MES- and PTZ-induced convulsions at 65.0% and 62.5%, respectively, but have no effect on rota-rod treadmill; TTP (20-160 mg/kg) significantly reduced the locomotor activities, shortened the onset of pentobarbital sodium-induced sleep; TTP decreased Glu and Asp levels in convulsive mice, but increased the GAD65 and GABA A expressions in chronic epileptic rats at doses usage. TTP extracted from P. cocos possessed potential antiepileptic properties and is a candidate for further antiepileptic drug development.

Persistent genital arousal disorder associated with functional hyperconnectivity of an epileptic focus.

PubMed

Anzellotti, F; Franciotti, R; Bonanni, L; Tamburro, G; Perrucci, M G; Thomas, A; Pizzella, V; Romani, G L; Onofrj, M

2010-04-28

Persistent Genital Arousal Disorder (PGAD) refers to the experience of persistent sensations of genital arousal that are felt to be unprovoked, intrusive and unrelieved by one or several orgasms. It is often mistaken for hypersexuality since PGAD often results in a high frequency of sexual behaviour. At present little is known with certainty about the etiology of this condition. We described a woman with typical PGAD symptoms and orgasmic seizures that we found to be related to a specific epileptic focus. We performed a EEG/MEG and fMRI spontaneous activity study during genital arousal symptoms and after the chronic administration of 300 mg/day of topiramate. From MEG data an epileptic focus was localized in the left posterior insular gyrus (LPIG). FMRI data evidenced that sexual excitation symptoms with PGAD could be correlated with an increased functional connectivity (FC) between different brain areas: LPIG (epileptic focus), left middle frontal gyrus, left inferior and superior temporal gyrus and left inferior parietal lobe. The reduction of the FC observed after antiepileptic therapy was more marked in the left than in the right hemisphere in agreement with the lateralization identified by MEG results. Treatment completely abolished PGAD symptoms and functional hyperconnectivity. The functional hyperconnectivity found in the neuronal network including the epileptic focus could suggest a possible central mechanism for PGAD. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

The epileptic encephalopathy jungle - from Dr West to the concepts of aetiology-related and developmental encephalopathies.

PubMed

Kalser, Judith; Cross, J Helen

2018-04-01

We aim to further disentangle the jungle of terminology of epileptic encephalopathy and provide some insights into the current understanding about the aetiology and pathophysiology of this process. We cover also the key features of epilepsy syndromes of infancy and childhood which are considered at high risk of developing an epileptic encephalopathy. The concept of 'epileptic encephalopathy' has progressively been elaborated by the International League Against Epilepsy according to growing clinical and laboratory evidence. It defines a process of neurological impairment caused by the epileptic activity itself and, therefore, potentially reversible with successful treatment, although to a variable extent. Epileptic activity interfering with neurogenesis, synaptogenesis, and normal network organization as well as triggering neuroinflammation are among the possible pathophysiological mechanisms leading to the neurological compromise. This differs from the newly introduced concept of 'developmental encephalopathy' which applies to where the epilepsy and developmental delay are both because of the underlying aetiology and aggressive antiepileptic treatment may not be helpful. The understanding and use of correct terminology is crucial in clinical practice enabling appropriate expectations of antiepileptic treatment. Further research is needed to elucidate underlying pathophysiological mechanisms, define clear outcome predictors, and find new treatment targets.

Comparative case-control study of homocysteine, vitamin B12, and folic acid levels in patients with epilepsy.

PubMed

Pulido Fontes, L; Pulido Fontes, M; Quesada Jiménez, P; Muruzabal Pérez, J; Mendioroz Iriarte, M

2017-09-01

Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B 12 . Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P=.084) and lower levels of folic acid (P<.05). Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Deletion of mTOR in Reactive Astrocytes Suppresses Chronic Seizures in a Mouse Model of Temporal Lobe Epilepsy.

PubMed

Wang, Xueqin; Sha, Longze; Sun, Nannan; Shen, Yan; Xu, Qi

2017-01-01

Germline and somatic mutations in key genes of the mammalian target of rapamycin (mTOR) pathway have been identified in seizure-associated disorders. mTOR mutations lead to aberrant activation of mTOR signaling, and, although affected neurons are critical for epileptogenesis, the role of mTOR activation in glial cells remains poorly understood. We previously reported a consistent activation of the mTOR pathway in astrocytes in the epileptic foci of temporal lobe epilepsy. In this study, it was demonstrated that mTOR deletion from reactive astrocytes prevents increases in seizure frequency over the disease course. By using a tamoxifen-inducible mTOR conditional knockout system and kainic acid, a model was developed that allowed astrocyte-specific mTOR gene deletion in mice with chronic epilepsy. Animals in which mTOR was deleted from 44 % of the astrocyte population exhibited a lower seizure frequency compared with controls. Down-regulation of mTOR significantly ameliorated astrogliosis in the sclerotic hippocampus but did not rescue mossy fiber sprouting. In cultured astrocytes, the mTOR pathway modulated the stability of the astroglial glutamate transporter 1 (Glt1) and influenced the ability of astrocytes to remove extracellular glutamate. Taken together, these data indicate that astrocytes with activated mTOR signaling may provide conditions that are favorable for spontaneous recurrent seizures.

Assortative mixing in functional brain networks during epileptic seizures

NASA Astrophysics Data System (ADS)

Bialonski, Stephan; Lehnertz, Klaus

2013-09-01

We investigate assortativity of functional brain networks before, during, and after one-hundred epileptic seizures with different anatomical onset locations. We construct binary functional networks from multi-channel electroencephalographic data recorded from 60 epilepsy patients; and from time-resolved estimates of the assortativity coefficient, we conclude that positive degree-degree correlations are inherent to seizure dynamics. While seizures evolve, an increasing assortativity indicates a segregation of the underlying functional network into groups of brain regions that are only sparsely interconnected, if at all. Interestingly, assortativity decreases already prior to seizure end. Together with previous observations of characteristic temporal evolutions of global statistical properties and synchronizability of epileptic brain networks, our findings may help to gain deeper insights into the complicated dynamics underlying generation, propagation, and termination of seizures.

Recording temporal lobe epileptic activity with MEG in a light-weight magnetic shield.

PubMed

Carrette, Evelien; Op de Beeck, Marc; Bourguignon, Mathieu; Boon, Paul; Vonck, Kristl; Legros, Benjamin; Goldman, Serge; Van Bogaert, Patrick; De Tiège, Xavier

2011-06-01

To assess the interictal epileptic discharges (IEDs) detection rate of magnetoencephalography (MEG) recordings performed in a new light-weight magnetic shielding (LMSR) concept in a large group of consecutive patients with presumed mesiotemporal lobe epilepsy (MTLE). Thirty-eight patients (23 women; age range: 6-63 years) with presumed MTLE were prospectively studied. MEG investigations were performed with the 306-channel Elekta Neuromag® MEG-system installed in a normal hospital environment into a LMSR (MaxShield, Elekta Oy). Equivalent current dipoles (ECD, g/% > 80%) corresponding to epileptic events were fitted to each patient's spherical head model at IEDs onset and peak and then superimposed on the patient's co-registered MRI. IEDs were observed in 26 out of 38 patients (68.4%). Temporal ECDs were mesial in 14 patients, anterior in 23 patients and posterior in 8 patients. Interestingly, in 6 patients, ECDs fitted at spike-onset were localized in the hippocampus while at the peak of the spike, they had an anterior temporal location. MEG using LMSR provides adequate signal to noise ratio (SNR) to allow reliable detection and localization of single epileptic abnormalities on continuous MEG data in 68% of patients with presumed MTLE. Moreover, mesial temporal epileptic sources were detected in 54% of patients with abnormal MEG. The SNR of MEG data acquired using the LMSR is therefore suitable for the non-invasive localization of epileptic foci in patients with MTLE. The use of LMSR, which are cheaper and smaller than conventional MSR, should facilitate the development of MEG in clinical environments. Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

An epileptic seizures detection algorithm based on the empirical mode decomposition of EEG.

PubMed

Orosco, Lorena; Laciar, Eric; Correa, Agustina Garces; Torres, Abel; Graffigna, Juan P

2009-01-01

Epilepsy is a neurological disorder that affects around 50 million people worldwide. The seizure detection is an important component in the diagnosis of epilepsy. In this study, the Empirical Mode Decomposition (EMD) method was proposed on the development of an automatic epileptic seizure detection algorithm. The algorithm first computes the Intrinsic Mode Functions (IMFs) of EEG records, then calculates the energy of each IMF and performs the detection based on an energy threshold and a minimum duration decision. The algorithm was tested in 9 invasive EEG records provided and validated by the Epilepsy Center of the University Hospital of Freiburg. In 90 segments analyzed (39 with epileptic seizures) the sensitivity and specificity obtained with the method were of 56.41% and 75.86% respectively. It could be concluded that EMD is a promissory method for epileptic seizure detection in EEG records.

Potent anti-seizure effects of D-leucine

PubMed Central

Hartman, Adam L.; Santos, Polan; O’Riordan, Kenneth J.; Stafstrom, Carl E.; Hardwick, J. Marie

2015-01-01

There are no effective treatments for millions of patients with intractable epilepsy. High-fat ketogenic diets may provide significant clinical benefit but are challenging to implement. Low carbohydrate levels appear to be essential for the ketogenic diet to work, but the active ingredients in dietary interventions remain elusive, and a role for ketogenesis has been challenged. A potential antiseizure role of dietary protein or of individual amino acids in the ketogenic diet is understudied. We investigated the two exclusively ketogenic amino acids, L-leucine and L-lysine, and found that only L-leucine potently protects mice when administered prior to the onset of seizures induced by kainic acid injection, but not by inducing ketosis. Unexpectedly, the D-enantiomer of leucine, which is found in trace amounts in the brain, worked as well or better than L-leucine against both kainic acid and 6 Hz electroshock-induced seizures. However, unlike L-leucine, D-leucine potently terminated seizures even after the onset of seizure activity. Furthermore, D-leucine, but not L-leucine, reduced long-term potentiation but had no effect on basal synaptic transmission in vitro. In a screen of candidate neuronal receptors, D-leucine failed to compete for binding by cognate ligands, potentially suggesting a novel target. Even at low doses, D-leucine suppressed ongoing seizures at least as effectively as diazepam but without sedative effects. These studies raise the possibility that D-leucine may represent a new class of anti-seizure agents, and that D-leucine may have a previously unknown function in eukaryotes. PMID:26054437

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy.

PubMed

Post, Julia M; Loch, Sebastian; Lerner, Raissa; Remmers, Floortje; Lomazzo, Ermelinda; Lutz, Beat; Bindila, Laura

2018-01-01

Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use. Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy. Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties. Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant. In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA). KA-induced epilepsy in rodents is assumed to resemble to different extents human temporal lobe epilepsy (TLE) depending on the route of KA administration; intracerebral (i

Localisation of epileptic foci using novel imaging modalities

PubMed Central

De Ciantis, Alessio; Lemieux, Louis

2013-01-01

Purpose of review This review examines recent reports on the use of advanced techniques to map the regions and networks involved during focal epileptic seizure generation in humans. Recent findings A number of imaging techniques are capable of providing new localizing information on the ictal processes and epileptogenic zone. Evaluating the clinical utility of these findings has been mainly performed through post-hoc comparison with the findings of invasive EEG and ictal single-photon emission computed tomography, using postsurgical seizure reduction as the main outcome measure. Added value has been demonstrated in MRI-negative cases. Improved understanding of the human ictiogenic processes and the focus vs. network hypothesis is likely to result from the application of multimodal techniques that combine electrophysiological, semiological, and whole-brain coverage of brain activity changes. Summary On the basis of recent research in the field of neuroimaging, several novel imaging modalities have been improved and developed to provide information about the localization of epileptic foci. PMID:23823464

Anti-epileptic drugs in pediatric traumatic brain injury.

PubMed

Tanaka, Tomoko; Litofsky, N Scott

2016-10-01

Pediatric post-traumatic epilepsy incidence varies depending on reporting mechanism and injury severity; anti-epileptic drug (AEDs) use also varies with lack of quality evidence-based data. Adverse AED effects are not negligible; some may negatively affect functional outcome. This review focuses on clarifying available data. This review discusses seizures associated with traumatic brain injury in children, including seizure incidence, relationship to severity of injury, potential detrimental effects of seizures, potential benefits of AED, adverse effects of AED, new developments in preventing epileptogenesis, and suggested recommendations for patient management. English language papers were identified from PubMed using search terms including but not excluding the following: adverse drug effects, anti-epileptic drugs, children, electroencephalogram, epilepsy, epileptogenesis, head injury, levetiracetam, pediatrics, phenytoin, post-traumatic epilepsy, prevention, prophylaxis, seizures, and traumatic brain injury. Expert commentary: Identification of high-risk patients for post-traumatic seizures is a key goal. Levetiracetam may prevent epileptogenesis, as may other developments.

[Analysis of gene mutation of early onset epileptic spasm with unknown reason].

PubMed

Yang, X; Pan, G; Li, W H; Zhang, L M; Wu, B B; Wang, H J; Zhang, P; Zhou, S Z

2017-11-02

Objective: To summarize the gene mutation of early onset epileptic spasm with unknown reason. Method: In this prospective study, data of patients with early onset epileptic spasm with unknown reason were collected from neurological department of Children's Hospital of Fudan University between March 2016 and December 2016. Patients with known disorders such as infection, metabolic, structural, immunological problems and known genetic mutations were excluded. Patients with genetic disease that can be diagnosed by clinical manifestations and phenotypic characteristics were also excluded. Genetic research methods included nervous system panel containing 1 427 epilepsy genes, whole exome sequencing (WES), analysis of copy number variation (CNV) and karyotype analysis of chromosome. The basic information, phenotypes, genetic results and the antiepileptic treatment of patients were analyzed. Result: Nine of the 17 cases with early onset epileptic spasm were boys and eight were girls. Patients' age at first seizure onset ranged from 1 day after birth to 8 months (median age of 3 months). The first hospital visit age ranged from 1 month to 2 years (median age of 4.5 months). The time of following-up ranged from 8 months to 3 years and 10 months. All the 17 patients had early onset epileptic spasm. Video electroencephalogram was used to monitor the spasm seizure. Five patients had Ohtahara syndrome, 10 had West syndrome, two had unclear classification. In 17 cases, 10 of them had detected pathogenic genes. Nine cases had point mutations, involving SCN2A, ARX, UNC80, KCNQ2, and GABRB3. Except one case of mutations in GABRB3 gene have been reported, all the other cases had new mutations. One patient had deletion mutation in CDKL5 gene. One CNV case had 6q 22.31 5.5MB repeats. Ten cases out of 17 were using 2-3 antiepileptic drugs (AEDs) and the drugs had no effect. Seven cases used adrenocorticotropic hormone (ACTH) and prednisone besides AEDs (a total course for 8 weeks

Cerebrospinal fluid findings after epileptic seizures.

PubMed

Chatzikonstantinou, Anastasios; Ebert, Anne D; Hennerici, Michael G

2015-12-01

We aimed to evaluate ictally-induced CSF parameter changes after seizures in adult patients without acute inflammatory diseases or infectious diseases associated with the central nervous system. In total, 151 patients were included in the study. All patients were admitted to our department of neurology following acute seizures and received an extensive work-up including EEG, cerebral imaging, and CSF examinations. CSF protein elevation was found in most patients (92; 60.9%) and was significantly associated with older age, male sex, and generalized seizures. Abnormal CSF-to-serum glucose ratio was found in only nine patients (5.9%) and did not show any significant associations. CSF lactate was elevated in 34 patients (22.5%) and showed a significant association with focal seizures with impaired consciousness, status epilepticus, the presence of EEG abnormalities in general and epileptiform potentials in particular, as well as epileptogenic lesions on cerebral imaging. Our results indicate that non-inflammatory CSF elevation of protein and lactate after epileptic seizures is relatively common, in contrast to changes in CSF-to-serum glucose ratio, and further suggest that these changes are caused by ictal activity and are related to seizure type and intensity. We found no indication that these changes may have further-reaching pathological implications besides their postictal character.

[Non-epileptic paroxysmal sleep disorders].

PubMed

Malagón-Valdez, Jorge

2013-09-06

Non-epileptic paroxysmal disorders during sleep are a great challenge for the clinician. It is important to know the various clinical manifestations for appropriate differential diagnosis, since alterations in sleep, mostly motor, are part of these disorders. Our paper describes the normal sleep stages and electroencephalographic characteristics and polysomnography basic data. The confusions especially with nocturnal frontal lobe epilepsy are frequent and cause unnecessary drugs administered, the emotional burden of the parents or caretakers, which is the diagnosis of epilepsy. We discuss the possible causes of diagnostic errors.

Emperor Napoleon Bonaparte: did he have seizures? Psychogenic or epileptic or both?

PubMed

Hughes, John R

2003-12-01

Napoleon Bonaparte was a general in the French army at 24 years of age, later conquering most of Europe. He was one of the greatest military geniuses the world has ever known, but also an extremely intelligent individual. Did he have seizures? The evidence shows that he had both psychogenic and epileptic attacks. The psychogenic attacks were likely related to the tremendous stress in his life, and the epileptic seizures were the result of chronic uremia from a severe urethral stricture caused by gonorrhea that was transmitted from his wife, Empress Josephine.

Emergence of semiology in epileptic seizures.

PubMed

Chauvel, Patrick; McGonigal, Aileen

2014-09-01

Semiology, the manifestation of epilepsy, is dependent upon electrical activity produced by epileptic seizures that are organized within existing neural pathways. Clinical signs evolve as the epileptic discharge spreads in both time and space. Studying the relation between these, of which the temporal component is at least as important as the spatial one, is possible using anatomo-electro-clinical correlations of stereoelectroencephalography (SEEG) data. The period of semiology production occurs with variable time lag after seizure onset and signs then emerge more or less rapidly depending on seizure type (temporal seizures generally propagating more slowly and frontal seizures more quickly). The subset of structures involved in semiological production, the "early spread network", is tightly linked to those constituting the epileptogenic zone. The level of complexity of semiological features varies according to the degree of involvement of the primary or associative cortex, with the former having a direct relation to peripheral sensory and motor systems with production of hallucinations (visual and auditory) or elementary sensorimotor signs. Depending on propagation pattern, these signs can occur in a "march" fashion as described by Jackson. On the other hand, seizures involving the associative cortex, having a less direct relation with the peripheral nervous system, and necessarily involving more widely distributed networks manifest with altered cognitive and/or behavioral signs whose neural substrate involves a network of cortical structures, as has been observed for normal cognitive processes. Other than the anatomical localization of these structures, the frequency of the discharge is a crucial determinant of semiological effect since a fast (gamma) discharge will tend to deactivate normal function, whereas a slower theta discharge can mimic physiological function. In terms of interaction between structures, the degree of synchronization plays a key role in

Using bivariate signal analysis to characterize the epileptic focus: the benefit of surrogates.

PubMed

Andrzejak, R G; Chicharro, D; Lehnertz, K; Mormann, F

2011-04-01

The disease epilepsy is related to hypersynchronous activity of networks of neurons. While acute epileptic seizures are the most extreme manifestation of this hypersynchronous activity, an elevated level of interdependence of neuronal dynamics is thought to persist also during the seizure-free interval. In multichannel recordings from brain areas involved in the epileptic process, this interdependence can be reflected in an increased linear cross correlation but also in signal properties of higher order. Bivariate time series analysis comprises a variety of approaches, each with different degrees of sensitivity and specificity for interdependencies reflected in lower- or higher-order properties of pairs of simultaneously recorded signals. Here we investigate which approach is best suited to detect putatively elevated interdependence levels in signals recorded from brain areas involved in the epileptic process. For this purpose, we use the linear cross correlation that is sensitive to lower-order signatures of interdependence, a nonlinear interdependence measure that integrates both lower- and higher-order properties, and a surrogate-corrected nonlinear interdependence measure that aims to specifically characterize higher-order properties. We analyze intracranial electroencephalographic recordings of the seizure-free interval from 29 patients with an epileptic focus located in the medial temporal lobe. Our results show that all three approaches detect higher levels of interdependence for signals recorded from the brain hemisphere containing the epileptic focus as compared to signals recorded from the opposite hemisphere. For the linear cross correlation, however, these differences are not significant. For the nonlinear interdependence measure, results are significant but only of moderate accuracy with regard to the discriminative power for the focal and nonfocal hemispheres. The highest significance and accuracy is obtained for the surrogate-corrected nonlinear

Using bivariate signal analysis to characterize the epileptic focus: The benefit of surrogates

NASA Astrophysics Data System (ADS)

Andrzejak, R. G.; Chicharro, D.; Lehnertz, K.; Mormann, F.

2011-04-01

The disease epilepsy is related to hypersynchronous activity of networks of neurons. While acute epileptic seizures are the most extreme manifestation of this hypersynchronous activity, an elevated level of interdependence of neuronal dynamics is thought to persist also during the seizure-free interval. In multichannel recordings from brain areas involved in the epileptic process, this interdependence can be reflected in an increased linear cross correlation but also in signal properties of higher order. Bivariate time series analysis comprises a variety of approaches, each with different degrees of sensitivity and specificity for interdependencies reflected in lower- or higher-order properties of pairs of simultaneously recorded signals. Here we investigate which approach is best suited to detect putatively elevated interdependence levels in signals recorded from brain areas involved in the epileptic process. For this purpose, we use the linear cross correlation that is sensitive to lower-order signatures of interdependence, a nonlinear interdependence measure that integrates both lower- and higher-order properties, and a surrogate-corrected nonlinear interdependence measure that aims to specifically characterize higher-order properties. We analyze intracranial electroencephalographic recordings of the seizure-free interval from 29 patients with an epileptic focus located in the medial temporal lobe. Our results show that all three approaches detect higher levels of interdependence for signals recorded from the brain hemisphere containing the epileptic focus as compared to signals recorded from the opposite hemisphere. For the linear cross correlation, however, these differences are not significant. For the nonlinear interdependence measure, results are significant but only of moderate accuracy with regard to the discriminative power for the focal and nonfocal hemispheres. The highest significance and accuracy is obtained for the surrogate-corrected nonlinear

Multimodal investigation of epileptic networks: The case of insular cortex epilepsy.

PubMed

Zerouali, Y; Ghaziri, J; Nguyen, D K

2016-01-01

The insula is a deep cortical structure sharing extensive synaptic connections with a variety of brain regions, including several frontal, temporal, and parietal structures. The identification of the insular connectivity network is obviously valuable for understanding a number of cognitive processes, but also for understanding epilepsy since insular seizures involve a number of remote brain regions. Ultimately, knowledge of the structure and causal relationships within the epileptic networks associated with insular cortex epilepsy can offer deeper insights into this relatively neglected type of epilepsy enabling the refining of the clinical approach in managing patients affected by it. In the present chapter, we first review the multimodal noninvasive tests performed during the presurgical evaluation of epileptic patients with drug refractory focal epilepsy, with particular emphasis on their value for the detection of insular cortex epilepsy. Second, we review the emerging multimodal investigation techniques in the field of epilepsy, that aim to (1) enhance the detection of insular cortex epilepsy and (2) unveil the architecture and causal relationships within epileptic networks. We summarize the results of these approaches with emphasis on the specific case of insular cortex epilepsy. © 2016 Elsevier B.V. All rights reserved.

Effect of ketogenic diet and other dietary therapies on anti-epileptic drug concentrations in patients with epilepsy.

PubMed

Heo, G; Kim, S H; Chang, M J

2017-12-01

The ketogenic diet (KD) is an effective high-fat, adequate-protein, low-carbohydrate diet for patients with refractory epilepsy. The aim of this study was to investigate the potential effects of the KD and other dietary therapies on the concentrations of anticonvulsants in patients with epilepsy. Patients with epilepsy who were treated with the KD and other dietary therapies for more than 30 days with at least one measurement performed both before and during the diet were evaluated. The mean serum concentrations and the mean serum concentrations per weight per daily dose per bioavailability (F) of anti-epileptic drugs (AEDs) before and during the treatment were assessed. We also compared the rates of events out of reference ranges of the AEDs between before and during the KD and other dietary therapies. We compared the serum albumin, alanine transaminase and aspartate transaminase data of patients with valproic acid before and during the KD. One-hundred thirty-nine patients including 81 male patients were enrolled. The median age of the patients was 2.91 (0.15-15.46) years. The median duration of the dietary therapies was 153 (35-2307) days. After the dietary therapies, the serum concentrations of carbamazepine, lamotrigine, levetiracetam, topiramate and valproic acid decreased, whereas that of phenobarbital slightly increased. However, statistical significance was found only with valproic acid (67.07±25.89 μg/mL vs 51.00±20.19 μg/mL, P<.05). The serum concentrations per weight per daily dose per drug F significantly decreased for valproic acid (1.38±1.39×10 -2 vs 0.82±0.82×10 -2  μg d mL -1  F -1 ) and phenobarbital (6.66±7.20×10 -2 vs 4.75±4.07×10 -2  μg d mL -1  F -1 , P<.05). The rate of occurrence of events out of reference ranges significantly increased with valproic acid (36.08% vs 57.23%, P<.05). Most anti-epileptic drug serum concentrations remained stable during the KD and other related dietary therapies except those of valproic

Altered expression and function of small-conductance (SK) Ca2+-activated K+ channels in pilocarpine-treated epileptic rats

PubMed Central

Oliveira, Mauro S.; Skinner, Frank; Arshadmansab, Massoud F.; Garcia, Ileana; Mello, Carlos F.; Knaus, Hans-Günther; Ermolinsky, Boris S.; Pacheco Otalora, Luis F.; Garrido-Sanabria, Emilio R.

2010-01-01

Small conductance calcium (Ca2+) activated SK channels are critical regulators of neuronal excitability in hippocampus. Accordingly, these channels are thought to play a key role in controlling neuronal activity in acute models of epilepsy. In this study, we investigate the expression and function of SK channels in the pilocarpine model of mesial temporal lobe epilepsy. For this purpose, protein expression was assessed using western blotting assays and gene expression was analyzed using TaqMan-based probes and the quantitative real-time polymerase chain reaction (qPCR) comparative method delta-delta cycle threshold (ΔΔCT) in samples extracted from control and epileptic rats. In addition, the effect of SK channel antagonist UCL1684 and agonist NS309 on CA1 evoked population spikes was studied in hippocampal slices. Western blotting analysis showed a significant reduction in the expression of SK1 and SK2 channels at 10 days following status epilepticus (SE), but levels recovered at 1 month and at more than 2 months after SE. In contrast, a significant down-regulation of SK3 channels was detected after 10 days of SE. Analysis of gene expression by qPCR revealed a significant reduction of transcripts for SK2 (Kcnn1) and SK3 (Kcnn3) channels as early as 10 days following pilocarpine-induced SE and during the chronic phase of the pilocarpine model. Moreover, bath application of UCL1684 (100 nM for 15 min) induced a significant increase of the population spike amplitude and number of spikes in the hippocampal CA1 area of slices obtained control and chronic epileptic rats. This effect was obliterated by co-administration of UCL1684 with SK channel agonist NS309 (1 μM). Application of NS309 failed to modify population spikes in the CA1 area of slices taken from control and epileptic rats. These data indicate an abnormal expression of SK channels and a possible dysfunction of these channels in experimental MTLE. PMID:20553876

Dynamic Imaging of Coherent Sources Reveals Different Network Connectivity Underlying the Generation and Perpetuation of Epileptic Seizures

PubMed Central

Anwar, Abdul Rauf; Deuschl, Günther; Stephani, Ulrich; Raethjen, Jan; Siniatchkin, Michael

2013-01-01

The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis. PMID:24194931

[Therapeutic Drug Monitoring of Valproic Acid in Children: A Prospective Study of The Effect of The Compliance and The Economic Level on the Trough Plasmatic Concentrations and Epileptic Seizures].

PubMed

Charfi, Rim; Lakhal, Mohamed; Klouz, Anis; Trabelsi, Sameh; Salouage, Issam

2015-01-01

Valproic acid (VA) is a widely used antiepileptic drug. Because of its pharmacokinetic variability and the influence of intrinsic and extrinsic factors such as the treatment compliance, VA therapeutic drug monitoring (TDM) is recommended in children. The aim of this study is to evaluate the effect of treatment compliance and the economic level on VA tough plasmatic concentration (TPC) and epileptic rhythm in children. A one-year prospective study (August 2008-August 2009) concerning children (age≤5 years) regularly treated by VA who had a VA TDM. So, 276 plasmatic samples from 238 children were collected. The children were divided in two groups as following: the group 1 (G1) presenting a good compliance and a reliable questioning and the group 2 (G2) presenting a bad compliance and a non reliable questioning. We evaluated the interindividual variability by correlating the TPC to the dose. Then, we divided the hole group in function of their economic levels (low-medium-high). Sex ratio male/female was 1.3. Median age was 5 years+/-3,9. The mean TPC was 62 µg/mL [0.12-131 µg/mL]. VA TPC were in the therapeutic range (TR) in 62%. Adverse drug reactions were noted in 4.2% of the children. G1 represented 70% of the children and G2, 30%. The TPC were in the TR in 67% of G1 and 51% of G2 (p=0.02). There was a significant difference between the TPC in G1 and G2 (p=0.02).There was no significative difference in the TPC in function of the economic levels. There was no correlation between TPC and the administered doses. The epileptic seizures were more spaced in children with therapeutic TPC than those with TPC in the TR (p=0.002) and in G1 than in G2 (p=0.03). Compliance should be appropriate in order to optimize the TDM rule. A good compliance and a therapeutic TPC allow a better control of epileptic seizures. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Antagonist effects of veratric acid against UVB-induced cell damages.

PubMed

Shin, Seoung Woo; Jung, Eunsun; Kim, Seungbeom; Lee, Kyung-Eun; Youm, Jong-Kyung; Park, Deokhoon

2013-05-10

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human epidermis, resulting in inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effect of UV irradiation is essential. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. The simple phenolic veratric acid (VA, 3,4-dimethoxybenzoic acid) is one of the major benzoic acid derivatives from vegetables and fruits and it also occurs naturally in medicinal mushrooms which have been reported to have anti-inflammatory and anti-oxidant activities. However, it has rarely been applied in skin care. This study, therefore, aimed to explore the possible roles of veratric acid in protection against UVB-induced damage in HaCaT cells. Results showed that veratric acid can attenuate cyclobutane pyrimidine dimers (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by UVB. Furthermore, veratric acid had inhibitory effects on the UVB-induced release of the inflammatory mediators such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of veratric acid on human skin. Overall, results demonstrated significant benefits of veratric acid on the protection of keratinocyte against UVB-induced injuries and suggested its potential use in skin photoprotection.

Genomics-Guided Precise Anti-Epileptic Drug Development.

PubMed

Delanty, Norman; Cavallleri, Gianpiero

2017-07-01

Traditional antiepileptic drug development approaches have yielded many important clinically valuable anti-epileptic drugs. However, the screening of promising compounds has been naturally agnostic to epilepsy etiology in individual human patients. Now, genomic medicine is changing the way we view human disease. International collaborations are unraveling the many molecular genetic causes of the epilepsies, including the early onset epileptic encephalopathies, and some of the familial focal epilepsies. Further advances in precision diagnostics will be facilitated by ongoing large collaborations and the wider availability of whole exome and whole genome sequencing in clinical practice. Securing a precise molecular diagnosis in some individual patients will pave the way for the advent of precision therapeutics of new and re-purposed compounds in the treatment of the epilepsies. This new approach is already beginning, e.g., with the use of everolimus in patients with tuberous sclerosis complex (and perhaps other mTORopathies), the use of quinidine in some children with KCNT1 mutations, and the use of the ketogenic diet in individuals with GLUT-1 deficiency. This article explores the promise of genomics guided drug development as an approach to complement the more traditional model.

Uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity.

PubMed

Yasutake, Yuichi; Tomita, Kengo; Higashiyama, Masaaki; Furuhashi, Hirotaka; Shirakabe, Kazuhiko; Takajo, Takeshi; Maruta, Koji; Sato, Hirokazu; Narimatsu, Kazuyuki; Yoshikawa, Kenichi; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Nagao, Shigeaki; Matsuo, Hirotaka; Miura, Soichiro; Hokari, Ryota

2017-11-01

Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus.

PubMed

Isokawa, M

1996-05-01

1. Inhibitory postsynaptic currents (IPSCs) were studied in hippocampal dentate granule cells (DGCs) in the pilocarpine model and human temporal lobe epilepsy, with the use of the whole cell patch-clamp recording technique in slice preparations. 2. In the pilocarpine model, hippocampal slices were prepared from rats that were allowed to experience spontaneous seizures for 2 mo. Human hippocampal specimens were obtained from epileptic patients who underwent surgical treatment for medically intractable seizures. 3. IPSCs were generated by single perforant path stimulation and recorded at a membrane potential (Vm) of 0 mV near the reversal potential of glutamate excitatory postsynaptic currents in the voltage-clamp recording. IPSCs were pharmacologically identified as gamma-aminobutyric acid-A (GABAA) IPSCs by 10 microM bicuculline methiodide. 4. During low-frequency stimulation, IPSCs were not different in amplitude among non-seizure-experienced rat hippocampi, human nonsclerotic hippocampi, seizure-experienced rat hippocampi, and human sclerotic hippocampi. In the last two groups of DGCs, current-clamp recordings indicated the presence of prolonged excitatory postsynaptic potentials (EPSPs) mediated by the N-methyl-D-aspartate (NMDA) receptor. 5. High-frequency stimulation, administered at Vm = -30 mV to activate NMDA currents, reduced GABAA IPSC amplitude specifically in seizure-experienced rat hippocampi (t = 2.5, P < 0.03) and human sclerotic hippocampi (t = 7.7, P < 0.01). This reduction was blocked by an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (50 microM). The time for GABAA IPSCs to recover to their original amplitude was also shortened by the application of APV. 6. I conclude that, when intensively activated, NMDA receptor-mediated excitatory transmission may interact with GABAergic synaptic inhibition in DGCs in seizure-experienced hippocampus to transiently reduce GABA(A) receptor-channel function. Such interactions may contribute to

Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

PubMed Central

Lee, Haejin; Yun, Seokhwan; Kim, Il-Sun; Lee, Il-Shin; Shin, Jeong Eun; Park, Soo Chul; Kim, Won-Joo; Park, Kook In

2014-01-01

Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (∼34%), APC-CC1+ oligodendrocytes (∼28%), and GFAP+ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal

Similar increases in extracellular lactic acid in the limbic system during epileptic and/or olfactory stimulation.

PubMed

Fornai, F; Bassi, L; Gesi, M; Giorgi, F S; Guerrini, R; Bonaccorsi, I; Alessandrì, M G

2000-01-01

Previous studies have shown that physiological stimulation of brain activity increases anaerobic glucose consumption, both in humans and in experimental animals. To investigate this phenomenon further, we measured extracellular lactate levels within different rat brain regions, using microdialysis. Experiments were performed comparing the effects of natural, physiological olfactory stimulation of the limbic system with experimental limbic seizures. Olfactory stimulation was carried out by using different odors (i.e. both conventional odors: 2-isobutyl-3-methoxypyrazine, green pepper essence; thymol; and 2-sec-butylthiazoline, a sexual pheromone). Limbic seizures were either induced by systemic injection of pilocarpine (200-400 mg/kg) or focally elicited by microinfusions of chemoconvulsants (bicuculline 118 pmol and cychlothiazide 1.2 nmol) within the anterior piriform cortex. Seizures induced by systemic pilocarpine tripled lactic acid within the hippocampus, whereas limbic seizures elicited by focal microinfusion of chemoconvulsants within the piriform cortex produced a less pronounced increase in extracellular lactic acid. Increases in extracellular lactate occurring during olfactory stimulation with the sexual pheromone (three times the baseline levels) were non-significantly different from those occurring after systemic pilocarpine. Increases in lactic acid following natural olfactory stimulation were abolished both by olfactory bulbectomy and by the focal microinfusion of tetrodotoxin, while they were significantly attenuated by the local application of the N-methyl-D-aspartate antagonist AP-5. Increases in hippocampal lactate induced by short-lasting stimuli (olfactory stimulation or microinfusion of subthreshold doses of chemoconvulsants, bicuculline 30 pmol) were reproducible after a short delay (1 h) and cumulated when applied sequentially. In contrast, limbic status epilepticus led to a long-lasting refractoriness to additional lactate-raising stimuli

The protection of glycyrrhetinic acid (GA) towards acetaminophen (APAP)-induced toxicity partially through fatty acids metabolic pathway.

PubMed

Yang, Hua; Jiang, Tingshu; Li, Ping; Mao, Qishan

2015-09-01

Acetaminophen (APAP)-induced liver toxicity remains the key factor limiting the clinical application of APAP, and herbs are the important sources for isolation of compounds preventing APAP-induced toxicity. To investigate the protection mechanism of glycyrrhetinic acid towards APAP-induced liver damage using metabolomics method. APAP-induced liver toxicity model was made through intraperitoneal injection (i.p.) of APAP (400 mg/kg). Glycyrrhetinic acid was dissolved in corn oil, and intraperitoneal injection (i.p.) of glycyrrhetinic acid (500 mg/kg body weight) was performed for 20 days before the injection of APAP. UPLC-ESI-QTOF MS was employed to analyze the metabolomic profile of serum samples. The pre-treatment of glycyrrhetinic acid significantly protected APAP-induced toxicity, indicated by the histology of liver, the activity of ALT and AST. Metabolomics showed that the level of palmtioylcarnitine and oleoylcarnitine significantly increased in serum of APAP-treated mice, and the pre-treatment with GA can prevent this elevation of these two fatty acid-carnitines. Reversing the metabolism pathway of fatty acid is an important mechanism for the protection of glycyrrhetinic acid towards acetaminophen-induced liver toxicity.

Epileptic syndrome in systemic lupus erythematosus and neuronal autoantibody associations.

PubMed

Kampylafka, E I; Alexopoulos, H; Fouka, P; Moutsopoulos, H M; Dalakas, M C; Tzioufas, A G

2016-10-01

We investigated systemic lupus erythematosus (SLE) patients with epilepsy, a major and organic neurological symptom. Our aim was to test patients for the autoimmune epilepsy-associated antibodies anti-GAD, anti-NMDAR, anti-AMPAR1/2, anti-GABABR and anti-VGKC. We tested sera from ten SLE patients with current or previous episodes of epileptic seizures. In addition, sera were tested for staining on primary hippocampal neurons. The patients' clinical and neuroimaging profile, disease activity and accumulated damage scores and therapeutic regimens administered were recorded, and correlations were evaluated. Patients were negative for all anti-neuronal autoantibodies tested, and showed no staining on primary hippocampal cells, which suggests the absence of autoantibodies against neuronal cell surface antigens. Epileptic seizures were all tonic-clonic, and all patients had high disease activity (mean SLE Damage Acticity Index score 19.3 ± 7.3). Six patients had minor or no brain magnetic resonance imaging findings, and three had major findings. 9/10 patients received immunosuppression for 5 ± 4 months, while anti-convulsive treatment was administered to all patients (4.2 ± 3 years). Our results suggest that the majority of SLE-related epileptic seizures cannot be attributed to the action of a single antibody against neuronal antigens. Studies with larger neuropsychiatric SLE populations and stricter inclusion criteria are necessary to verify these findings. © The Author(s) 2016.

Epileptic seizure prediction by non-linear methods

DOEpatents

Hively, Lee M.; Clapp, Ned E.; Daw, C. Stuart; Lawkins, William F.

1999-01-01

Methods and apparatus for automatically predicting epileptic seizures monitor and analyze brain wave (EEG or MEG) signals. Steps include: acquiring the brain wave data from the patient; digitizing the data; obtaining nonlinear measures of the data via chaotic time series analysis tools; obtaining time serial trends in the nonlinear measures; comparison of the trend to known seizure predictors; and providing notification that a seizure is forthcoming.

The offspring of epileptic mother.

PubMed

Tamer, S K; Misra, S; Jaiswal, S

1996-01-01

The offspring of an epileptic mother is an issue-currently getting attention because of its several implications. A complex interaction between epilepsy during pregnancy and its adverse impact on foetus, labor, neonate, congenital malformation, psychosocial and medico-social concern and treatment challenges of such cases is increasingly being realised. Some of the significant observations has been reviewed extensively in this article. Maternal epilepsy is likely to adversely affect the off-spring at its various stages of development amounting to increased morbidity and mortality. Increased seizure frequency during pregnancy with resultant increased risk is well documented but its mechanism is poorly understood. Low apgar score, increased still birth rates (1.3 to 14%) in offspring of epileptic mother (OEM) is reported. So also, the neonatal and perinatal deaths are twice more common in OEMS than normal control. Small for dates, and prematurity in OEM is reported to be 7 to 10% and 4-11% respectively. Adverse impact on labor and delivery like preclampsia, abruptio placentae, polyhydramnios, assisted delivery, cesarean section and IUGR poses particular challenges to the obstetrician. Pediatrician's alertness is needed to anticipate and deal with the bleeding manifestation due to deficiency of Vit-K dependent clotting factors and various anticonvulsant drug (AED) withdrawal symptoms. Significant risk of developing congenital malformation is the result of epilepsy perse and the AED used during pregnancy. AED exposure leads to other distinct clinical syndromes, the orofacial clefts and cardiac anomalies being the commonest manifestation. Epilepsy in mother but not in father has significant adverse impact. Management strategies in the context of available observation has been discussed.

[Epilepsy from a metaphysical perspective: an interpretation of the biblical story of the epileptic boy and Raphael's Transfiguration].

PubMed

Janz, D

1994-01-01

Raphael's last painting reveals, in the upper half of the picture, Christ's transfiguration on Mount Tabor and, in the lower half, the young boy's epileptic seizure at the foot of the mountain in the presence of the other disciples. Raphael depicts both events, which are told in succession in the Gospels, as if they took place at the same time. By synchronizing both scenes, Raphael demonstrated a significant correspondence between Christ and the epileptic boy which reveals the epileptic seizure as a symbolic representation of a transcendental event. This metaphysical aspect of epilepsy depicted by Raphael can also be found in the corresponding biblical passages. In the Gospels, the metamorphosis caused by the epileptic seizure is used as a simile for Christ's transfiguration through suffering, death and resurrection.

Distribution entropy analysis of epileptic EEG signals.

PubMed

Li, Peng; Yan, Chang; Karmakar, Chandan; Liu, Changchun

2015-01-01

It is an open-ended challenge to accurately detect the epileptic seizures through electroencephalogram (EEG) signals. Recently published studies have made elaborate attempts to distinguish between the normal and epileptic EEG signals by advanced nonlinear entropy methods, such as the approximate entropy, sample entropy, fuzzy entropy, and permutation entropy, etc. Most recently, a novel distribution entropy (DistEn) has been reported to have superior performance compared with the conventional entropy methods for especially short length data. We thus aimed, in the present study, to show the potential of DistEn in the analysis of epileptic EEG signals. The publicly-accessible Bonn database which consisted of normal, interictal, and ictal EEG signals was used in this study. Three different measurement protocols were set for better understanding the performance of DistEn, which are: i) calculate the DistEn of a specific EEG signal using the full recording; ii) calculate the DistEn by averaging the results for all its possible non-overlapped 5 second segments; and iii) calculate it by averaging the DistEn values for all the possible non-overlapped segments of 1 second length, respectively. Results for all three protocols indicated a statistically significantly increased DistEn for the ictal class compared with both the normal and interictal classes. Besides, the results obtained under the third protocol, which only used very short segments (1 s) of EEG recordings showed a significantly (p <; 0.05) increased DistEn for the interictal class in compassion with the normal class, whereas both analyses using relatively long EEG signals failed in tracking this difference between them, which may be due to a nonstationarity effect on entropy algorithm. The capability of discriminating between the normal and interictal EEG signals is of great clinical relevance since it may provide helpful tools for the detection of a seizure onset. Therefore, our study suggests that the Dist

Paroxysmal non-epileptic events in infants and toddlers: A phenomenologic analysis.

PubMed

Chen, Li; Knight, Elia M Pestana; Tuxhorn, Ingrid; Shahid, Asim; Lüders, Hans O

2015-06-01

The aim of this study was to analyze in detail the clinical phenomenology of paroxysmal non-epileptic events (PNEE) in infants and toddlers. We studied all children aged ≤2 years who were diagnosed with PNEE based on video-electroencephalographic (VEEG) recordings. We analyzed the following four clinical domains of each clinical event: (i) motor manifestations (body/limb jerking, complex motor, and asymmetric limb posturing); (ii) oral/vocal (crying, vocalization, sighing); (iii) behavioral change (arrest of activity, staring); (iv) and autonomic (facial flushing, breath holding). Thirty-one of 81 (38.3%) infants and toddlers had 38 PNEE recorded during the study period (12 girls and 19 boys, mean age 10.5 months). The predominant clinical features were as follows: motor in 26/38 events, oral/verbal in 14/38 events, behavioral in 11/38 events, and autonomic in 8/38 events. Epileptic seizures and PNEE coexisted in four children (12.9%). Seventeen children (54.8%) had one or more risk factors suggestive of epilepsy. Twelve children (38.7%) had a normal neurologic examination, 10 (32.3%) had developmental delay, and eight (25.8%) had a family history of epilepsy or seizures. VEEG recorded PNEE in nearly 40% of 81 infants and toddlers referred for unclear paroxysmal events in our cohort. Non-epileptic staring spells and benign sleep myoclonus were the most common events recorded, followed by shuddering attacks and infantile masturbation. In addition, greater than one-half of the infants and toddlers had risk factors, raising a concern for epilepsy in the family and prompting the VEEG evaluation, suggesting that paroxysmal non-epileptic seizures may frequently coexist in young children with epilepsy. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

PubMed

Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

2015-02-01

Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chiral acidic amino acids induce chiral hierarchical structure in calcium carbonate

PubMed Central

Jiang, Wenge; Pacella, Michael S.; Athanasiadou, Dimitra; Nelea, Valentin; Vali, Hojatollah; Hazen, Robert M.; Gray, Jeffrey J.; McKee, Marc D.

2017-01-01

Chirality is ubiquitous in biology, including in biomineralization, where it is found in many hardened structures of invertebrate marine and terrestrial organisms (for example, spiralling gastropod shells). Here we show that chiral, hierarchically organized architectures for calcium carbonate (vaterite) can be controlled simply by adding chiral acidic amino acids (Asp and Glu). Chiral, vaterite toroidal suprastructure having a ‘right-handed' (counterclockwise) spiralling morphology is induced by L-enantiomers of Asp and Glu, whereas ‘left-handed' (clockwise) morphology is induced by D-enantiomers, and sequentially switching between amino-acid enantiomers causes a switch in chirality. Nanoparticle tilting after binding of chiral amino acids is proposed as a chiral growth mechanism, where a ‘mother' subunit nanoparticle spawns a slightly tilted, consequential ‘daughter' nanoparticle, which by amplification over various length scales creates oriented mineral platelets and chiral vaterite suprastructures. These findings suggest a molecular mechanism for how biomineralization-related enantiomers might exert hierarchical control to form extended chiral suprastructures. PMID:28406143

Alteration in 5-HT₂C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

PubMed

Krishnakumar, Amee; Anju, T R; Abraham, Pretty Mary; Paulose, C S

2015-01-01

Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

Excitatory amino acid transmitters in epilepsy.

PubMed

Meldrum, B S

1991-01-01

For the majority of human epilepsy syndromes, the molecular and cellular basis for the epileptic activity remains largely conjectural. The principal hypotheses currently concern: defects in membrane ionic conductances or transport mechanisms; defects in gamma-aminobutyric acid (GABA)-mediated inhibitory processes; and enhanced or abnormal excitatory synaptic action. Substantial evidence exists in humans and animals for acquired abnormalities in excitatory amino acid neurotransmission that may participate in the abnormal patterns of neuronal discharge, and this could provide the morphological basis for a recurrent excitatory pathway sustaining seizure discharges in temporal lobe epilepsy. In practice, two approaches appear significant in the suppression of seizures. One is to act postsynaptically on receptors to decrease the excitation induced by glutamate, and the other is to decrease synaptic release of glutamate and aspartate. Agents acting upon adenosine or GABAB receptors decrease glutamate release in vitro but do not have significant anticonvulsant activity, probably because of their predominant actions at other sites. Lamotrigine blocks stimulated release of glutamate and shows anticonvulsant activity in a wide range of animal models.

Strain-dependent effects of sub-chronically infused losartan against kainic acid-induced seizures, oxidative stress, and heat shock protein 72 expression.

PubMed

Tchekalarova, Jane; Ivanova, Natasha; Pechlivanova, Daniela; Ilieva, Kalina; Atanasova, Milena

2014-01-01

We studied the involvement of angiotensin (Ang) II AT1 receptors in the pathophysiology of kainate (KA)-induced neurotoxicity, focusing on the regulation of the oxidative stress state and expression of HSP 72 in the frontal cortex and hippocampus in two strains, spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The KA injection was executed after the rats were infused subcutaneously via osmotic mini-pumps with losartan (10 mg/kg day) for 14 days. Losartan delayed the onset of KA-induced seizures in SHRs but not in Wistar rats without affecting the seizure intensity score. This selective AT1 receptor antagonist decreased the lipid peroxidation only in naive SHRs. However, it attenuated the KA-induced increase in lipid peroxidation in both SHRs and Wistar rats. The adaptive enhancement of cytosolic superoxide dismutase (SOD) activity in KA-treated SHRs was recovered to control level after sub-chronic losartan infusion while no change in mitochondrial SOD activity was detected in the two strains. Both losartan and KA produced a higher expression of HSP 72 in the hippocampus of the two strains compared to naive rats infused with vehicle. Taken together, our findings demonstrate that the efficacy of a sub-chronic systemic losartan infusion in preventing the KA-induced seizure activity and neurotoxicity is more pronounced in SHRs, considered as a model of essential hypertension, than in normotenisve Wistar rats. The results suggest that the blockade of AT1 receptors, commonly used as a strategy for prevention of high blood pressure, may be useful as an adjunctive treatment in status epilepticus to reduce oxidative stress and neurotoxicity.

Inhibition of p38 mitogen-activated protein kinase signaling reduces multidrug transporter activity and anti-epileptic drug resistance in refractory epileptic rats.

PubMed

Shao, Yiye; Wang, Cuicui; Hong, Zhen; Chen, Yinghui

2016-03-01

It is widely recognized that P-glycoprotein (P-gp) mediates drug resistance in refractory epilepsy. However, the molecular mechanism underlying the up-regulation of P-gp expression remains unclear. Our previous studies have demonstrated that p38 mitogen-activated protein kinase (MAPK) regulates P-gp expression in cultured K562 cells. However, a lack of in vivo research leaves unanswered questions regarding whether p38MAPK regulates P-gp expression or drug resistance in refractory epilepsy. This in vivo study examined the effects of p38MAPK on the expression of P-gp and mdr1 in the rat brain and quantified antiepileptic drug (AED) concentrations in the hippocampal extracellular fluid. In addition, the role of p38MAPK in electrical and behavioral activity in a rat epilepsy model was studied. The results indicated that p38MAPK inhibition by SB202190 reduced P-gp expression, while increasing AED concentration in the hippocampal extracellular fluid in refractory epileptic rats. SB202190 also reduced the resistance to AEDs in drug-resistant rats and significantly reduced the severity of seizure activity. These results suggest that p38MAPK could participate in drug resistance in refractory epilepsy through the regulation of P-gp. We show that the specific inhibitor of p38MAPK could down-regulate the expression of multidrug transporter (P-glycoprotein) in blood-brain barrier, increase the concentration of antiepileptic drugs in the hippocampal extracellular fluid and reduce anti-epileptic drug resistance in refractory epileptic rats. We propose that the p38MAPK signaling pathway participates in drug resistance in refractory epilepsy through the regulation of P-glycoprotein expression. © 2015 International Society for Neurochemistry.

Ursolic acid improves domoic acid-induced cognitive deficits in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Dong-mei; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province; Lu, Jun, E-mail: lu-jun75@163.com

Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less

Gallic Acid Induces Apoptosis in Human Gastric Adenocarcinoma Cells.

PubMed

Tsai, Chung-Lin; Chiu, Ying-Ming; Ho, Tin-Yun; Hsieh, Chin-Tung; Shieh, Dong-Chen; Lee, Yi-Ju; Tsay, Gregory J; Wu, Yi-Ying

2018-04-01

Gastric cancer is one of the most common malignant cancers with a poor prognosis and high mortality rate worldwide. Current treatment of gastric cancer includes surgery and chemotherapy as the main modalities, but the potentially severe side-effects of chemotherapy present a considerable challenge. Gallic acid is a trihydroxybenzoic acid found to exert an anticancer effect against a variety of cancer cells. The purpose of this study was to determine the anti-cancer activity of Galla chinensis and its main component gallic acid on human gastric adenocarcinoma cells. MTT assay and cell death ELISA were used to determine the apoptotic effect of Gallic Chinensis and gallic acid on human gastric adenocarcinoma cells. To determine the pathway and relevant components by which gallic acid-induced apoptosis is mediated through, cells were transfected with siRNA (Fas, FasL, DR5, p53) using Lipofectamine 2000. Reults: Gallic Chinensis and gallic acid induced apoptosis of human gastric adenocarcinoma cells. Gallic acid induced up-regulation of Fas, FasL, and DR5 expression in AGS cells. Transfection of cells with Fas, FasL, or DR5 siRNA reduced gallic acid-induced cell death. In addition, p53 was shown to be involved in gallic acid-mediated Fas, FasL, and DR5 expression as well as cell apoptosis in AGS cells. These results suggest that gallic acid has a potential role in the treatment of gastric cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Epileptic seizure prediction by non-linear methods

DOEpatents

Hively, L.M.; Clapp, N.E.; Day, C.S.; Lawkins, W.F.

1999-01-12

This research discloses methods and apparatus for automatically predicting epileptic seizures monitor and analyze brain wave (EEG or MEG) signals. Steps include: acquiring the brain wave data from the patient; digitizing the data; obtaining nonlinear measures of the data via chaotic time series analysis tools; obtaining time serial trends in the nonlinear measures; comparison of the trend to known seizure predictors; and providing notification that a seizure is forthcoming. 76 figs.

Epileptic seizure classification of EEG time-series using rational discrete short-time fourier transform.

PubMed

Samiee, Kaveh; Kovács, Petér; Gabbouj, Moncef

2015-02-01

A system for epileptic seizure detection in electroencephalography (EEG) is described in this paper. One of the challenges is to distinguish rhythmic discharges from nonstationary patterns occurring during seizures. The proposed approach is based on an adaptive and localized time-frequency representation of EEG signals by means of rational functions. The corresponding rational discrete short-time Fourier transform (DSTFT) is a novel feature extraction technique for epileptic EEG data. A multilayer perceptron classifier is fed by the coefficients of the rational DSTFT in order to separate seizure epochs from seizure-free epochs. The effectiveness of the proposed method is compared with several state-of-art feature extraction algorithms used in offline epileptic seizure detection. The results of the comparative evaluations show that the proposed method outperforms competing techniques in terms of classification accuracy. In addition, it provides a compact representation of EEG time-series.

Limited efficacy of the ketogenic diet in the treatment of highly refractory epileptic spasms.

PubMed

Hussain, Shaun A; Shin, Ji Hyun; Shih, Evan J; Murata, Kristina K; Sewak, Sarika; Kezele, Michele E; Sankar, Raman; Matsumoto, Joyce H

2016-02-01

Numerous studies have suggested that the ketogenic diet is effective in the treatment of epileptic spasms, even in refractory cases. However, there has been very limited demonstration of prompt and complete (video-EEG confirmed) response. We set out to describe our center's experience with the ketogenic diet in the treatment of children with highly refractory epileptic spasms, with rigorous seizure outcome assessment. Children treated with the ketogenic diet for epileptic spasms between April, 2010 and June, 2014 were retrospectively identified. Seizure burden was tabulated at baseline and after 1, 3, 6, and 12-months of ketogenic diet exposure. Adverse events were similarly ascertained. We identified a cohort of 22 consecutive patients who received ketogenic diet therapy, with median age of onset of epileptic spasms of 5.2 (IQR 2.0-9.0) months, with diet initiation beginning a median of 26.4 (12.5-38.7) months after onset, and following a median of 7 (IQR 5-7) treatment failures. Only 2 patients exhibited a complete response during ketogenic diet exposure, and response was more reasonably attributed to alternative therapies in both cases. A modest early reduction in seizure frequency was not sustained beyond 1 month of diet exposure. The diet was well tolerated, and continued in 6 patients with subjective and/or partial response. In contrast to prior studies reporting substantial efficacy of the ketogenic diet, our findings suggest limited efficacy, albeit in a highly refractory cohort. Prospective studies in both refractory and new-onset populations, with both video-EEG confirmation of response and rigorous cognitive outcome assessment, would be of great value to more clearly define the utility of the ketogenic diet in the treatment of epileptic spasms. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Compare Of the West Syndrome with Other Syndromes in the Epileptic Encephalopathy - Kosovo Experience

PubMed Central

Zeka, Naim; Gërguri, Abdurrahim; Bejiqi, Ramush; Retkoceri, Ragip; Vuciterna, Armend

2017-01-01

BACKGROUND: West Syndrome (WS) represents as a specific epileptic encephalopathy characterised with a unique type of attacks, called infantile spasms, severe forms of abnormalities in electroencephalographic (EEG) records as a hypsarythmias and delays in the psychomotoric development. The characteristics of the disease, mostly affecting male gender, are infantile spasms and typical findings in EEG as a hypsarythmia. Infantile spasms are a consequence of many factors in the undeveloped brain. AIM: We aimed: (1) to see the incidence of the illness and the spreading out because of gender in rapport with other syndromes in the epileptic encephalopathies group; (2) to show principles of the treatment for the illness; and (3) to present the effects of the disease in the psycho-motoric development of affected children. METHODS: The study was designed as a cross-sectional study of the patients with epileptic encephalopathies, treated in Paediatric Clinic in Prishtina, from 1st of January 2013 until the 31st of December 2015. RESULTS: From the cohort group of 97 children diagnosed with epileptic encephalopathies, in 14 of them clinical and EEG signs of WS were noted. The earliest age of disease manifestation was 74 days (± 63.8 days). On the group of children with WS, 13 of them with Natrium Valpropat were treated, with the doses of 301.9 mg (± 64.1). From the cohort group, in 89 children (91.8%) psychomotoric retardation was documented, within the higher reoccurrence in the undifferentiated epileptic encephalopathies (96%) and the WS (78.6%). CONCLUSION: WS is a frequent disease of the encephalopathies with the epileptogenic framework. The resistance in anticonvulsive therapy is huge, and psychomotoric retardation follows a big percentage of children with this syndrome. PMID:29362620

Mapping Epileptic Activity: Sources or Networks for the Clinicians?

PubMed Central

Pittau, Francesca; Mégevand, Pierre; Sheybani, Laurent; Abela, Eugenio; Grouiller, Frédéric; Spinelli, Laurent; Michel, Christoph M.; Seeck, Margitta; Vulliemoz, Serge

2014-01-01

Epileptic seizures of focal origin are classically considered to arise from a focal epileptogenic zone and then spread to other brain regions. This is a key concept for semiological electro-clinical correlations, localization of relevant structural lesions, and selection of patients for epilepsy surgery. Recent development in neuro-imaging and electro-physiology and combinations, thereof, have been validated as contributory tools for focus localization. In parallel, these techniques have revealed that widespread networks of brain regions, rather than a single epileptogenic region, are implicated in focal epileptic activity. Sophisticated multimodal imaging and analysis strategies of brain connectivity patterns have been developed to characterize the spatio-temporal relationships within these networks by combining the strength of both techniques to optimize spatial and temporal resolution with whole-brain coverage and directional connectivity. In this paper, we review the potential clinical contribution of these functional mapping techniques as well as invasive electrophysiology in human beings and animal models for characterizing network connectivity. PMID:25414692

Low-frequency repetitive transcranial magnetic simulation prevents chronic epileptic seizure

PubMed Central

Wang, Yinxu; Wang, Xiaoming; Ke, Sha; Tan, Juan; Hu, Litian; Zhang, Yaodan; Cui, Wenjuan

2013-01-01

Although low-frequency repetitive transcranial magnetic simulation can potentially treat epilepsy, its underlying mechanism remains unclear. This study investigated the influence of low-frequency re-petitive transcranial magnetic simulation on changes in several nonlinear dynamic electroence-phalographic parameters in rats with chronic epilepsy and explored the mechanism underlying petitive transcranial magnetic simulation-induced antiepileptic effects. An epilepsy model was es-tablished using lithium-pilocarpine intraperitoneal injection into adult Sprague-Dawley rats, which were then treated with repetitive transcranial magnetic simulation for 7 consecutive days. Nonlinear electroencephalographic parameters were obtained from the rats at 7, 14, and 28 days post-stimulation. Results showed significantly lower mean correlation-dimension and Kolmogo-rov-entropy values for stimulated rats than for non-stimulated rats. At 28 days, the complexity and point-wise correlation dimensional values were lower in stimulated rats. Low-frequency repetitive transcranial magnetic simulation has suppressive effects on electrical activity in epileptic rats, thus explaining its effectiveness in treating epilepsy. PMID:25206567

Triglyceride accumulation protects against fatty acid-induced lipotoxicity

PubMed Central

Listenberger, Laura L.; Han, Xianlin; Lewis, Sarah E.; Cases, Sylvaine; Farese, Robert V.; Ory, Daniel S.; Schaffer, Jean E.

2003-01-01

Excess lipid accumulation in non-adipose tissues is associated with insulin resistance, pancreatic β-cell apoptosis and heart failure. Here, we demonstrate in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates. Oleic acid supplementation leads to triglyceride accumulation and is well tolerated, whereas excess palmitic acid is poorly incorporated into triglyceride and causes apoptosis. Unsaturated fatty acids rescue palmitate-induced apoptosis by channeling palmitate into triglyceride pools and away from pathways leading to apoptosis. Moreover, in the setting of impaired triglyceride synthesis, oleate induces lipotoxicity. Our findings support a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against lipotoxicity though promotion of triglyceride accumulation. PMID:12629214

Nonlinear analysis of EEG for epileptic seizures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hively, L.M.; Clapp, N.E.; Daw, C.S.

1995-04-01

We apply chaotic time series analysis (CTSA) to human electroencephalogram (EEG) data. Three epoches were examined: epileptic seizure, non-seizure, and transition from non-seizure to seizure. The CTSA tools were applied to four forms of these data: raw EEG data (e-data), artifact data (f-data) via application of a quadratic zero-phase filter of the raw data, artifact-filtered data (g- data) and that was the residual after subtracting f-data from e-data, and a low-pass-filtered version (h-data) of g-data. Two different seizures were analyzed for the same patient. Several nonlinear measures uniquely indicate an epileptic seizure in both cases, including an abrupt decrease inmore » the time per wave cycle in f-data, an abrupt increase in the Kolmogorov entropy and in the correlation dimension for e-h data, and an abrupt increase in the correlation dimension for e-h data. The transition from normal to seizure state also is characterized by distinctly different trends in the nonlinear measures for each seizure and may be potential seizure predictors for this patient. Surrogate analysis of e-data shows that statistically significant nonlinear structure is present during the non-seizure, transition , and seizure epoches.« less

Glycyrrhizin and glycyrrhetinic acid inhibits alpha-naphthyl isothiocyanate-induced liver injury and bile acid cycle disruption.

PubMed

Wang, Haina; Fang, Zhong-Ze; Meng, Ran; Cao, Yun-Feng; Tanaka, Naoki; Krausz, Kristopher W; Gonzalez, Frank J

2017-07-01

Alpha-naphthyl isothiocyanate (ANIT) is a common hepatotoxicant experimentally used to reproduce the pathologies of drug-induced liver injury in humans, but the mechanism of its toxicity remains unclear. To determine the metabolic alterations following ANIT exposure, metabolomic analyses was performed by use of liquid chromatography-mass spectrometry. Partial least squares discriminant analysis (PLS-DA) of liver, serum, bile, ileum, and cecum of vehicle- and ANIT-treated mice revealed significant alterations of individual bile acids, including increased tauroursodeoxycholic acid, taurohydrodeoxycholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid, and decreased ω-, β- and tauro-α/β- murideoxycholic acid, cholic acid, and taurocholic acid in the ANIT-treated groups. In accordance with these changes, ANIT treatment altered the expression of mRNAs encoded by genes responsible for the metabolism and transport of bile acids and cholesterol. Pre-treatment of glycyrrhizin (GL) and glycyrrhetinic acid (GA) prevented ANIT-induced liver damage and reversed the alteration of bile acid metabolites and Cyp7a1, Npc1l1, Mttp, and Acat2 mRNAs encoding bile acid transport and metabolism proteins. These results suggested that GL/GA could prevent drug-induced liver injury and ensuing disruption of bile acid metabolism in humans. Published by Elsevier B.V.

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

PubMed

Rösche, J; Uhlmann, C; Weber, R; Fröscher, W

2003-04-01

Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Classifying epileptic EEG signals with delay permutation entropy and Multi-Scale K-means.

PubMed

Zhu, Guohun; Li, Yan; Wen, Peng Paul; Wang, Shuaifang

2015-01-01

Most epileptic EEG classification algorithms are supervised and require large training datasets, that hinder their use in real time applications. This chapter proposes an unsupervised Multi-Scale K-means (MSK-means) MSK-means algorithm to distinguish epileptic EEG signals and identify epileptic zones. The random initialization of the K-means algorithm can lead to wrong clusters. Based on the characteristics of EEGs, the MSK-means MSK-means algorithm initializes the coarse-scale centroid of a cluster with a suitable scale factor. In this chapter, the MSK-means algorithm is proved theoretically superior to the K-means algorithm on efficiency. In addition, three classifiers: the K-means, MSK-means MSK-means and support vector machine (SVM), are used to identify seizure and localize epileptogenic zone using delay permutation entropy features. The experimental results demonstrate that identifying seizure with the MSK-means algorithm and delay permutation entropy achieves 4. 7 % higher accuracy than that of K-means, and 0. 7 % higher accuracy than that of the SVM.

Epileptic Seizure Forewarning by Nonlinear Techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hively, L.M.

2002-04-19

This report describes work that was performed under a Cooperative Research and Development Agreement (CRADA) between UT-Battelle, LLC (Contractor) and a commercial participant, VIASYS Healthcare Inc. (formerly Nicolet Biomedical, Inc.). The Contractor has patented technology that forewarns of impending epileptic events via scalp electroencephalograph (EEG) data and successfully demonstrated this technology on 20 datasets from the Participant under pre-CRADA effort. This CRADA sought to bridge the gap between the Contractor's existing research-class software and a prototype medical device for subsequent commercialization by the Participant. The objectives of this CRADA were (1) development of a combination of existing computer hardware andmore » Contractor-patented software into a clinical process for warning of impending epileptic events in human patients, and (2) validation of the epilepsy warning methodology. This work modified the ORNL research-class FORTRAN for forewarning to run under a graphical user interface (GUI). The GUI-FORTRAN software subsequently was installed on desktop computers at five epilepsy monitoring units. The forewarning prototypes have run for more than one year without any hardware or software failures. This work also reported extensive analysis of model and EEG datasets to demonstrate the usefulness of the methodology. However, the Participant recently chose to stop work on the CRADA, due to a change in business priorities. Much work remains to convert the technology into a commercial clinical or ambulatory device for patient use, as discussed in App. H.« less

Ferulic acid prevents cerebral ischemic injury-induced reduction of hippocalcin expression.

PubMed

Koh, Phil-Ok

2013-07-01

Intracellular calcium overload is a critical pathophysiological factor in ischemic injury. Hippocalcin is a neuronal calcium sensor protein that buffers intracellular calcium levels and protects cells from apoptotic stimuli. Ferulic acid exerts a neuroprotective effect in cerebral ischemia through its anti-oxidant and anti-inflammation activity. This study investigated whether ferulic acid contributes to hippocalcin expression during cerebral ischemia and glutamate exposure-induced neuronal cell death. Rats were immediately treated with vehicle or ferulic acid (100 mg/kg, i.v.) after middle cerebral artery occlusion (MCAO). Brain tissues were collected 24 h after MCAO and followed by assessment of cerebral infarct. Ferulic acid reduced MCAO-induced infarct regions. A proteomics approach elucidated a decrease in hippocalcin in MCAO-operated animals, ferulic acid attenuates the injury-induced decrease in hippocalcin expression. Reverse transcription-polymerase chain reaction and Western blot analyses confirmed that ferulic acid prevents the injury-induced decrease in hippocalcin. In cultured HT22 hippocampal cells, glutamate exposure increased the intracellular Ca(2+) levels, whereas ferulic acid attenuated this increase. Moreover, ferulic acid attenuated the glutamate toxicity-induced decrease in hippocalcin expression. These findings can suggest the possibility that ferulic acid exerts a neuroprotective effect through modulating hippocalcine expression and regulating intracellular calcium levels. Copyright © 2013 Wiley Periodicals, Inc.

Temporal lobe interictal epileptic discharges affect cerebral activity in “default mode” brain regions

PubMed Central

Laufs, Helmut; Hamandi, Khalid; Salek-Haddadi, Afraim; Kleinschmidt, Andreas K; Duncan, John S; Lemieux, Louis

2007-01-01

A cerebral network comprising precuneus, medial frontal, and temporoparietal cortices is less active both during goal-directed behavior and states of reduced consciousness than during conscious rest. We tested the hypothesis that the interictal epileptic discharges affect activity in these brain regions in patients with temporal lobe epilepsy who have complex partial seizures. At the group level, using electroencephalography-correlated functional magnetic resonance imaging in 19 consecutive patients with focal epilepsy, we found common decreases of resting state activity in 9 patients with temporal lobe epilepsy (TLE) but not in 10 patients with extra-TLE. We infer that the functional consequences of TLE interictal epileptic discharges are different from those in extra-TLE and affect ongoing brain function. Activity increases were detected in the ipsilateral hippocampus in patients with TLE, and in subthalamic, bilateral superior temporal and medial frontal brain regions in patients with extra-TLE, possibly indicating effects of different interictal epileptic discharge propagation. PMID:17133385

[Anxiety and depression among the epileptics in general population in Benin (Western Africa)].

PubMed

Nubukpo, P; Houinato, D; Preux, P-M; Avodé, G; Clément, J-P

2004-01-01

In order to assess prevalence of depression and anxiety among epileptic patients and to compare it to a control population, a matched case-control survey was performed in 196 persons above 18 Year old (98 epileptics and 98 controls matched according to sex, age 10 and social environment) in Republic of Benin (West Africa), using Goldberg's Depression and Anxiety scale. Two main investigators helped by 5 sociology students were trained on a questionnaire by a psychiatrist skilled with public health matters. People taking part in the survey are epileptic patients who already used health services. Inclusions took place within 17 communes of four departments (Mono, Zou, Ouémé, Atlantique) located in Southern part of Benin. The questionnaire used an Identity sheet and the Goldberg Depression Scale. Results are shown as mean standard deviations, for quantitative values, and percents for qualitative ones. Comparisons of proportions in qualitative variables are carried out using c2 test or Fisher's exact test. Comparisons of means rates between subject's groups are carried out with a Student t test or variance analysis. The correlations between two quantitative variables were assessed by linear correlation coefficient. Significance threshold chosen for the whole set of statistics analysis is 0.05. The majority of interviewed epileptic patients is young (average 32.6 11.5 Years old). A male predominance exists (sex ratio 1.28). 93% of interviewed persons live within their family, are married or cohabit (controls: 98.2%; cases: 87.9%); 57.4% are married (controls: 70%; cases: 44%). The most represented professional categories are craftsmen and shopkeepers (29.2%) as well as farmers (19.5%). Most of recruited patients live in an urban setting (55.4%) and 63.6% of interviewed persons had been living in the area of survey for over 10 Years. The most represented religion within the sample is Christian religion (67.7%), Animists (23.3%) and Muslims (5.8%). 97% of epileptic

Should epidural drain be recommended after supratentorial craniotomy for epileptic patients?

PubMed

Guangming, Zhang; Huancong, Zuo; Wenjing, Zhou; Guoqiang, Chen; Xiaosong, Wang

2009-08-01

ED was once and is still commonly applied to prevent mainly EH and subgaleal CSF collection. We designed this study to observe if ED could decrease the incidence and volume of EH and subgaleal CSF collection after supratentorial craniotomy in epileptic patients. Three hundred forty-two epileptic patients were divided into 2 groups according to their first craniotomy date (group 1 in odd date and group 2 in even date). Patients in group 1 had ED and those in group 2 had no ED. The patient numbers and volumes of EH and subgaleal CSF collections in both groups were recorded and statistically analyzed. There were 22 EHs in group 1 and 20 EHs in group 2. There were 11 and 10 subgaleal CSF collections in groups 1 and 2, respectively. The average volume of EH was 13.5 +/- 8.12 and 14.65 +/- 7.72 mL in groups 1 and 2, respectively. The average volume of subgaleal CSF collection was 42.76 +/- 12.09 and 43.75 +/- 11.44 mL in groups 1 and 2, respectively. There were no statistical differences in the incidence and average volume of EH and subgaleal CSF collection between the 2 groups. ED cannot decrease the incidence and volume of EH and subgaleal CSF collection. ED should not be recommended after supratentorial epileptic craniotomy.

UV-induced solvent free synthesis of truxillic acid-bile acid conjugates

NASA Astrophysics Data System (ADS)

Koivukorpi, Juha; Kolehmainen, Erkki

2009-07-01

The solvent free UV-induced [2 + 2] intermolecular cycloaddition of two molecules of 3α-cinnamic acid ester of methyl lithocholate produced in 99% yield of α- and ɛ-truxillic acid-bis(methyl lithocholate) isomers, which possess two structurally different potential binding sites. A prerequisite for this effective solid state reaction is a proper self-assembled crystal structure of the starting conjugate crystallized from acetonitrile. The crystallization of cinnamic acid ester of methyl lithocholate from acetonitrile produces two different crystalline forms (polymorphs), which is the reason for the solid state formation of two isomers of truxillic acid-bis(methyl lithocholate).

A novel mutation in STXBP1 gene in a child with epileptic encephalopathy and an atypical electroclinical pattern.

PubMed

Romaniello, Romina; Zucca, Claudio; Tenderini, Erika; Arrigoni, Filippo; Ragona, Francesca; Zorzi, Giovanna; Bassi, Maria Teresa; Borgatti, Renato

2014-02-01

Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-year-old boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of "STXBP1-related encephalopathy" suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects.

The quantitative measurement of consciousness during epileptic seizures.

PubMed

Nani, Andrea; Cavanna, Andrea E

2014-01-01

The assessment of consciousness is a fundamental element in the classification of epileptic seizures. It is, therefore, of great importance for clinical practice to develop instruments that enable an accurate and reliable measurement of the alteration of consciousness during seizures. Over the last few years, three psychometric scales have been specifically proposed to measure ictal consciousness: the Ictal Consciousness Inventory (ICI), the Consciousness Seizure Scale (CSS), and the Responsiveness in Epilepsy Scale--versions I and II (RES-I and RES-II). The ICI is a self-report psychometric instrument which retrospectively assesses ictal consciousness along the dimensions of the level/arousal and contents/awareness. The CSS has been used by clinicians to quantify the impairment of consciousness in order to establish correlations with the brain mechanisms underlying alterations of consciousness during temporal lobe seizures. The most recently developed observer-rated instrument is the RES-I, which has been used to assess responsiveness during epileptic seizures in patients undergoing video-EEG. The implementation of standardized psychometric tools for the assessment of ictal consciousness can complement clinical observations and contribute to improve accuracy in seizure classification. © 2013.

Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts.

PubMed

Maeda-Sano, Katsura; Gotoh, Mari; Morohoshi, Toshiro; Someya, Takao; Murofushi, Hiromu; Murakami-Murofushi, Kimiko

2014-09-01

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR1, Gi/o protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor κB induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR1-Gi/o followed by the PI3K, ERK, and CREB signaling pathway. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Causes of mortality in early infantile epileptic encephalopathy: A systematic review.

PubMed

Radaelli, Graciane; de Souza Santos, Francisco; Borelli, Wyllians Vendramini; Pisani, Leonardo; Nunes, Magda Lahorgue; Scorza, Fulvio Alexandre; da Costa, Jaderson Costa

2018-06-12

Early infantile epileptic encephalopathy syndrome (EIEE), also known as Ohtahara syndrome, is an age-dependent epileptic encephalopathy syndrome defined by clinical features and electroencephalographic findings. Epileptic disorders with refractory seizures beginning in the neonatal period and/or early infancy have a potential risk of premature mortality, including sudden death. We aimed to identify the causes of death in EIEE and conducted a literature survey of fatal outcomes. We performed a literature search in MEDLINE, EMBASE, and Web of Science for data from inception until September 2017. The terms "death sudden," "unexplained death," "SUDEP," "lethal," and "fatal" and the medical subject heading terms "epileptic encephalopathy," "mortality," "death," "sudden infant death syndrome," and "human" were used in the search strategy. The EIEE case report studies reporting mortality were included. The search yielded 1360 articles. After screening for titles and abstracts and removing duplicate entries, full texts of 15 articles were reviewed. After reading full texts, 11 articles met the inclusion criteria (9 articles in English and 2 in Japanese, dated from 1976 to 2015). The review comprised 38 unique cases of EIEE, 17 of which had death as an outcome. In all cases, the suppression-burst pattern on electroencephalographies (EEGs) was common. Most cases (55%) involved male infants. The mean (standard deviation [SD]) age at onset of seizure was 19.6 ± 33 days. The mean (SD) age at death was 12.9 ± 14.1 months. Most infants (58.8%) survived less than one year. The cause of death was described only in eight (47%) patients; the cause was pneumonia/respiratory illness or sudden unexpected death in epilepsy (SUDEP). The results show EIEE as a severe disease associated with a premature mortality, evidenced by a very young age at death. Increasing interest in the detection of new molecular bases of EIEE is leading us to a better understanding of this severe

Quantitative analysis of surface electromyography during epileptic and nonepileptic convulsive seizures.

PubMed

Beniczky, Sándor; Conradsen, Isa; Moldovan, Mihai; Jennum, Poul; Fabricius, Martin; Benedek, Krisztina; Andersen, Noémi; Hjalgrim, Helle; Wolf, Peter

2014-07-01

To investigate the characteristics of sustained muscle activation during convulsive epileptic and psychogenic nonepileptic seizures (PNES), as compared to voluntary muscle activation. The main goal was to find surface electromyography (EMG) features that can distinguish between convulsive epileptic seizures and convulsive PNES. In this case-control study, surface EMG was recorded from the deltoid muscles during long-term video-electroencephalography (EEG) monitoring in 25 patients and in 21 healthy controls. A total of 46 clinical episodes were recorded: 28 generalized tonic-clonic seizures (GTCS) from 14 patients with epilepsy, and 18 convulsive PNES from 12 patients (one patient had both GTCS and PNES). The healthy controls were simulating GTCS. To quantitatively characterize the signals we calculated the following parameters: root mean square (RMS) of the amplitude, median frequency (MF), coherence, and duration of the seizures, of the clonic EMG discharges, and of the silent periods between the cloni. Based on wavelet analysis, we distinguished between a low-frequency component (LF 2-8 Hz) and a high-frequency component (HF 64-256 Hz). Duration of the seizure, and separation between the tonic and the clonic phases distinguished at group-level but not at individual level between convulsive PNES and GTCS. RMS, temporal dynamics of the HF/LF ratio, and the evolution of the silent periods differentiated between epileptic and nonepileptic convulsive seizures at the individual level. A combination between HF/LF ratio and RMS separated all PNES from the GTCS. A blinded review of the EMG features distinguished correctly between GTCS and convulsive PNES in all cases. The HF/LF ratio and the RMS of the PNES were smaller compared to the simulated seizures. In addition to providing insight into the mechanism of muscle activation during convulsive PNES, these results have diagnostic significance, at the individual level. Surface EMG features can accurately distinguish

Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study.

PubMed

Spagnoli, Carlotta; Kugathasan, Umaiyal; Brittain, Helen; Boyd, Stewart G

2015-08-01

Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25-50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients. We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011. All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed. Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz's grade 2-4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1s to a maximum of 9s. In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures.

PubMed

Castillo, Claudia G; Mendoza-Trejo, Soledad; Aguilar, Manuel B; Freed, William J; Giordano, Magda

2008-11-03

We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [Castillo CG, Mendoza S, Freed WJ, Giordano M. Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat. Behav Brain Res 2006;171:109-15] in an animal model. In the present study, recurrent spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague-Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O CL-4 transplants, the death rate was reduced to less than 20%. The M213-2O CL-4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67 cDNA, as well as increased gamma-aminobutyric acid (GABA) levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

Alterations in the contents of consciousness in partial epileptic seizures.

PubMed

Johanson, Mirja; Valli, Katja; Revonsuo, Antti; Chaplin, John E; Wedlund, Jan-Eric

2008-08-01

Epilepsy research suffers from a deficiency of systematic studies concerning the phenomenology of the contents of consciousness during seizures, partially because of the lack of suitable research methods. The Phenomenology of Consciousness Inventory (PCI), a standardized, valid, and reliable questionnaire, was used here to study which dimensions of the contents of consciousness are distorted during partial epileptic seizures compared with baseline. Further, the similarity of the altered pattern of subjective experiences across recurring seizures was also explored. Our results indicate that patients with epilepsy report alterations on most dimensions of the contents of consciousness in conjunction with seizures, but individual seizure experiences remain similar from one seizure to another. The PCI was found suitable for the assessment of subjective experiences during epileptic seizures and could be a valuable tool in providing new information about phenomenal consciousness in epilepsy in both the research and clinical settings.

Ethical Dilemmas in Pediatric and Adolescent Psychogenic Non-Epileptic Seizures

PubMed Central

Cole, Cristie M.; Falcone, Tatiana; Caplan, Rochelle; Timmons-Mitchell, Jane; Jares, Kristine; Ford, Paul J.

2014-01-01

To date only a very narrow window of ethical dilemmas in psychogenic non-epileptic seizures (PNES) have been explored. Numerous distinct ethical dilemmas arise in diagnosing and treating pediatric and adolescent patients with PNES. Important ethical values at stake include trust, transparency, confidentiality, professionalism, autonomy of all stakeholders and justice. In order to further elucidate the ethical challenges in caring for this population, an ethical analysis of the special challenges faced in four specific domains is undertaken: (1) conducting and communicating a diagnosis of PNES; (2) advising patients about full transparency and disclosure to community including patients’ peers; (3) responding to requests to continue anti-epileptic drugs; and (4) managing challenges arising from school policy and procedure. An analysis of these ethical issues is essential for the advancement of best care practices that promote the overall well-being of patients and their families. PMID:25022823

Differential diagnosis of epileptic seizures in infancy including the neonatal period.

PubMed

Cross, J Helen

2013-08-01

It is important to accurately diagnose epileptic seizures in early life to optimise management and prognosis. Conversely, however, many different movements and behaviours may manifest in the neonatal period and infancy that may not have at their root cause a change in electrical activity of the brain. It is important to distinguish them from epileptic seizures to avoid over- and inappropriate treatment. Some are physiological in the normal infant, such as neonatal tremor, benign neonatal sleep myoclonus, and shuddering attacks, whereas others may herald alternative rare neurological diagnoses with differing prognoses such as hyperekplexia, paroxysmal extreme pain disorder and alternating hemiplegia of childhood. Here are highlighted the key clinical features that distinguish some of these disorders, their management and prognosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage

PubMed Central

Kumaran, Kandaswamy Senthil

2010-01-01

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat’s heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients. PMID:20376586

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage.

PubMed

Kumaran, Kandaswamy Senthil; Prince, Ponnian Stanely Mainzen

2010-11-01

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat's heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients.

Rat epileptic seizures evoked by BmK {alpha}IV and its possible mechanisms involved in sodium channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chai Zhifang; Bai Zhantao; Zhang Xuying

2007-05-01

This study showed that rat unilateral intracerebroventricular injection of BmK {alpha}IV, a sodium channel modulator derived from scorpion Buthus martensi Karsch, induced clusters of spikes, epileptic discharges and convulsion-related behavioral changes. BmK {alpha}IV potently promoted the release of endogenous glutamate from rat cerebrocortical synaptosomes. In vitro examination of the effect of BmK {alpha}IV on intrasynaptosomal free calcium concentration [Ca{sup 2+}]{sub i} and sodium concentration [Na{sup +}]{sub i} revealed that BmK {alpha}IV-evoked glutamate release from synaptosomes was associated with an increase in Ca{sup 2+} and Na{sup +} influx. Moreover, BmK {alpha}IV-mediated glutamate release and ion influx was completely blocked by tetrodotoxin,more » a blocker of sodium channel. Together, these results suggest that the induction of BmK {alpha}IV-evoked epileptic seizures may be involved in the modulation of BmK {alpha}IV on tetrodotoxin-sensitive sodium channels located on the nerve terminal, which subsequently enhances the Ca{sup 2+} influx to cause an increase of glutamate release. These findings may provide some insight regarding the mechanism of neuronal action of BmK {alpha}IV in the central nervous system for understanding epileptogenesis involved in sodium channels.« less

Budget impact analysis of adjunctive therapy with lacosamide for partial-onset epileptic seizures in Belgium.

PubMed

Simoens, Steven

2011-01-01

This study aims to compute the budget impact of lacosamide, a new adjunctive therapy for partial-onset seizures in epilepsy patients from 16 years of age who are uncontrolled and having previously used at least three anti-epileptic drugs from a Belgian healthcare payer perspective. The budget impact analysis compared the 'world with lacosamide' to the 'world without lacosamide' and calculated how a change in the mix of anti-epileptic drugs used to treat uncontrolled epilepsy would impact drug spending from 2008 to 2013. Data on the number of patients and on the market shares of anti-epileptic drugs were taken from Belgian sources and from the literature. Unit costs of anti-epileptic drugs originated from Belgian sources. The budget impact was calculated from two scenarios about the market uptake of lacosamide. The Belgian target population is expected to increase from 5333 patients in 2008 to 5522 patients in 2013. Assuming that the market share of lacosamide increases linearly over time and is taken evenly from all other anti-epileptic drugs (AEDs), the budget impact of adopting adjunctive therapy with lacosamide increases from €5249 (0.1% of reference drug budget) in 2008 to €242,700 (4.7% of reference drug budget) in 2013. Assuming that 10% of patients use standard AED therapy plus lacosamide, the budget impact of adopting adjunctive therapy with lacosamide is around €800,000-900,000 per year (or 16.7% of the reference drug budget). Adjunctive therapy with lacosamide would raise drug spending for this patient population by as much as 16.7% per year. However, this budget impact analysis did not consider the fact that lacosamide reduces costs of seizure management and withdrawal. The literature suggests that, if savings in other healthcare costs are taken into account, adjunctive therapy with lacosamide may be cost saving.

Nonlinear times series analysis of epileptic human electroencephalogram (EEG)

NASA Astrophysics Data System (ADS)

Li, Dingzhou

The problem of seizure anticipation in patients with epilepsy has attracted significant attention in the past few years. In this paper we discuss two approaches, using methods of nonlinear time series analysis applied to scalp electrode recordings, which is able to distinguish between epochs temporally distant from and just prior to, the onset of a seizure in patients with temporal lobe epilepsy. First we describe a method involving a comparison of recordings taken from electrodes adjacent to and remote from the site of the seizure focus. In particular, we define a nonlinear quantity which we call marginal predictability. This quantity is computed using data from remote and from adjacent electrodes. We find that the difference between the marginal predictabilities computed for the remote and adjacent electrodes decreases several tens of minutes prior to seizure onset, compared to its value interictally. We also show that these difl'crcnc es of marginal predictability intervals are independent of the behavior state of the patient. Next we examine the please coherence between different electrodes both in the long-range and the short-range. When time is distant from seizure onsets ("interictally"), epileptic patients have lower long-range phase coherence in the delta (1-4Hz) and beta (18-30Hz) frequency band compared to nonepileptic subjects. When seizures approach (''preictally"), we observe an increase in phase coherence in the beta band. However, interictally there is no difference in short-range phase coherence between this cohort of patients and non-epileptic subjects. Preictally short-range phase coherence also increases in the alpha (10-13Hz) and the beta band. Next we apply the quantity marginal predictability on the phase difference time series. Such marginal predictabilities are lower in the patients than in the non-epileptic subjects. However, when seizure approaches, the former moves asymptotically towards the latter.

Factors associated with hopelessness in epileptic patients

PubMed Central

Pompili, Maurizio; Serafini, Gianluca; Innamorati, Marco; Montebovi, Franco; Lamis, Dorian A; Milelli, Mariantonietta; Giuliani, Manuela; Caporro, Matteo; Tisei, Paolo; Lester, David; Amore, Mario; Girardi, Paolo; Buttinelli, Carla

2014-01-01

AIM: To investigate factors related to hopelessness in a sample of epileptic patients, including measures of depression and quality of life (QOL). METHODS: Sixty-nine participants were administered the following psychometric instruments: Beck Depression Inventory-II, Beck Hopelessness Scale (BHS), and QOL in Epilepsy (QOLIE)-89. Patients were dichotomized into two categories: those affected by epilepsy with generalized tonic-clonic seizures vs those having epilepsy with partial seizures. RESULTS: The groups differed on the QOLIE Role Limitation/Emotional dimension. Patients with generalized seizures reported more limitations in common social/role activities related to emotional problems than patients with other types of epilepsy (89.57 ± 25.49 vs 72.86 ± 36.38; t63 = -2.16; P < 0.05). All of the respondents reported moderate to severe depression, and 21.7% of patients with generalized seizures and 28.6% of patients with other diagnoses had BHS total scores ≥ 9 indicating a higher suicidal risk. The study did not control for years of the illness. CONCLUSION: Patients with generalized seizures reported more limitations in common social/role activities related to emotional problems compared to patients with other types of seizures. Patients at increased suicide risk as evaluated by the BHS were older than those who had a lower suicidal risk. Future studies are required to further investigate the impact of hopelessness on the outcome of epileptic patients. PMID:25540729

Effects of lipoic Acid on acrylamide induced testicular damage.

PubMed

Lebda, Mohamed; Gad, Shereen; Gaafar, Hossam

2014-06-01

Acrylamide is very toxic to various organs and associated with significant increase of oxidative stress and depletion of antioxidants. Alpha-lipoic acid enhances cellular antioxidant defense capacity, thereby protecting cells from oxidative stress. This study aimed to evaluate the protective role of alpha-lipoic acid on the oxidative damage induced by acrylamide in testicular and epididymal tissues. Forty adult male rats were divided into four groups (10 rats each). Control group; acrylamide treated group administered acrylamide 0.05% (w/v) in drinking water for 21 days; alpha-lipoic acid group received basal diet supplemented with 1% alpha-lipoic acid and forth group was exposed to acrylamide and treated with alpha-lipoic acid at the same doses and treatment regimen mentioned before. The administration of acrylamide resulted in significant elevation in testicular and epididymal malondialdehyde level (MDA) and significant reduction in the level of reduced glutathione (GSH) and the activities of glutathione-S-transferase (GST), glutathione peroxidase (GPX) and glutathione reductase (GR). Also, acrylamide significantly reduced serum total testosterone and progesterone but increased estradiol (E2) levels. Treatment with alpha-lipoic acid prior to acrylamide induced protective effects and attenuated these biochemical changes. Alpha-lipoic acid has been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by acrylamide administration.

Hidden pattern discovery on epileptic EEG with 1-D local binary patterns and epileptic seizures detection by grey relational analysis.

PubMed

Kaya, Yılmaz

2015-09-01

This paper proposes a novel approach to detect epilepsy seizures by using Electroencephalography (EEG), which is one of the most common methods for the diagnosis of epilepsy, based on 1-Dimension Local Binary Pattern (1D-LBP) and grey relational analysis (GRA) methods. The main aim of this paper is to evaluate and validate a novel approach, which is a computer-based quantitative EEG analyzing method and based on grey systems, aimed to help decision-maker. In this study, 1D-LBP, which utilizes all data points, was employed for extracting features in raw EEG signals, Fisher score (FS) was employed to select the representative features, which can also be determined as hidden patterns. Additionally, GRA is performed to classify EEG signals through these Fisher scored features. The experimental results of the proposed approach, which was employed in a public dataset for validation, showed that it has a high accuracy in identifying epileptic EEG signals. For various combinations of epileptic EEG, such as A-E, B-E, C-E, D-E, and A-D clusters, 100, 96, 100, 99.00 and 100% were achieved, respectively. Also, this work presents an attempt to develop a new general-purpose hidden pattern determination scheme, which can be utilized for different categories of time-varying signals.

Hypochlorous and peracetic acid induced oxidation of dairy proteins.

PubMed

Kerkaert, Barbara; Mestdagh, Frédéric; Cucu, Tatiana; Aedo, Philip Roger; Ling, Shen Yan; De Meulenaer, Bruno

2011-02-09

Hypochlorous and peracetic acids, both known disinfectants in the food industry, were compared for their oxidative capacity toward dairy proteins. Whey proteins and caseins were oxidized under well controlled conditions at pH 8 as a function of the sanitizing concentration. Different markers for protein oxidation were monitored. The results established that the protein carbonyl content was a rather unspecific marker for protein oxidation, which did not allow one to differentiate the oxidant used especially at the lower concentrations. Cysteine, tryptophan, and methionine were proven to be the most vulnerable amino acids for degradation upon hypochlorous and peracetic acid treatment, while tyrosine was only prone to degradation in the presence of hypochlorous acid. Hypochlorous acid induced oxidation gave rise to protein aggregation, while during peracetic acid induced oxidation, no high molecular weight aggregates were observed. Protein aggregation upon hypochlorous acid oxidation could primarily be linked to tryptophan and tyrosine degradation.

'Epileptic', 'epileptic person' or 'person with epilepsy'? Bringing quantitative and qualitative evidence on the views of UK patients and carers to the terminology debate.

PubMed

Noble, Adam J; Robinson, Abbey; Snape, Darlene; Marson, Anthony G

2017-02-01

How to refer to someone with epilepsy is a divisive topic. Arguments for and against different approaches, including traditional adjective labels, disability-first labels, and person-first terms have been presented. The preferences of those with epilepsy and their family and friends have, though, never been determined. This study provides this information for the first time. Via epilepsy interest groups and organizations in the UK and Republic of Ireland, 638 patients and 333 significant others completed an online survey. Three distinct phrases were presented: "They're epileptic" (traditional label), "They're an epileptic person" (disability-first) and "That person has epilepsy" (person-first). Participants identified which they preferred and explained their choices. Patients' median age was 39, with 69% having experienced seizures in the prior 12months. Significant others were typically parents. Most (86.7%) patients and significant others (93.4%) favored the person-first term. Traditional and disability-first terms were "Disliked"/"Strongly disliked". Regression found it was not possible to reliably distinguish between participants favoring the different terms on the basis of demographics. Qualitative analysis of answers to open-ended questions, however, revealed most favored person-first terminology as by not including the word 'epileptic' and by affirming personhood before disability, it was felt to less likely restrict a listener's expectations or evoke the condition's negative association. It was also considered to suggest the person being referred to might have some mastery over their condition. The findings indicate consensus amongst these key stakeholders others for the use of person-first terminology in English. A truly informed debate on the topic can now begin. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Dynamics of regional brain activity in epilepsy: a cross-disciplinary study on both intracranial and scalp-recorded epileptic seizures.

PubMed

Minadakis, George; Ventouras, Errikos; Gatzonis, Stylianos D; Siatouni, Anna; Tsekou, Hara; Kalatzis, Ioannis; Sakas, Damianos E; Stonham, John

2014-04-01

Recent cross-disciplinary literature suggests a dynamical analogy between earthquakes and epileptic seizures. This study extends the focus of inquiry for the applicability of models for earthquake dynamics to examine both scalp-recorded and intracranial electroencephalogram recordings related to epileptic seizures. First, we provide an updated definition of the electric event in terms of magnitude and we focus on the applicability of (i) a model for earthquake dynamics, rooted in a nonextensive Tsallis framework, (ii) the traditional Gutenberg and Richter law and (iii) an alternative method for the magnitude-frequency relation for earthquakes. Second, we apply spatiotemporal analysis in terms of nonextensive statistical physics and we further examine the behavior of the parameters included in the nonextensive formula for both types of electroencephalogram recordings under study. We confirm the previously observed power-law distribution, showing that the nonextensive formula can adequately describe the sequences of electric events included in both types of electroencephalogram recordings. We also show the intermittent behavior of the epileptic seizure cycle which is analogous to the earthquake cycles and we provide evidence of self-affinity of the regional electroencephalogram epileptic seizure activity. This study may provide a framework for the analysis and interpretation of epileptic brain activity and other biological phenomena with similar underlying dynamical mechanisms.

Dynamics of regional brain activity in epilepsy: a cross-disciplinary study on both intracranial and scalp-recorded epileptic seizures

NASA Astrophysics Data System (ADS)

Minadakis, George; Ventouras, Errikos; Gatzonis, Stylianos D.; Siatouni, Anna; Tsekou, Hara; Kalatzis, Ioannis; Sakas, Damianos E.; Stonham, John

2014-04-01

Objective. Recent cross-disciplinary literature suggests a dynamical analogy between earthquakes and epileptic seizures. This study extends the focus of inquiry for the applicability of models for earthquake dynamics to examine both scalp-recorded and intracranial electroencephalogram recordings related to epileptic seizures. Approach. First, we provide an updated definition of the electric event in terms of magnitude and we focus on the applicability of (i) a model for earthquake dynamics, rooted in a nonextensive Tsallis framework, (ii) the traditional Gutenberg and Richter law and (iii) an alternative method for the magnitude-frequency relation for earthquakes. Second, we apply spatiotemporal analysis in terms of nonextensive statistical physics and we further examine the behavior of the parameters included in the nonextensive formula for both types of electroencephalogram recordings under study. Main results. We confirm the previously observed power-law distribution, showing that the nonextensive formula can adequately describe the sequences of electric events included in both types of electroencephalogram recordings. We also show the intermittent behavior of the epileptic seizure cycle which is analogous to the earthquake cycles and we provide evidence of self-affinity of the regional electroencephalogram epileptic seizure activity. Significance. This study may provide a framework for the analysis and interpretation of epileptic brain activity and other biological phenomena with similar underlying dynamical mechanisms.

Epileptic seizure detection from EEG signals with phase-amplitude cross-frequency coupling and support vector machine

NASA Astrophysics Data System (ADS)

Liu, Yang; Wang, Jiang; Cai, Lihui; Chen, Yingyuan; Qin, Yingmei

2018-03-01

As a pattern of cross-frequency coupling (CFC), phase-amplitude coupling (PAC) depicts the interaction between the phase and amplitude of distinct frequency bands from the same signal, and has been proved to be closely related to the brain’s cognitive and memory activities. This work utilized PAC and support vector machine (SVM) classifier to identify the epileptic seizures from electroencephalogram (EEG) data. The entropy-based modulation index (MI) matrixes are used to express the strength of PAC, from which we extracted features as the input for classifier. Based on the Bonn database, which contains five datasets of EEG segments obtained from healthy volunteers and epileptic subjects, a 100% classification accuracy is achieved for identifying seizure ictal from healthy data, and an accuracy of 97.67% is reached in the classification of ictal EEG signals from inter-ictal EEGs. Based on the CHB-MIT database which is a group of continuously recorded epileptic EEGs by scalp electrodes, a 97.50% classification accuracy is obtained and a raising sign of MI value is found at 6s before seizure onset. The classification performance in this work is effective, and PAC can be considered as a useful tool for detecting and predicting the epileptic seizures and providing reference for clinical diagnosis.

Cognitive-Behavioral Treatment of Depressed Affect among Epileptics: Preliminary Findings.

ERIC Educational Resources Information Center

Davis, Gay R.; And Others

1984-01-01

Evaluated a program where cognitive-behavioral methods were utilized in a structured learning format with clinically depressed epileptics (N=13). Results indicated that cognitive behavioral interventions result in significant decreases in depression and increases in related areas of psychosocial functioning that are maintained over time. (LLL)

Reduced tonic inhibition after stroke promotes motor performance and epileptic seizures

PubMed Central

Jaenisch, Nadine; Liebmann, Lutz; Guenther, Madlen; Hübner, Christian A.; Frahm, Christiane; Witte, Otto W.

2016-01-01

Stroke survivors often recover from motor deficits, either spontaneously or with the support of rehabilitative training. Since tonic GABAergic inhibition controls network excitability, it may be involved in recovery. Middle cerebral artery occlusion in rodents reduces tonic GABAergic inhibition in the structurally intact motor cortex (M1). Transcript and protein abundance of the extrasynaptic GABAA-receptor complex α4β3δ are concurrently reduced (δ-GABAARs). In vivo and in vitro analyses show that stroke-induced glutamate release activates NMDA receptors, thereby reducing KCC2 transporters and down-regulates δ-GABAARs. Functionally, this is associated with improved motor performance on the RotaRod, a test in which mice are forced to move in a similar manner to rehabilitative training sessions. As an adverse side effect, decreased tonic inhibition facilitates post-stroke epileptic seizures. Our data imply that early and sometimes surprisingly fast recovery following stroke is supported by homeostatic, endogenous plasticity of extrasynaptic GABAA receptors. PMID:27188341

Comparison of frailty of primary neurons, embryonic, and aging mouse cortical layers.

PubMed

Fugistier, Patrick; Vallet, Philippe G; Leuba, Geneviève; Piotton, Françoise; Marin, Pascale; Bouras, Constantin; Savioz, Armand

2014-02-01

Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aβ peptides than deep layers V to VI in aging. Three models of layers were used to investigate this pattern of frailty. First, primary neurons from E14 and E17 embryonic murine cortices, corresponding respectively to future deep and superficial layers, were treated either with Aβ(1-42), okadaic acid, or kainic acid. Second, whole E14 and E17 embryonic cortices, and third, in vitro separated deep and superficial layers of young and old C57BL/6J mice, were treated identically. We observed that E14 and E17 neurons in culture were prone to death after the Aβ and particularly the kainic acid treatment. This was also the case for the superficial layers of the aged cortex, but not for the embryonic, the young cortex, and the deep layers of the aged cortex. Thus, the aged superficial layers appeared to be preferentially vulnerable against Aβ and kainic acid. This pattern of vulnerability corresponds to enhanced accumulation of senile plaques in the superficial cortical layers with aging and Alzheimer's disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Lipopolysaccharide Stimulates Butyric Acid-Induced Apoptosis in Human Peripheral Blood Mononuclear Cells

PubMed Central

Kurita-Ochiai, Tomoko; Fukushima, Kazuo; Ochiai, Kuniyasu

1999-01-01

We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3+-T-cell apoptosis followed by similar levels of both CD4+- and CD8+-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3+ PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4+ and CD8+ cells. PMID:9864191

Acetobacter pasteurianus metabolic change induced by initial acetic acid to adapt to acetic acid fermentation conditions.

PubMed

Zheng, Yu; Zhang, Renkuan; Yin, Haisong; Bai, Xiaolei; Chang, Yangang; Xia, Menglei; Wang, Min

2017-09-01

Initial acetic acid can improve the ethanol oxidation rate of acetic acid bacteria for acetic acid fermentation. In this work, Acetobacter pasteurianus was cultured in ethanol-free medium, and energy production was found to increase by 150% through glucose consumption induced by initial acetic acid. However, oxidation of ethanol, instead of glucose, became the main energy production pathway when upon culturing ethanol containing medium. Proteome assay was used to analyze the metabolism change induced by initial acetic acid, which provided insight into carbon metabolic and energy regulation of A. pasteurianus to adapt to acetic acid fermentation conditions. Results were further confirmed by quantitative real-time PCR. In summary, decreased intracellular ATP as a result of initial acetic acid inhibition improved the energy metabolism to produce more energy and thus adapt to the acetic acid fermentation conditions. A. pasteurianus upregulated the expression of enzymes related to TCA and ethanol oxidation to improve the energy metabolism pathway upon the addition of initial acetic acid. However, enzymes involved in the pentose phosphate pathway, the main pathway of glucose metabolism, were downregulated to induce a change in carbon metabolism. Additionally, the enhancement of alcohol dehydrogenase expression promoted ethanol oxidation and strengthened the acetification rate, thereby producing a strong proton motive force that was necessary for energy production and cell tolerance to acetic acid.

Differential conserted activity induced regulation of Nogo receptors (1-3), LOTUS and Nogo mRNA in mouse brain.

PubMed

Karlsson, Tobias E; Koczy, Josefin; Brené, Stefan; Olson, Lars; Josephson, Anna

2013-01-01

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity.

A comparative study of a theoretical neural net model with MEG data from epileptic patients and normal individuals.

PubMed

Kotini, A; Anninos, P; Anastasiadis, A N; Tamiolakis, D

2005-09-07

The aim of this study was to compare a theoretical neural net model with MEG data from epileptic patients and normal individuals. Our experimental study population included 10 epilepsy sufferers and 10 healthy subjects. The recordings were obtained with a one-channel biomagnetometer SQUID in a magnetically shielded room. Using the method of x2-fitting it was found that the MEG amplitudes in epileptic patients and normal subjects had Poisson and Gauss distributions respectively. The Poisson connectivity derived from the theoretical neural model represents the state of epilepsy, whereas the Gauss connectivity represents normal behavior. The MEG data obtained from epileptic areas had higher amplitudes than the MEG from normal regions and were comparable with the theoretical magnetic fields from Poisson and Gauss distributions. Furthermore, the magnetic field derived from the theoretical model had amplitudes in the same order as the recorded MEG from the 20 participants. The approximation of the theoretical neural net model with real MEG data provides information about the structure of the brain function in epileptic and normal states encouraging further studies to be conducted.

Epileptic seizures in Neuro-Behcet disease: why some patients develop seizure and others not?

PubMed

Kutlu, Gulnihal; Semercioglu, Sencer; Ucler, Serap; Erdal, Abidin; Inan, Levent E

2015-03-01

Behcet disease (BD) is a chronic relapsing inflammatory disorder. Neuro BD (NBD) is seen in approximately 5% of all patients. The aim of this study is to investigate the frequency, type and prognosis of epileptic seizures in different forms of NBD. All files of 42 patients with NBD were evaluated between 2006 and 2012, retrospectively. The demographic data, the presentation of NBD, clinical findings including seizures, EEG and neuroimaging findings were reviewed. The mean age of patients was 35.02±8.43 years. Thirty (71.4%) patients were male; the remaining 12 of them were female. Twenty-four patients had brainstem lesions; 16 patients had cerebral venous thrombosis. Spinal cord involvement was seen in two patients. Seven patients had epileptic seizures (six partial onset seizures with or without secondary generalization). Six of them had cerebral sinus thrombosis (CVT). Four patients had a seizure as the first symptom of the thrombosis. One patient had late onset seizure due to chronic venous infarct. The other patient with seizure had brainstem involvement. The remaining was diagnosed as epilepsy before the determination of NBD. CVT seen in BD seems to be the main risk factor for epileptic seizures in patients with NBD. The prognosis is usually good especially in patients with CVT. Epileptic seizures in patients with brainstem involvement may be an indicator for poor prognosis. Superior sagittal thrombosis or cortical infarct would be predictor of seizures occurrence because of the high ratio in patients with seizures. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Modulation of ATP-induced inward currents by docosahexaenoic acid and other fatty acids in rat nodose ganglion neurons.

PubMed

Eto, Kei; Arimura, Yukiko; Mizuguchi, Hiroko; Nishikawa, Masazumi; Noda, Mami; Ishibashi, Hitoshi

2006-11-01

The effects of docosahexaenoic acid (DHA) and other fatty acids on P2X-receptor-mediated inward currents in rat nodose ganglion neurons were studied using the nystatin perforated patch-clamp technique. DHA accelerated the desensitization rate of the ATP-induced current. DHA showed use-dependent inhibition of the peak ATP-induced current. Other polyunsaturated fatty acids, such as arachidonic acid and eicosapentaenoic acid, displayed a similar use-dependent inhibition. The inhibitory effects of saturated fatty acids including palmitic acid and arachidic acid were weaker than those of polyunsaturated fatty acids. The results suggest that fatty acids may modulate the P2X receptor-mediated response when the channel is in the open-state.

Valproic acid induced hyperammonaemic encephalopathy.

PubMed

Amanat, Saima; Shahbaz, Naila; Hassan, Yasmin

2013-01-01

To observe clinical and laboratory features of valproic acid-induced hyperammonaemic encephalopathy in patients taking valproic acid. Observational study was conducted at the Neurology Department, Dow University of Health Sciences, Civil Hospital, Karachi, from February 26, 2010 to March 20, 2011. Ten patients on valproic acid therapy of any age group with idiopathic or secondary epilepsy, who presented with encephalopathic symptoms, were registered and followed up during the study. Serum ammonia level, serum valproic acid level, liver function test, cerebrospinal fluid examination, electroencephalogram and brain imaging of all the patients were done. Other causes of encephalopathy were excluded after clinical and appropriate laboratory investigations. Microsoft Excell 2007 was used for statistical analysis. Hyperammonaemia was found in all patients with encephalopathic symptoms. Rise in serum ammonia was independent of dose and serum level of valproic acid. Liver function was also found to be normal in 80% (n = 8) of the patients. Valproic acid was withdrawn in all patients. Three (30%) patients improved only after the withdrawal of valproic acid. Six (60%) patients improved after L-Carnitine replacement, one (10%) after sodium benzoate. On followup, serum ammonia had reduced to normal in five (50%) patients and to more than half of the baseline level in two (20%) patients. Three (30%) patients were lost to followup after complete clinical improvement. Within therapeutic dose and serum levels, valproic acid can cause symptomatic hyperammonaemia resulting in encephalopathy. All patients taking valproic acid presenting with encephalopathic symptoms must be monitored for the condition.

Low oleic acid-derived repression of jasmonic acid-inducible defense responses requires the WRKY50 and WRKY51 proteins

USDA-ARS?s Scientific Manuscript database

Signaling induced upon a reduction in oleic acid (18:1) levels simultaneously up-regulates salicylic acid (SA)-mediated responses and inhibits jasmonic acid (JA)-inducible defenses, resulting in enhanced resistance to biotrophs but increased susceptibility to necrotrophs. SA and the signaling compon...

MicroRNA-34a upregulation during seizure-induced neuronal death

PubMed Central

Sano, T; Reynolds, J P; Jimenez-Mateos, E M; Matsushima, S; Taki, W; Henshall, D C

2012-01-01

MicroRNAs (miRNAs) are short, noncoding RNAs that function as posttranscriptional regulators of gene expression by controlling translation of mRNAs. A subset of miRNAs may be critical for the control of cell death, including the p53-regulated miRNA, miR-34a. Because seizures activate p53, and p53-deficient mice are reportedly resistant to damage caused by prolonged seizures, we investigated the role of miR-34a in seizure-induced neuronal death in vivo. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in mice. This led to an early (2 h) multifold upregulation of miR-34a in the CA3 and CA1 hippocampal subfields and lower protein levels of mitogen-activated kinase kinase kinase 9, a validated miR-34a target. Immunoprecipitation of the RNA-induced silencing complex component, Argonaute-2, eluted significantly higher levels of miR-34a after seizures. Injection of mice with pifithrin-α, a putative p53 inhibitor, prevented miR-34a upregulation after seizures. Intracerebroventricular injection of antagomirs targeting miR-34a reduced hippocampal miR-34a levels and had a small modulatory effect on apoptosis-associated signaling, but did not prevent hippocampal neuronal death in models of either severe or moderate severity status epilepticus. Thus, prolonged seizures cause subfield-specific, temporally restricted upregulation of miR-34a, which may be p53 dependent, but miR-34a is probably not important for seizure-induced neuronal death in this model. PMID:22436728

Epileptic negative drop attacks in atypical benign partial epilepsy: a neurophysiological study.

PubMed

Hirano, Yoshiko; Oguni, Hirokazu; Osawa, Makiko

2009-03-01

We conducted a computer-assisted polygraphic analysis of drop attacks in a child with atypical benign partial epilepsy (ABPE) to investigate neurophysiological characteristics. The patient was a six-year two-month-old girl, who had started to have focal motor seizures, later combined with daily epileptic negative myoclonus (ENM) and drop attacks, causing multiple injuries. We studied episodes of ENM and drop attacks using video-polygraphic and computer-assisted back-averaging analysis. A total of 12 ENM episodes, seven involving the left arm (ENMlt) and five involving both arms (ENMbil), and five drop attacks were captured for analysis. All episodes were time-locked to spike-and-wave complexes (SWC) arising from both centro-temporo-parietal (CTP) areas. The latency between the onset of SWC and ENMlt, ENMbil, and drop attacks reached 68 ms, 42 ms, and 8 ms, respectively. The height of the spike as well as the slow-wave component of SWC for drop attacks were significantly larger than that for both ENMlt and ENMbil (p < 0.05). Drop attacks were considered to be epileptic negative myoclonus involving not only upper proximal but also axial muscles, causing the body to fall. Thus, drop attacks in ABPE are considered to be epileptic negative drop attacks arising from bilateral CTP foci and differ from drop attacks of a generalized origin seen in Lennox-Gastaut syndrome and myoclonic-astatic epilepsy.

Differential Conserted Activity Induced Regulation of Nogo Receptors (1–3), LOTUS and Nogo mRNA in Mouse Brain

PubMed Central

Karlsson, Tobias E.; Koczy, Josefin; Brené, Stefan; Olson, Lars; Josephson, Anna

2013-01-01

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity. PMID:23593344

d-Leucine: Evaluation in an epilepsy model.

PubMed

Holden, Kylie; Hartman, Adam L

2018-01-01

Current medicines do not provide sufficient seizure control for nearly one-third of patients with epilepsy. New options are needed to address this treatment gap. We recently found that the atypical amino acid d-leucine protected against acutely-induced seizures in mice, but its effect in chronic seizures has not been explored. We hypothesized that d-leucine would protect against spontaneous recurrent seizures. We also investigated whether mice lacking a previously-described d-leucine receptor (Tas1R2/R3) would be protected against acutely-induced seizures. Male FVB/NJ mice were subjected to kainic acid-induced status epilepticus and monitored by video-electroencephalography (EEG) (surgically implanted electrodes) for 4weeks before, during, and after treatment with d-leucine. Tas1R2/R3 knockout mice and controls underwent the maximal electroshock threshold (MES-T) and 6-Hz tests. There was no difference in number of calendar days with seizures or seizure frequency with d-leucine treatment. In an exploratory analysis, mice treated with d-leucine had a lower number of dark cycles with seizures. Tas1R2/R3 knockout mice had elevated seizure thresholds in the MES-T test but not the 6-Hz test. d-Leucine treatment was ineffective against chronic seizures after kainic acid-induced status epilepticus, but there was some efficacy during the dark cycle. Because d-leucine is highly concentrated in the pineal gland, these data suggest that d-leucine may be useful as a tool for studying circadian patterns in epilepsy. Deletion of the Tas1R2/R3 receptor protected against seizures in the MES-T test and, therefore, may be a novel target for treating seizures. Published by Elsevier Inc.

Spatiotemporal and Long Lasting Modulation of 11 Key Nogo Signaling Genes in Response to Strong Neuroexcitation

PubMed Central

Karlsson, Tobias E.; Wellfelt, Katrin; Olson, Lars

2017-01-01

Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-Myelin glycoprotein (OMgp), Nogo receptor 1 (NgR1), NgR2, NgR3, Lingo-1, TNF receptor orphan Y (Troy), Olfactomedin, Lateral olfactory tract usher substance (Lotus) and membrane-type matrix metalloproteinase-3 (MT3-MPP)), as well as BDNF and GAPDH. Expression was analyzed in nine different brain areas before, and at eight time points during the first 3 days after a strong neuroexcitatory stimulation, caused by one kainic acid injection. A temporo-spatial pattern of orderly transcriptional regulations emerges that strengthens the role of Nogo-signaling mechanisms for synaptic plasticity in synchrony with transcriptional increases of BDNF mRNA. For most Nogo-type signaling genes, the largest alterations of mRNA levels occur in the dentate gyrus, with marked alterations also in the CA1 region. Changes occurred somewhat later in several areas of the cerebral cortex. The detailed spatio-temporal pattern of mRNA presence and kainic acid-induced transcriptional response is gene-specific. We reveal that several different gene alterations combine to decrease (and later increase) Nogo-like signaling, as expected to allow structural plasticity responses. Other genes are altered in the opposite direction, suggesting that the system prepares in advance in order to rapidly restore balance. However, the fact that Lingo-1 shows a seemingly opposite, plasticity inhibiting response to kainic acid (strong increase of mRNA in the dentate gyrus), may instead suggest a plasticity-enhancing intracellular function of this presumed NgR1 co-receptor. PMID:28442990

Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

PubMed

Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

2017-11-01

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epileptic Hypergraphia: The Impact of Prolific Writing on Language Creativity

ERIC Educational Resources Information Center

Ammari, Elham H.

2012-01-01

Catalyzed academic concerns have been shown so far to tackle the issue of temporal lobe epileptic hypergraphia and the extent of its creativity. Temporal lobe epilepsy hence, (TLE) as a neurological brain disorder, has captured the attention of concerned scholars ever since. A constellation of TLE and its cohorts have baffled scientists,…

Mapping interictal epileptic discharges using mutual information between concurrent EEG and fMRI.

PubMed

Caballero-Gaudes, César; Van de Ville, Dimitri; Grouiller, Frédéric; Thornton, Rachel; Lemieux, Louis; Seeck, Margitta; Lazeyras, François; Vulliemoz, Serge

2013-03-01

The mapping of haemodynamic changes related to interictal epileptic discharges (IED) in simultaneous electroencephalography (EEG) and functional MRI (fMRI) studies is usually carried out by means of EEG-correlated fMRI analyses where the EEG information specifies the model to test on the fMRI signal. The sensitivity and specificity critically depend on the accuracy of EEG detection and the validity of the haemodynamic model. In this study we investigated whether an information theoretic analysis based on the mutual information (MI) between the presence of epileptic activity on EEG and the fMRI data can provide further insights into the haemodynamic changes related to interictal epileptic activity. The important features of MI are that: 1) both recording modalities are treated symmetrically; 2) no requirement for a-priori models for the haemodynamic response function, or assumption of a linear relationship between the spiking activity and BOLD responses, and 3) no parametric model for the type of noise or its probability distribution is necessary for the computation of MI. Fourteen patients with pharmaco-resistant focal epilepsy underwent EEG-fMRI and intracranial EEG and/or surgical resection with positive postoperative outcome (seizure freedom or considerable reduction in seizure frequency) was available in 7/14 patients. We used nonparametric statistical assessment of the MI maps based on a four-dimensional wavelet packet resampling method. The results of MI were compared to the statistical parametric maps obtained with two conventional General Linear Model (GLM) analyses based on the informed basis set (canonical HRF and its temporal and dispersion derivatives) and the Finite Impulse Response (FIR) models. The MI results were concordant with the electro-clinically or surgically defined epileptogenic area in 8/14 patients and showed the same degree of concordance as the results obtained with the GLM-based methods in 12 patients (7 concordant and 5 discordant). In

A note on a phrase in Shakespeare's play King Lear: 'a plague upon your epileptic visage'.

PubMed

Betts, T; Betts, H

1998-10-01

In Shakespeare's play King Lear the word 'epileptic' appears (used in a derogatory manner). This is held to be the first appearance of the word in the English language (although we have found earlier English references to the word which Shakespeare may have read). Textual analysis of the lines following the use of 'epileptic' suggests that it is actually a reference to the pock-marks of syphilis, endemic in Elizabethan England, and is not actually a reference to epilepsy itself.

Sudden death in epileptic rats exposed to nocturnal magnetic fields that simulate the shape and the intensity of sudden changes in geomagnetic activity: an experiment in response to Schnabel, Beblo and May

NASA Astrophysics Data System (ADS)

Persinger, M. A.; McKay, B. E.; O'Donovan, C. A.; Koren, S. A.

2005-03-01

To test the hypothesis that sudden unexplained death (SUD) in some epileptic patients is related to geomagnetic activity we exposed rats in which limbic epilepsy had been induced to experimentally produced magnetic fields designed to simulate sudden storm commencements (SSCs). Prior studies with rats had shown that sudden death in groups of rats in which epilepsy had been induced months earlier was associated with the occurrence of SSCs and increased geomagnetic activity during the previous night. Schnabel et al. [(2000) Neurology 54:903 908) found no relationship between SUD in human patients and geomagnetic activity. A total of 96 rats were exposed to either 500, 50, 10 40 nT or sham (less than 10 nT) magnetic fields for 6 min every hour between midnight and 0800 hours (local time) for three successive nights. The shape of the complex, amplitude-modulated magnetic fields simulated the shape and structure of an average SSC. The rats were then seized with lithium and pilocarpine and the mortality was monitored. Whereas 10% of the rats that had been exposed to the sham field died within 24 h, 60% of the rats that had been exposed to the experimental magnetic fields simulating natural geomagnetic activity died (P<.001) during this period. These results suggest that correlational analyses between SUD in epileptic patients and increased geomagnetic activity can be simulated experimentally in epileptic rats and that potential mechanisms might be testable directly.

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect

PubMed Central

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy. PMID:26309534

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect.

PubMed

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy.

Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids.

PubMed

Sauvat, Allan; Chen, Guo; Müller, Kevin; Tong, Mingming; Aprahamian, Fanny; Durand, Sylvère; Cerrato, Giulia; Bezu, Lucillia; Leduc, Marion; Franz, Joakim; Rockenfeller, Patrick; Sadoshima, Junichi; Madeo, Frank; Kepp, Oliver; Kroemer, Guido

2018-04-01

Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids. Copyright © 2018 German Center for Neurodegenerative Diseases (DZNE). Published by Elsevier B.V. All rights reserved.

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats

PubMed Central

Clere-Jehl, Raphaël; Le Borgne, Pierrick; Merdji, Hamid; Auger, Cyril; Schini-Kerth, Valérie; Meziani, Ferhat

2017-01-01

Introduction Long chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction. Methods In a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments. Results We have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 μg/kg/min respectively versus 17.4±19.3 μg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IκB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti-inflammatory metabolites. Conclusions DHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects. PMID:29261735

Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus.

PubMed

Foffani, Guglielmo; Uzcategui, Yoryani G; Gal, Beatriz; Menendez de la Prida, Liset

2007-09-20

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.

Anticipating epileptic seizures: from mathematics to clinical applications.

PubMed

Le Van Quyen, Michel

2005-02-01

The study of dynamical changes in the neural activity preceding an epileptic seizure allows the characterization of a preictal state several minutes prior to seizure onset. This opens new perspectives for studying the mechanisms of ictogenesis as well as for possible therapeutic interventions that represent a major breakthrough. In this review we present and discuss the results from our group in this domain using nonlinear analysis of brain signals, as well as its limitation and open questions.

Decursinol and decursin protect primary cultured rat cortical cells from glutamate-induced neurotoxicity.

PubMed

Kang, So Young; Kim, Young Choong

2007-06-01

We previously reported six neuroprotective decursinol derivatives, coumarins from Angelica gigas (Umbelliferae) roots. To elucidate the action patterns of decursinol derivatives, we investigated the neuroprotective effects of decursinol and decursin, which showed highly significant activity and were major constituents of A. gigas, using primary cultures of rat cortical cells in-vitro. At concentrations of 0.1-10.0 microM, both decursinol and decursin exerted a significant neuroprotective activity pretreatment and throughout treatment. In addition, decursin had a neuroprotective impact in the post-treatment paradigm implying that decursin might possess different action mechanisms from that of decursinol in the protection of neurons against glutamate injury. Both decursinol and decursin effectively reduced the glutamate-induced increased intracellular calcium ([Ca(2+)](i)) in cortical cells, suggesting that these two coumarins may exert neuroprotection by reducing calcium influx by overactivation of glutamate receptors. This suggestion was supported by the result that decursinol and decursin protected neurons against kainic acid (KA)-induced neurotoxicity better than against that induced by N-methyl-D-aspartate (NMDA). Moreover, both decursinol and decursin significantly prevented glutamate-induced decreases in glutathione, a cellular antioxidant, and glutathione peroxidase activity. In addition, both compounds efficiently reduced the overproduction of cellular peroxide in glutamate-injured cortical cells. These results suggested that both decursinol and decursin protected primary cultured rat cortical cells against glutamate-induced oxidative stress by both reducing calcium influx and acting on the cellular antioxidative defence system. Moreover, decursin is considered to probably have a different action mechanism from that of decursinol in protecting cortical cells against glutamate injury.

Classification of epileptic seizures using wavelet packet log energy and norm entropies with recurrent Elman neural network classifier.

PubMed

Raghu, S; Sriraam, N; Kumar, G Pradeep

2017-02-01

Electroencephalogram shortly termed as EEG is considered as the fundamental segment for the assessment of the neural activities in the brain. In cognitive neuroscience domain, EEG-based assessment method is found to be superior due to its non-invasive ability to detect deep brain structure while exhibiting superior spatial resolutions. Especially for studying the neurodynamic behavior of epileptic seizures, EEG recordings reflect the neuronal activity of the brain and thus provide required clinical diagnostic information for the neurologist. This specific proposed study makes use of wavelet packet based log and norm entropies with a recurrent Elman neural network (REN) for the automated detection of epileptic seizures. Three conditions, normal, pre-ictal and epileptic EEG recordings were considered for the proposed study. An adaptive Weiner filter was initially applied to remove the power line noise of 50 Hz from raw EEG recordings. Raw EEGs were segmented into 1 s patterns to ensure stationarity of the signal. Then wavelet packet using Haar wavelet with a five level decomposition was introduced and two entropies, log and norm were estimated and were applied to REN classifier to perform binary classification. The non-linear Wilcoxon statistical test was applied to observe the variation in the features under these conditions. The effect of log energy entropy (without wavelets) was also studied. It was found from the simulation results that the wavelet packet log entropy with REN classifier yielded a classification accuracy of 99.70 % for normal-pre-ictal, 99.70 % for normal-epileptic and 99.85 % for pre-ictal-epileptic.

Bile-acid-induced cell injury and protection

PubMed Central

Perez, Maria J; Briz, Oscar

2009-01-01

Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties. PMID:19360911

Measurement of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid in the cerebrospinal fluid of children.

PubMed

Akiyama, Tomoyuki; Akiyama, Mari; Hayashi, Yumiko; Shibata, Takashi; Hanaoka, Yoshiyuki; Toda, Soichiro; Imai, Katsumi; Hamano, Shin-Ichiro; Okanishi, Tohru; Yoshinaga, Harumi; Kobayashi, Katsuhiro

2017-03-01

We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in the cerebrospinal fluid (CSF) of children and to investigate the effect of age, sex, epilepsy, and anti-epileptic drug (AED) therapy on these vitamers. CSF samples prospectively collected from 116 pediatric patients were analyzed. PLP, PL, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age, sex, epilepsy, and AEDs on these vitamers and the PLP/PL ratio were evaluated using multiple linear regression models. The PLP, PL, and PA concentrations were correlated negatively with age and the PLP/PL ratio was correlated positively with age. Multiple regression analysis revealed that the presence of epilepsy was associated with lower PLP concentrations and PLP/PL ratios but sex and AED therapy had no influence on these values. The observed ranges of these vitamers in epileptic and non-epileptic patients were demonstrated. We showed the age dependence of PLP and PL in CSF from pediatric patients. Epileptic patients had lower PLP concentrations and PLP/PL ratios than non-epileptic patients, but it is unknown whether this is the cause, or a result, of epilepsy. Copyright © 2016 Elsevier B.V. All rights reserved.

L-Carnitine suppresses oleic acid-induced membrane permeability transition of mitochondria.

PubMed

Oyanagi, Eri; Yano, Hiromi; Kato, Yasuko; Fujita, Hirofumi; Utsumi, Kozo; Sasaki, Junzo

2008-10-01

Membrane permeability transition (MPT) of mitochondria has an important role in apoptosis of various cells. The classic type of MPT is characterized by increased Ca(2+) transport, membrane depolarization, swelling, and sensitivity to cyclosporin A. In this study, we investigated whether L-carnitine suppresses oleic acid-induced MPT using isolated mitochondria from rat liver. Oleic acid-induced MPT in isolated mitochondria, inhibited endogenous respiration, caused membrane depolarization, and increased large amplitude swelling, and cytochrome c (Cyt. c) release from mitochondria. L-Carnitine was indispensable to beta-oxidation of oleic acid in the mitochondria, and this reaction required ATP and coenzyme A (CoA). In the presence of ATP and CoA, L-carnitine stimulated oleic acid oxidation and suppressed the oleic acid-induced depolarization, swelling, and Cyt. c release. L-Carnitine also contributed to maintaining mitochondrial function, which was decreased by the generation of free fatty acids with the passage of time after isolation. These results suggest that L-carnitine acts to maintain mitochondrial function and suppresses oleic acid-mediated MPT through acceleration of beta-oxidation. Copyright (c) 2008 John Wiley & Sons, Ltd.

Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures

PubMed Central

Baxendale, Sarah; Holdsworth, Celia J.; Meza Santoscoy, Paola L.; Harrison, Michael R. M.; Fox, James; Parkin, Caroline A.; Ingham, Philip W.; Cunliffe, Vincent T.

2012-01-01

SUMMARY The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for the treatment of people with epilepsy. We found that exposure of 2-day-old zebrafish embryos to the convulsant agent pentylenetetrazole (PTZ) rapidly induces the expression of synaptic-activity-regulated genes in the CNS, and elicited vigorous episodes of calcium (Ca2+) flux in muscle cells as well as intense locomotor activity. We then screened a library of ∼2000 known bioactive small molecules and identified 46 compounds that suppressed PTZ-inducedtranscription of the synaptic-activity-regulated gene fos in 2-day-old (2 dpf) zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and newly identified anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced fos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for fos transcription in the zebrafish embryonic CNS is a robust, high-throughput in vivo indicator of the neural response to convulsant treatment and lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced fos expression provides a sensitive means of identifying compounds with anticonvulsant activities. PMID:22730455

Soybean Aphid Infestation Induces Changes in Fatty Acid Metabolism in Soybean

PubMed Central

Kanobe, Charles; McCarville, Michael T.; O’Neal, Matthew E.; Tylka, Gregory L.; MacIntosh, Gustavo C.

2015-01-01

The soybean aphid (Aphis glycines Matsumura) is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of “metabolic hijacking” by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor. PMID:26684003

Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity.

PubMed

Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L; Okamura, Kayo; Kendrick, Jessica; Chonchol, Michel; Offermanns, Stefan; Ntambi, James M; Kuro-O, Makoto; Miyazaki, Makoto

2015-10-26

Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.

Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects.

PubMed

Hong, Ye-Ji; Ahn, Hyo-Ju; Shin, Jongdae; Lee, Joon H; Kim, Jin-Hoi; Park, Hwan-Woo; Lee, Sung Ki

2018-02-01

Dysregulated serum fatty acids are associated with a lipotoxic placental environment, which contributes to increased pregnancy complications via altered trophoblast invasion. However, the role of saturated and unsaturated fatty acids in trophoblastic autophagy has yet to be explored. Here, we demonstrated that prolonged exposure of saturated fatty acids interferes with the invasiveness of human extravillous trophoblasts. Saturated fatty acids (but not unsaturated fatty acids) inhibited the fusion of autophagosomes and lysosomes, resulting in the formation of intracellular protein aggregates. Furthermore, when the trophoblast cells were exposed to saturated fatty acids, unsaturated fatty acids counteracted the effects of saturated fatty acids by increasing degradation of autophagic vacuoles. Saturated fatty acids reduced the levels of the matrix metalloproteinases (MMP)-2 and MMP-9, while unsaturated fatty acids maintained their levels. In conclusion, saturated fatty acids induced decreased trophoblast invasion, of which autophagy dysfunction plays a major role. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of ictal slow waves in epileptic spasms.

PubMed

Honda, Ryoko; Saito, Yoshiaki; Okumura, Akihisa; Abe, Shinpei; Saito, Takashi; Nakagawa, Eiji; Sugai, Kenji; Sasaki, Masayuki

2015-12-01

We characterized the clinico-neurophysiological features of epileptic spasms, particularly focusing on high-voltage slow waves during ictal EEG. We studied 22 patients with epileptic spasms recorded during digital video-scalp EEG, including five individuals who still had persistent spasms after callosotomy. We analysed the duration, amplitude, latency to onset of electromyographic bursts, and distribution of the highest positive and negative peaks of slow waves in 352 spasms. High-voltage positive slow waves preceded the identifiable muscle contractions of spasms. The mean duration of these positive waves was 569±228 m, and the mean latency to electromyographic onset was 182±127 m. These parameters varied markedly even within a patient. The highest peak of the positive component was distributed in variable regions, which was not consistent with the location of lesions on MRI. The peak of the negative component following the positivity was distributed in the neighbouring or opposite areas of the positive peak distribution. No changes were evident in the pre- or post-surgical distributions of the positive peak, or in the interhemispheric delay between both hemispheres, in individuals with callosotomy. Our data imply that ictal positive slow waves are the most common EEG changes during spasms associated with a massive motor component. Plausible explanations for these widespread positive slow waves include the notion that EEG changes possibly reflect involvement of both cortical and subcortical structures.

“Resting” CBF in the Epileptic Baboon: Correlation with Ketamine Dose and Interictal Epileptic Discharges

PubMed Central

Szabó, C. Ákos; Narayana, Shalini; Franklin, Crystal; Knape, Koyle D.; Davis, M. Duff; Fox, Peter T.; Leland, M. Michelle; Williams, Jeff T.

2011-01-01

Background Photosensitive epileptic (SZ) baboons demonstrate different cerebral blood flow (CBF) activation patterns from asymptomatic controls (CTL) during intermittent light stimulation (ILS). This study compares “resting” CBF between PS and CTL animals, and CBF correlations with ketamine dose and interictal epileptic discharges (IEDs) between PS and CTL animals. Methods Continuous intravenous ketamine was administered to eight PS and eight CTL baboons (matched for gender and weight), and maintained at subanesthetic doses (4.8–14.6 mg/kg/hr). Three resting H215O-PET studies were attempted in each animal (CTI/Siemens HR+ scanner). Images were acquired in 3D mode (63 contiguous slices, 2.4 mm thickness). PET images were co-registered with MRI images (3T Siemens Trio, T1-weighted 3D Turboflash sequence, TE/TR/TI = 3.04/2100/785 msec, flip angle=13 degrees). EEG was used to monitor depth of sedation and for quantification of IED rates. Regional CBF was compared between PS and CTL groups and correlations were analyzed for ketamine dose and IED rates. Results When subsets of animals of either group, receiving similar doses of ketamine were compared, PS animals demonstrated relative CBF increases in the occipital lobes and decreases in the frontal lobes. Correlation analyses with ketamine dose confirmed the frontal and occipital lobe changes in the PS animals. The negative correlations of CBF with ketamine dose and IED rate overlapped frontally. While frontal lobe CBF was also negatively correlated with IED rate, positive correlations were found in the parietal lobe. Conclusions “Resting” CBF differs between PS and CTL baboons. Correlation analyses of CBF and ketamine dose reveal that occipital lobe CBF increases and frontal lobe in PS animals are driven by ketamine. While frontal lobe CBF decreases may be related to ketamine’s propensity to activate IEDs, positive CBF correlations with IED rate suggest involvement of the parietal lobes in their generation

Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bai, Xupeng; Hong, Weipeng; Cai, Peiheng

Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36),more » an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the

Eicosapentaenoic acid and docosahexaenoic acid reduce UVB- and TNF-alpha-induced IL-8 secretion in keratinocytes and UVB-induced IL-8 in fibroblasts.

PubMed

Storey, Amy; McArdle, Frank; Friedmann, Peter S; Jackson, Malcolm J; Rhodes, Lesley E

2005-01-01

Omega-3 polyunsaturated fatty acids (n-3 PUFA) inhibit ultraviolet B (UVB)-induced inflammation and other inflammatory states, in vivo. We examined whether this may be mediated by modulation of interleukin (IL)-8, a chemokine pivotal to skin inflammation induced by UVB, in epidermal and dermal cells. We also explored the ability of n-3 PUFA to protect against tumor necrosis factor (TNF)-alpha induction of IL-8, and assessed relative potencies of the principal dietary n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Pre-supplementation, both HaCaT keratinocyte and CCD922SK fibroblast cell lines showed dose-responses for UVB-induced IL-8 release (p<0.001), assessed 48 h post-irradiation. Cells were supplemented with > or =90% purified EPA, DHA, oleic acid (OA) or vehicle control, for 4.5 d. EPA and DHA supplements were bioavailable to keratinocytes and fibroblasts. In keratinocytes, EPA and DHA were shown to reduce basal secretion of IL-8 by 66% and 63%, respectively (p<0.05), and UVB-induced levels by 66% and 65% at 48 h after 100 mJ per cm2, respectively, (p<0.01). A similar pattern occurred in fibroblasts, whereas OA had no influence on IL-8 release in either cell line. In addition, TNF-alpha-induced IL-8 secretion by keratinocytes was reduced by 54% and 42%, respectively, by EPA and DHA (p<0.001). Hence both n-3 PUFA inhibit production of UVB- and TNF-alpha-induced IL-8 in skin cells; this may be important in the photoprotective and other anti-inflammatory effects conferred by these agents.

Study on the Relationships between Intrinsic Functional Connectivity of the Default Mode Network and Transient Epileptic Activity.

PubMed

Lopes, Renaud; Moeller, Friederike; Besson, Pierre; Ogez, François; Szurhaj, William; Leclerc, Xavier; Siniatchkin, Michael; Chipaux, Mathilde; Derambure, Philippe; Tyvaert, Louise

2014-01-01

Simultaneous recording of electroencephalogram and functional MRI (EEG-fMRI) is a powerful tool for localizing epileptic networks via the detection of hemodynamic changes correlated with interictal epileptic discharges (IEDs). fMRI can be used to study the long-lasting effect of epileptic activity by assessing stationary functional connectivity during the resting-state period [especially, the connectivity of the default mode network (DMN)]. Temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) are associated with low responsiveness and disruption of DMN activity. A dynamic functional connectivity approach might enable us to determine the effect of IEDs on DMN connectivity and to better understand the correlation between DMN connectivity changes and altered consciousness. We studied dynamic changes in DMN intrinsic connectivity and their relation to IEDs. Six IGE patients (with generalized spike and slow-waves) and 6 TLE patients (with unilateral left temporal spikes) were included. Functional connectivity before, during, and after IEDs was estimated using a sliding window approach and compared with the baseline period. No dependence on window size was observed. The baseline DMN connectivity was decreased in the left hemisphere (ipsilateral to the epileptic focus) in TLEs and was less strong but remained bilateral in IGEs. We observed an overall increase in DMN intrinsic connectivity prior to the onset of IEDs in both IGEs and TLEs. After IEDs in TLEs, we found that DMN connectivity increased before it returned to baseline values. Most of the DMN regions with increased connectivity before and after IEDs were lateralized to the left hemisphere in TLE (i.e., ipsilateral to the epileptic focus). RESULTS suggest that DMN connectivity may facilitate IED generation and may be affected at the time of the IED. However, these results need to be confirmed in a larger independent cohort.

Study on the Relationships between Intrinsic Functional Connectivity of the Default Mode Network and Transient Epileptic Activity

PubMed Central

Lopes, Renaud; Moeller, Friederike; Besson, Pierre; Ogez, François; Szurhaj, William; Leclerc, Xavier; Siniatchkin, Michael; Chipaux, Mathilde; Derambure, Philippe; Tyvaert, Louise

2014-01-01

Rationale: Simultaneous recording of electroencephalogram and functional MRI (EEG–fMRI) is a powerful tool for localizing epileptic networks via the detection of hemodynamic changes correlated with interictal epileptic discharges (IEDs). fMRI can be used to study the long-lasting effect of epileptic activity by assessing stationary functional connectivity during the resting-state period [especially, the connectivity of the default mode network (DMN)]. Temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) are associated with low responsiveness and disruption of DMN activity. A dynamic functional connectivity approach might enable us to determine the effect of IEDs on DMN connectivity and to better understand the correlation between DMN connectivity changes and altered consciousness. Method: We studied dynamic changes in DMN intrinsic connectivity and their relation to IEDs. Six IGE patients (with generalized spike and slow-waves) and 6 TLE patients (with unilateral left temporal spikes) were included. Functional connectivity before, during, and after IEDs was estimated using a sliding window approach and compared with the baseline period. Results: No dependence on window size was observed. The baseline DMN connectivity was decreased in the left hemisphere (ipsilateral to the epileptic focus) in TLEs and was less strong but remained bilateral in IGEs. We observed an overall increase in DMN intrinsic connectivity prior to the onset of IEDs in both IGEs and TLEs. After IEDs in TLEs, we found that DMN connectivity increased before it returned to baseline values. Most of the DMN regions with increased connectivity before and after IEDs were lateralized to the left hemisphere in TLE (i.e., ipsilateral to the epileptic focus). Conclusion: Results suggest that DMN connectivity may facilitate IED generation and may be affected at the time of the IED. However, these results need to be confirmed in a larger independent cohort. PMID:25346721

Expression of mRNAs encoding dopamine receptors in striatal regions is differentially regulated by midbrain and hippocampal neurons.

PubMed

Brené, S; Herrera-Marschitz, M; Persson, H; Lindefors, N

1994-02-01

The glutamate analogue kainic acid was injected into the hippocampus of intact or 6-hydroxydopamine deafferented rats to investigate the influence of hippocampal neurons on the expression of dopamine D1 and D2 receptor mRNAs in subregions of the striatal complex and possible modulation by dopaminergic neurons. Quantitative in situ hybridization using 35S-labeled oligonucleotide probes specific for dopamine D1 and D2 receptor mRNAs, respectively, were used. It was found that an injection of kainic acid into the hippocampal formation had alone no significant effect on dopamine D1 or D2 receptor mRNA levels in any of the analyzed striatal subregions in animals analyzed 4 h after the injections. Kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion produced an increase in D1 receptor mRNA levels in the ipsilateral medial caudate-putamen, and a bilateral increase in core and shell of nucleus accumbens (ventral striatal limbic regions). A unilateral 6-hydroxydopamine lesion alone caused an increase in D2 receptor mRNA in the lateral caudate-putamen (dorsal striatal motor region) ipsilateral to the lesion and an increase in D1 receptor mRNA in the accumbens core ipsilateral to the lesion. However, in dopamine-lesioned animals, dopamine D1 receptor mRNA levels were increased bilaterally in nucleus accumbens core and shell and in the ipsilateral medial caudate-putamen following kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion. These results indicate a differential regulation of the expression of dopamine D1 and D2 receptor mRNAs by midbrain and hippocampal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of physiological and epileptic HFO generation

PubMed Central

Jefferys, John G.R.; de la Prida, Liset Menendez; Wendling, Fabrice; Bragin, Anatol; Avoli, Massimo; Timofeev, Igor; Lopes da Silva, Fernando H.

2016-01-01

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs. PMID:22420980

Inhibition of glycogen synthase kinase 3 increased subventricular zone stem cells proliferation.

PubMed

Pachenari, Narges; Kiani, Sahar; Javan, Mohammad

2017-09-01

The effects of Wnt signaling modifiers on cell proliferation, seem to be cell specific. Enhancing the proliferation of subventricular zone (SVZ) progenitors has been in the focus of research in recent years. Here we investigate the effect of CHIR99021, a Glycogen Synthase Kinase 3 (GSk-3) inhibitor, on SVZ progenitor's proliferation both in vivo and in vitro. Neural stem cells were extracted from the adult C57bl/6 by mincing and trypsin treatment followed by culturing in specific medium. Sphere cells formed within about 7-10days and were characterized by immunostaining. Number of spheres and their size was assessed following exposure to different concentration of CHIR99021 or vehicle. For in vivo studies, animals received intracerebroventricular (i.c.v.) injection of CHIR99021 or vehicle for four days. A subgroup of animals, after 4days treatment with CHIR99021 received intranasal kainic acid to induce local neurodegeneration in CA3 area of hippocampus. Inhibition of GSk-3 by CHIR99021 increased neural progenitor proliferation and the effect of CHIR99021 was long lasting so that the treated cells showed higher proliferation even after CHIR99021 removal. In vivo administration of CHIR99021 increased the number of neural progenitors at the rims of lateral ventricles especially when the treatment was followed by kainic acid administration which induces neural insult. Results showed that direct administration of CHIR99021 into the culture medium or animal brain increased the number of SVZ progenitors, especially when a neural insult was induced in the hippocampus. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Comparison of acid-induced cell wall loosening in Valonia ventricosa and in oat coleoptiles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tepfer, M.; Cleland, R.E.

The acid-induced loosening of cell walls of Valonia ventricosa has been compared to that of frozen-thawed oat coleoptiles. The two acid extension responses are similar in regard to the shape of the pH response curve and the increase in plastic compliance induced by acid treatment. In both systems the acid response can be inhibited by Ca/sup 2 +/ and in both the removal of the protons leads to a rapid termination of wall loosening. The two responses differ in several significant ways, however. The acid-induced extension of Valonia walls is more rapid than that of coleoptile walls, but of smallermore » total magnitude. Acid-induced loosening can occur in Valonia without the wall being under tension, but not in coleoptiles. The acid-induced extension of Valonia walls is not inhibited by 8 molar urea, whereas the response in oat coleoptiles is completely inhibited by this treatment. Ethylenediaminetetraacetate (EDTA) can cause wall loosening in Valonia comparable to that produced by low pH, whereas in coleoptiles EDTA causes a much smaller response. These results with Valonia are consistent with a mechanism of acid-induced wall loosening in which a central role is played by the displacement of Ca/sup 2 +/ from the wall, while the larger part of acid-induced wall loosening in oat coleoptiles appears to be via a different mechanism.« less

Mechanism of alpha-lipoic acid in attenuating kanamycin-induced ototoxicity☆

PubMed Central

Wang, Aimei; Hou, Ning; Bao, Dongyan; Liu, Shuangyue; Xu, Tao

2012-01-01

In view of the theory that alpha-lipoic acid effectively prevents cochlear cells from injury caused by various factors such as cisplatin and noise, this study examined whether alpha-lipoic acid can prevent kanamycin-induced ototoxicity. To this end, healthy BALB/c mice were injected subcutaneously with alpha-lipoic acid and kanamycin for 14 days. Auditory brainstem response test showed that increased auditory brainstem response threshold shifts caused by kanamycin were significantly inhibited. Immunohistochemical staining and western blot analysis showed that the expression of phosphorylated p38 mitogen-activated protein kinase and phosphorylated c-Jun N-terminal kinase in mouse cochlea was significantly decreased. The experimental findings suggest that phosphorylated p38 and phosphorylated c-Jun N-terminal kinase mediated kanamycin-induced ototoxic injury in BALB/c mice. Alpha-lipoic acid effectively attenuated kanamycin ototoxicity by inhibiting the kanamycin-induced high expression of phosphorylated p38 and phosphorylated c-Jun N-terminal kinase. PMID:25317129

Exploring the Epileptic Brain Network Using Time-Variant Effective Connectivity and Graph Theory.

PubMed

Storti, Silvia Francesca; Galazzo, Ilaria Boscolo; Khan, Sehresh; Manganotti, Paolo; Menegaz, Gloria

2017-09-01

The application of time-varying measures of causality between source time series can be very informative to elucidate the direction of communication among the regions of an epileptic brain. The aim of the study was to identify the dynamic patterns of epileptic networks in focal epilepsy by applying multivariate adaptive directed transfer function (ADTF) analysis and graph theory to high-density electroencephalographic recordings. The cortical network was modeled after source reconstruction and topology modulations were detected during interictal spikes. First a distributed linear inverse solution, constrained to the individual grey matter, was applied to the averaged spikes and the mean source activity over 112 regions, as identified by the Harvard-Oxford Atlas, was calculated. Then, the ADTF, a dynamic measure of causality, was used to quantify the connectivity strength between pairs of regions acting as nodes in the graph, and the measure of node centrality was derived. The proposed analysis was effective in detecting the focal regions as well as in characterizing the dynamics of the spike propagation, providing evidence of the fact that the node centrality is a reliable feature for the identification of the epileptogenic zones. Validation was performed by multimodal analysis as well as from surgical outcomes. In conclusion, the time-variant connectivity analysis applied to the epileptic patients can distinguish the generator of the abnormal activity from the propagation spread and identify the connectivity pattern over time.

Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice.

PubMed

Ince, Sinan; Keles, Hikmet; Erdogan, Metin; Hazman, Omer; Kucukkurt, Ismail

2012-07-01

The protective effect of boric acid against liver damage was evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male albino mice were treated intraperitoneally (i.p.) with boric acid (50, 100, and 200 mg/kg) or silymarin daily for 7 days and received 0.2% CCl(4) in olive oil (10 mL/kg, i.p.) on day 7. Results showed that administration of boric acid significantly reduced the elevation in serum levels of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and the level of malondialdehyde in the liver that were induced by CCl(4) in mice. Boric acid treatment significantly increased glutathione content, as well as the activities of superoxide dismutase and catalase in the liver. Boric acid treatment improved the catalytic activity of cytochrome P450 2E1 and maintained activation of nuclear factor kappa light-chain enhancer of activated B cell gene expression, with no effect on inducible nitric oxide synthase gene expression in the livers of mice. Histopathologically, clear decreases in the severity of CCl(4)-induced lesions were observed, particularly at high boric acid concentrations. Results suggest that boric acid exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely the result of both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

Automated Detection of Epileptic Biomarkers in Resting-State Interictal MEG Data

PubMed Central

Soriano, Miguel C.; Niso, Guiomar; Clements, Jillian; Ortín, Silvia; Carrasco, Sira; Gudín, María; Mirasso, Claudio R.; Pereda, Ernesto

2017-01-01

Certain differences between brain networks of healthy and epilectic subjects have been reported even during the interictal activity, in which no epileptic seizures occur. Here, magnetoencephalography (MEG) data recorded in the resting state is used to discriminate between healthy subjects and patients with either idiopathic generalized epilepsy or frontal focal epilepsy. Signal features extracted from interictal periods without any epileptiform activity are used to train a machine learning algorithm to draw a diagnosis. This is potentially relevant to patients without frequent or easily detectable spikes. To analyze the data, we use an up-to-date machine learning algorithm and explore the benefits of including different features obtained from the MEG data as inputs to the algorithm. We find that the relative power spectral density of the MEG time-series is sufficient to distinguish between healthy and epileptic subjects with a high prediction accuracy. We also find that a combination of features such as the phase-locked value and the relative power spectral density allow to discriminate generalized and focal epilepsy, when these features are calculated over a filtered version of the signals in certain frequency bands. Machine learning algorithms are currently being applied to the analysis and classification of brain signals. It is, however, less evident to identify the proper features of these signals that are prone to be used in such machine learning algorithms. Here, we evaluate the influence of the input feature selection on a clinical scenario to distinguish between healthy and epileptic subjects. Our results indicate that such distinction is possible with a high accuracy (86%), allowing the discrimination between idiopathic generalized and frontal focal epilepsy types. PMID:28713260

Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Yi, E-mail: yi.luo@pfizer.com; Rana, Payal; Will, Yvonne

Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting thatmore » fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain.

PubMed

Bonansco, Christian; Fuenzalida, Marco

2016-01-01

Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks.

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

PubMed Central

Bonansco, Christian; Fuenzalida, Marco

2016-01-01

Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks. PMID:27006834

Protective effect of lipoic acid on cyclophosphamide-induced testicular toxicity.

PubMed

Selvakumar, Elangovan; Prahalathan, Chidambaram; Sudharsan, Periyasamy Thandavan; Varalakshmi, Palaninathan

2006-05-01

Cyclophosphamide (CP), a widely used anticancer and immunosuppressive drug causes severe testicular toxicity. We investigated the protective effect of lipoic acid in CP-induced testicular toxicity. Two groups of male Wistar rats (140+/-20 g) were administered CP (15 mg/kg body weight, oral gavage) once a week for 10 weeks to induce testicular toxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight, i.p., 24 h prior to CP administration) once a week for 10 weeks. A vehicle treated control and a lipoic acid control groups were also included. The untreated CP exposed rats showed a significant increase in testicular reactive oxygen species (ROS) level, along with a significant decrease in cellular thiol levels. The activities of testicular marker enzymes such as gamma-glutamyl transferase, beta-glucuronidase, acid phosphatase and alkaline phosphatase were increased whereas the activities of sorbitol dehydrogenase and lactate dehydrogenase-X were decreased significantly in the animals treated with CP. In contrast, rats pretreated with lipoic acid showed normal marker enzymic patterns and normal levels of ROS and thiols. Testicular protection by lipoic acid is further substantiated by the normal histologic findings as against shrunken seminiferous tubules with impaired spermatogenesis in the CP administered rats. By the reversal of biochemical and morphological changes towards normalcy, the cytoprotective role of lipoic acid is illuminated in CP-induced testicular toxicity.

Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: Expansion of the genotypic and phenotypic spectrum.

PubMed

Hundallah, Khaled; Alenizi, Asma'a; AlHashem, Amal; Tabarki, Brahim

2016-07-01

Recently, de novo loss- or gain-of-function mutations in the KCNA2 gene; have been described in individuals with epileptic encephalopathy, ataxia or intellectual disability. In this report, we describe a further case of KCNA2-early-onset epileptic encephalopathy. The patient presented since birth with intractable seizures, progressive microcephaly, developmental delay, and progressive brain atrophy. Whole-exome sequencing showed a novel de novo mutation in the KCNA2 gene: c.1120A > G (p.Thr374Ala). This case expands the genotypic and phenotypic disease spectrum of this genetic form of KCNA2-early onset epileptic encephalopathy. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Altered Expression of CXCL13 and CXCR5 in Intractable Temporal Lobe Epilepsy Patients and Pilocarpine-Induced Epileptic Rats.

PubMed

Li, Ruohan; Ma, Limin; Huang, Hao; Ou, Shu; Yuan, Jinxian; Xu, Tao; Yu, Xinyuan; Liu, Xi; Yang, Juan; Chen, Yangmei; Peng, Xi

2017-02-01

The mechanisms that underlie the pathogenesis of epilepsy are still unclear. Recent studies have indicated that inflammatory processes occurring in the brain are involved in a common and crucial mechanism in epileptogenesis. C-X-C motif chemokine ligand 13 (CXCL13) and its only receptor, C-X-C motif chemokine receptor 5 (CXCR5), are highly expressed in the central nervous system (CNS) and participate in inflammatory responses. The present study aimed to assess the expression of CXCL13 and CXCR5 in the brain tissues of both patients with intractable epilepsy (IE) and a rat model (lithium-pilocarpine) of temporal lobe epilepsy (TLE) to identify possible roles of the CXCL13-CXCR5 signaling pathway in epileptogenesis. Real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemical, double-labeled immunofluorescence and Western blot analyses were performed in this study. CXCL13 and CXCR5 mRNA expression and protein levels were found to be significantly up-regulated in the TLE patients and TLE rats. Further, CXCL13 and CXCR5 protein levels were altered during the different epileptic phases after onset of status epilepticus (SE) in the pilocarpine model rats, including the acute phase (6, 24, and 72 h), latent phase (7 and 14 days) and chronic phase (30 and 60 days groups). Moreover, double-labeled immunofluorescence analysis revealed that CXCL13 was mainly expressed in the cytomembranes and cytoplasm of neurons and astrocytes, while CXCR5 was mainly expressed in the cytomembranes and cytoplasm of neurons. Thus, the CXCL13-CXCR5 signaling pathway may play a possible pathogenic role in IE. CXCL13 and CXCR5 may represent potential biomarkers of brain inflammation in epileptic patients.

Phenolic acids potentiate colistin-mediated killing of Acinetobacter baumannii by inducing redox imbalance.

PubMed

Ajiboye, Taofeek O; Skiebe, Evelyn; Wilharm, Gottfried

2018-05-01

Phenolic acids with catechol groups are good prooxidants because of their low redox potential. In this study, we provided data showing that phenolic acids, caffeic acid, gallic acid and protocatechuic acid, enhanced colistin-mediated bacterial death by inducing redox imbalance. The minimum inhibitory concentrations of these phenolic acids against Acinetobacter baumannii AB5075 were considerably lowered for ΔsodB and ΔkatG mutants. Checkerboard assay shows synergistic interactions between colistin and phenolic acids. The phenolic acids exacerbated colistin-induced oxidative stress in A. baumannii AB5075 through increased superoxide anion generation, NAD + /NADH and ADP/ATP ratio. In parallel, the level of reduced glutathione was significantly lowered. We conclude that phenolic acids potentiate colistin-induced oxidative stress in A. baumannii AB5075 by increasing ROS generation, energy metabolism and electron transport chain activity with a concomitant decrease in glutathione. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Inhibition of acid-induced lung injury by hyperosmolar sucrose in rats.

PubMed

Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

2005-10-15

Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration.

Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

PubMed Central

Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

2005-01-01

Rationale: Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. Objectives: The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Methods: Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. Results: In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. Conclusions: We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration. PMID:16109982

Dietary eicosapentaenoic acid prevents systemic immunosuppression in mice induced by UVB radiation.

PubMed

Moison, R M; Beijersbergen Van Henegouwen, G M

2001-07-01

Moison, R. M. W. and Beijersbergen van Henegouwen, G. M. J. Dietary Eicosapentaenoic Acid Prevents Systemic Immunosuppression in Mice Induced by UVB Radiation. Radiat. Res. 156, 36-44 (2001). Reactive oxygen species (ROS) contribute to the immunosuppression induced by UVB radiation. Omega-3 fatty acids in fish oil, e.g. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can modulate immunoresponsiveness, but because of their susceptibility to ROS-induced damage, they can also challenge the epidermal antioxidant defense system. The influence of dietary supplementation with different omega-3 fatty acids on systemic immunosuppression induced in mice by UVB radiation was studied using the contact hypersensitivity response to trinitrochlorobenzene. In an attempt to study the mechanisms involved, UVB-radiation-induced changes in epidermal antioxidant status were also studied. Mice received high-fat (25% w/w) diets enriched with either oleic acid (control diet), EPA, DHA, or EPA + DHA (MaxEPA). Immunosuppression induced by UVB radiation was 53% in mice fed the oleic acid diet and 69% in mice fed the DHA diet. In contrast, immunosuppression was only 4% and 24% in mice fed the EPA and MaxEPA diets, respectively. Increased lipid peroxidation and decreased vitamin E levels (P < 0.05) were found in unirradiated mice fed the MaxEPA and DHA diets. For all diets, exposure to UVB radiation increased lipid peroxidation (P < 0.05), but levels of glutathione (P < 0.05) and vitamin C (P > 0.05) decreased only in the mice given fish oil. UVB irradiation did not influence vitamin E levels. In conclusion, dietary EPA, but not DHA, protects against UVB-radiation-induced immunosuppression in mice. The degree of protection appears to be related to the amount of EPA incorporated and the ability of the epidermis to maintain an adequate antioxidant level after irradiation.

Unusual association of SCN2A epileptic encephalopathy with severe cortical dysplasia detected by prenatal MRI.

PubMed

Bernardo, Silvia; Marchionni, Enrica; Prudente, Sabrina; De Liso, Paola; Spalice, Alberto; Giancotti, Antonella; Manganaro, Lucia; Pizzuti, Antonio

2017-05-01

We present an atypical association of SCN2A epileptic encephalopathy with severe cortical dysplasia. SCN2A mutations are associated with epileptic syndromes from benign to extremely severe in absence of such macroscopic brain findings. Prenatal MRI (Magnetic Resonance Imaging) in a 32 weeks fetus, with US (Ultrasonography) diagnosis of isolated ventriculomegaly showed CNS (Central Nervous System) dysplasia characterized by lack of differentiation between cortical and subcortical layers, pachygyria and corpus callosum dysgenesis. Postnatal MRI confirmed the prenatal findings. On day 6 the baby presented a focal status epilepticus, partially controlled by phenobarbital, phenytoin, and levetiracetam. After three weeks a moderate improvement in seizure control has been achieved with carbamazepine. Exome sequencing detected a de novo heterozygous mutation in the SCN2A gene, encoding the α II -subunit of a sodium channel. The patient findings expand the phenotype spectrum of SCN2A mutations to epileptic encephalopathies with macroscopic brain developmental features. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Profiling Abscisic Acid-Induced Changes in Fatty Acid Composition in Mosses.

PubMed

Shinde, Suhas; Devaiah, Shivakumar; Kilaru, Aruna

2017-01-01

In plants, change in lipid composition is a common response to various abiotic stresses. Lipid constituents of bryophytes are of particular interest as they differ from that of flowering plants. Unlike higher plants, mosses have high content of very long-chain polyunsaturated fatty acids. Such lipids are considered to be important for survival of nonvascular plants. Here, using abscisic acid (ABA )-induced changes in lipid composition in Physcomitrella patens as an example, a protocol for total lipid extraction and quantification by gas chromatography (GC) coupled with flame ionization detector (FID) is described.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

PubMed

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Nicotinic acid modulates Legionella pneumophila gene expression and induces virulence traits.

PubMed

Edwards, Rachel L; Bryan, Andrew; Jules, Matthieu; Harada, Kaoru; Buchrieser, Carmen; Swanson, Michele S

2013-03-01

In response to environmental fluctuations or stresses, bacteria can activate transcriptional and phenotypic programs to coordinate an adaptive response. The intracellular pathogen Legionella pneumophila converts from a noninfectious replicative form to an infectious transmissive form when the bacterium encounters alterations in either amino acid concentrations or fatty acid biosynthesis. Here, we report that L. pneumophila differentiation is also triggered by nicotinic acid, a precursor of the central metabolite NAD(+). In particular, when replicative L. pneumophila are treated with 5 mM nicotinic acid, the bacteria induce numerous transmissive-phase phenotypes, including motility, cytotoxicity toward macrophages, sodium sensitivity, and lysosome avoidance. Transcriptional profile analysis determined that nicotinic acid induces the expression of a panel of genes characteristic of transmissive-phase L. pneumophila. Moreover, an additional 213 genes specific to nicotinic acid treatment were altered. Although nearly 25% of these genes lack an assigned function, the gene most highly induced by nicotinic acid treatment encodes a putative major facilitator superfamily transporter, Lpg0273. Indeed, lpg0273 protects L. pneumophila from toxic concentrations of nicotinic acid as judged by analyzing the growth of the corresponding mutant. The broad utility of the nicotinic acid pathway to couple central metabolism and cell fate is underscored by this small metabolite's modulation of gene expression by diverse microbes, including Candida glabrata, Bordetella pertussis, Escherichia coli, and L. pneumophila.

Abscisic acid-regulated protein degradation causes osmotic stress-induced accumulation of branched-chain amino acids in Arabidopsis thaliana.

PubMed

Huang, Tengfang; Jander, Georg

2017-10-01

Whereas proline accumulates through de novo biosynthesis in plants subjected to osmotic stress, leucine, isoleucine, and valine accumulation in drought-stressed Arabidopsis thaliana is caused by abscisic acid-regulated protein degradation. In response to several kinds of abiotic stress, plants greatly increase their accumulation of free amino acids. Although stress-induced proline increases have been studied the most extensively, the fold-increase of other amino acids, in particular branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), is often higher than that of proline. In Arabidopsis thaliana (Arabidopsis), BCAAs accumulate in response to drought, salt, mannitol, polyethylene glycol, herbicide treatment, and nitrogen starvation. Plants that are deficient in abscisic acid signaling accumulate lower amounts of BCAAs, but not proline and most other amino acids. Previous bioinformatic studies had suggested that amino acid synthesis, rather than protein degradation, is responsible for the observed BCAA increase in osmotically stressed Arabidopsis. However, whereas treatment with the protease inhibitor MG132 decreased drought-induced BCAA accumulation, inhibition of BCAA biosynthesis with the acetolactate synthase inhibitors chlorsulfuron and imazapyr did not. Additionally, overexpression of BRANCHED-CHAIN AMINO ACID TRANSFERASE2 (BCAT2), which is upregulated in response to osmotic stress and functions in BCAA degradation, decreased drought-induced BCAA accumulation. Together, these results demonstrate that BCAA accumulation in osmotically stressed Arabidopsis is primarily the result of protein degradation. After relief of the osmotic stress, BCAA homeostasis is restored over time by amino acid degradation involving BCAT2. Thus, drought-induced BCAA accumulation is different from that of proline, which is accumulated due to de novo synthesis in an abscisic acid-independent manner and remains elevated for a more prolonged period of time after removal of

Caffeic acid attenuates lipopolysaccharide-induced sickness behaviour and neuroinflammation in mice.

PubMed

Basu Mallik, Sanchari; Mudgal, Jayesh; Nampoothiri, Madhavan; Hall, Susan; Dukie, Shailendra Anoopkumar-; Grant, Gary; Rao, C Mallikarjuna; Arora, Devinder

2016-10-06

Accumulating data links inflammation, oxidative stress and immune system in the pathophysiology of major depressive disorders. Sickness behaviour is a set of behavioural changes that develop during infection, eventually leading to decrease in mobility and depressed behaviour. Lipopolysaccharide (LPS) induces a depression-like state in animals that mimics sickness behaviour. Caffeic acid, a naturally occurring polyphenol, possesses antioxidant and anti-inflammatory properties. The present study was designed to explore the potential of caffeic acid against LPS-induced sickness behaviour in mice. Caffeic acid (30mg/kg) and imipramine (15mg/kg) were administered orally one hour prior to LPS (1.5mg/kg) challenge. Behavioural assessment was carried out between 1 and 2h and blood samples were collected at 3h post-LPS injection. Additionally, cytokines (brain and serum) and brain oxidative stress markers were estimated. LPS increased the systemic and brain cytokine levels, altered the anti-oxidant defence and produced key signs of sickness behaviour in animals. Caffeic acid treatment significantly reduced the LPS-induced changes, including reduced expression of inflammatory markers in serum and whole brain. Caffeic acid also exerted an anti-oxidant effect, which was evident from the decreased levels of oxidative stress markers in whole brain. Our data suggests that caffeic acid can prevent the neuroinflammation-induced acute and probably the long term neurodegenerative changes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epileptic Encephalopathies and Their Relationship to Developmental Disorders: Do Spikes Cause Autism?

ERIC Educational Resources Information Center

Tharp, Barry R.

2004-01-01

Epileptic encephalopathies are progressive clinical and electroencephalographic syndromes where deterioration is thought to be caused by frequent seizures and abundant EEG epileptiform activity. Seizures occur in approximately 10-15% of children with pervasive developmental disorders (PDD) and 8-10% have epileptiform EEG abnormalities without…

Age-Dependency of Location of Epileptic Foci in "Continuous Spike-and-Waves during Sleep": A Parallel to the Posterior-Anterior Trajectory of Slow Wave Activity.

PubMed

Bölsterli Heinzle, Bigna Katrin; Bast, Thomas; Critelli, Hanne; Huber, Reto; Schmitt, Bernhard

2017-02-01

Epileptic encephalopathy with continuous spike-and-waves during sleep (CSWS) occurs during childhood and is characterized by an activation of spike wave complexes during slow wave sleep. The location of epileptic foci is variable, as is etiology. A relationship between the epileptic focus and age has been shown in various focal epilepsies following a posterior-anterior trajectory, and a link to brain maturation has been proposed. We hypothesize that in CSWS, maximal spike wave activity, corresponding to the epileptic focus, is related to age and shows a posterior-anterior evolution. In a retrospective cross-sectional study on CSWS (22 EEGs of 22 patients aged 3.1–13.5 years), the location of the epileptic focus is related to age and follows a posterior-anterior course. Younger patients are more likely to have posterior foci than older ones. We propose that the posterior-anterior trajectory of maximal spike waves in CSWS might reflect maturational changes of maximal expression of sleep slow waves, which follow a comparable course. Epileptic spike waves, that is, “hyper-synchronized slow waves” may occur at the place where the highest and therefore most synchronized slow waves meet brain tissue with an increased susceptibility to synchronization. Georg Thieme Verlag KG Stuttgart · New York.