scholarly journals Leukocyte–Endothelial Adhesion Mechanisms in Epilepsy: Cheers and Jeers

2009 ◽  
Vol 9 (4) ◽  
pp. 118-121 ◽  
Author(s):  
Annamaria Vezzani ◽  
Damir Janigro
Keyword(s):  
Neuronal Excitability ◽  
World Population ◽  
Brain Vessels ◽  
Acute Seizures ◽  
Leukocyte Integrins ◽  
Acute Seizure ◽  
Elevated Expression ◽  
Vascular Adhesion ◽  
Spontaneous Recurrent Seizures ◽  
Blocking Antibodies

A Role for Leukocyte-Endothelial Adhesion Mechanisms in Epilepsy. Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. Nat Med 2008;14(12):1377–1383. The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1,2,3. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins41 and L2. Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.

Pharmacological mechanism of topiramate in the prophylaxis and treatment of migraine: a review

2018 ◽  
pp. 190-195
Author(s):  
Emanuela Paz Rosas ◽  
Raisa Ferreira Costa ◽  
Silvania Tavares Paz ◽  
Ana Paula Fernandes da Silva ◽  
Manuela Freitas Lyra de Freitas
Keyword(s):  
Cortical Spreading Depression ◽  
Molecular Mechanisms ◽  
Spreading Depression ◽  
Neuronal Excitability ◽  
Mechanisms Of Action ◽  
World Population ◽  
Gamma Aminobutyric Acid ◽  
Pharmacological Mechanism ◽  
Calcium Ion Channels ◽  
Voltage Dependent

Objective: This review sought to bring evidence of studies addressing the mechanisms of action of topiramate in the prevention and treatment of migraine. Background: Migraine is a neurovascular disorder that affects a large part of the world population. The use of prophylactics contributes to the decrease in the frequency and severity of this disease. Among the antiepileptic drugs, the topiramate, has proven to be the most effective for the treatment of migraine. Although the mechanism of action of this drug is still not well elucidated in the literature, there are several molecular mechanisms proposed. Methodology: A survey was carried out in the literature, from February to March 2018, in different databases, using the descriptors: topiramate, migraine and mechanisms of action. After a careful selection, 25 manuscripts were chosen for this review. Results: Evidence from a number of studies has indicated that the main mechanisms of action of topiramate are related to the modulation of voltage-dependent sodium and calcium ion channels, blockade of excitatory glutamate transmission and inhibition by gamma-aminobutyric acid receptors (GABA), AMPA/kainate and some isoenzymes of carbonic anhydrase. In addition, topiramate is involved in the suppression of cortical spreading depression, besides influencing trigeminovascular activity, and neuronal excitability. Conclusion: Thus, topiramate could be involved in the prevention of major events of the pathophysiology of migraine. Acting directly on cortical spreading depression (DAC), trigeminovascular signals and decreased central sensitization of migraine pain.

scholarly journals Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice

Blood ◽  
2019 ◽  
Vol 133 (3) ◽  
pp. 193-204 ◽  
Author(s):  
Miguel Alejandro Lopez-Ramirez ◽  
Angela Pham ◽  
Romuald Girard ◽  
Tine Wyseure ◽  
Preston Hale ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Recurrent Bleeding ◽  
Cerebral Cavernous Malformations ◽  
Endothelial Protein C Receptor ◽  
Cavernous Malformations ◽  
Genetic Inactivation ◽  
Elevated Expression ◽  
Hemorrhagic Risk ◽  
Blocking Antibodies

Abstract Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1ECKO) or Pdcd10 (Pdcd10ECKO), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10. Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the Thbd gene decreases brain hemorrhage in Pdcd10ECKO mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10ECKO mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.

scholarly journals Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

2012 ◽  
Vol 87 (3) ◽  
pp. 1849-1860 ◽  
Author(s):  
Matthew F. Cusick ◽  
Jane E. Libbey ◽  
Dipan C. Patel ◽  
Daniel J. Doty ◽  
Robert S. Fujinami
Keyword(s):  
Proinflammatory Cytokines ◽  
Neuronal Excitability ◽  
Viral Infections ◽  
Cell Types ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Antiviral Immune Response ◽  
Acute Seizures ◽  
Tnf Α ◽  
The Central Nervous System

ABSTRACTViral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

scholarly journals Status Epilepticus: The Slow and Agonizing Death of Phenytoin

2020 ◽  
Vol 25 (1) ◽  
pp. 4-6 ◽  
Author(s):  
Elizabeth A. Hall ◽  
James W. Wheless ◽  
Stephanie J. Phelps
Keyword(s):  
Status Epilepticus ◽  
Adverse Effects ◽  
Drug Interactions ◽  
Mechanism Of Action ◽  
Adult Patients ◽  
Evidence Based ◽  
Insufficient Evidence ◽  
First Line ◽  
Acute Seizures ◽  
Acute Seizure

Since its introduction in 1950, phenytoin (PHT) has been the premier parenteral anticonvulsant used in the management of generalized convulsive status epileptics (GCSE) that is refractory to benzodiazepines. Without question, its arrival was vital to the care of patients with acute seizures and was a welcomed alternative to paraldehyde and phenobarbital. However, after more than half a century of use, there continues to be insufficient evidence-based data to support its efficacy over other anticonvulsants as a first-line agent in pediatric or adult patients with GCSE. This coupled with its narrow mechanism of action, complex pharmacokinetics and pharmacogenomics, drug-drug interactions, unique adverse effects, and formulation issues that make administration difficult mandates that PHT be replaced by safer and superiorly effective anticonvulsants for the treatment of GCSE when benzodiazepines are ineffective. We believe that levetiracetam should become the preferred agent for seizures unresponsive to or recurring after treatment with a benzodiazepine as it is at least equally effective to PHT and has several important advantages. PHT has overstayed its welcome and it is simply time for it to exit the realm of acute seizure management as a first-line agent for benzodiazepine-refractory GCSE.

scholarly journals The association between systemic autoimmune disorders and epilepsy and its clinical implications

Brain ◽  
2020 ◽  
Author(s):  
Claude Steriade ◽  
Maarten J Titulaer ◽  
Annamaria Vezzani ◽  
Josemir W Sander ◽  
Roland D Thijs
Keyword(s):  
Lupus Erythematosus ◽  
Neuronal Excitability ◽  
Clinical Signs ◽  
Autoimmune Encephalitis ◽  
Autoimmune Disorders ◽  
Barrier Dysfunction ◽  
Acute Seizures ◽  
Immunosuppressive Medications ◽  
Symptomatic Seizures ◽  
Patients With Epilepsy

Abstract Systemic autoimmune disorders occur more frequently in patients with epilepsy than in the general population, suggesting shared disease mechanisms. The risk of epilepsy is elevated across the spectrum of systemic autoimmune disorders but is highest in systemic lupus erythematosus and type 1 diabetes mellitus. Vascular and metabolic factors are the most important mediators between systemic autoimmune disorders and epilepsy. Systemic immune dysfunction can also affect neuronal excitability, not only through innate immune activation and blood–brain barrier dysfunction in most epilepsies but also adaptive immunity in autoimmune encephalitis. The presence of systemic autoimmune disorders in subjects with acute seizures warrants evaluation for infectious, vascular, toxic and metabolic causes of acute symptomatic seizures, but clinical signs of autoimmune encephalitis should not be missed. Immunosuppressive medications may have antiseizure properties and trigger certain drug interactions with antiseizure treatments. A better understanding of mechanisms underlying the co-existence of epilepsy and systemic autoimmune disorders is needed to guide new antiseizure and anti-epileptogenic treatments. This review aims to summarize the epidemiological evidence for systemic autoimmune disorders as comorbidities of epilepsy, explore potential immune and non-immune mechanisms, and provide practical implications on diagnostic and therapeutic approach to epilepsy in those with comorbid systemic autoimmune disorders.

scholarly journals SGK1.1 activation causes early seizure termination via effects on M-current

2019 ◽  
Author(s):  
Natalia Armas-Capote ◽  
Laura E. Maglio ◽  
Leonel Pérez-Atencio ◽  
Elva Martin-Batista ◽  
Antonio Reboreda ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Neuronal Excitability ◽  
Active Form ◽  
Cellular Level ◽  
Adverse Outcomes ◽  
Early Termination ◽  
Ca1 Neurons ◽  
M Current ◽  
Acute Seizures ◽  
Hippocampal Ca1

AbstractEarly termination of status epilepticus affords protection against brain damage and associated pathologies. Regulation of Kv7.2/7.3 potassium channels, underlying the neuronal M-current, is key for seizure control. This conductance is maintained during initiation of action potentials, affecting neuronal excitability and thus inhibiting epileptic discharges. The M-current is upregulated by the neuronal isoform of the serum and glucocorticoid-regulated kinase SGK1 (SGK1.1). We tested whether SGK1.1 is an anticonvulsant factor using the kainic acid (KA) model of acute seizures in a transgenic mouse model with expression of a constitutively active form of the kinase. Our results demonstrate that SGK1.1 confers robust protection against seizures associated to lower mortality levels, independently of sex or genetic background. SGK1.1-dependent protection results in reduced number, shorter duration, and early termination of EEG seizures. At the cellular level, it is associated to increased M-current amplitude mediated by Nedd4-2 phosphorylation, leading to decreased excitability of hippocampal CA1 neurons without alteration of basal synaptic transmission. Altogether, our results reveal that SGK1.1-mediated M-current upregulation in the hippocampus is a key component of seizure resistance in the KA epileptic paradigm, suggesting that regulation of this anticonvulsant pathway may improve adverse outcomes to status epilepticus, constituting a potential target for antiepileptic drugs.

scholarly journals Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Samuel Mucio-Ramírez ◽  
Oleksandr Makeyev
Keyword(s):  
Neuronal Damage ◽  
Complementary Therapy ◽  
World Population ◽  
Concentric Ring ◽  
Acute Seizures ◽  
Seizure Models ◽  
Significant Difference ◽  
Hippocampal Ca3 ◽  
Full Factorial ◽  
The Brain

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n=36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71) nor due to the delay after the last stimulation dose (p = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200 μs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

scholarly journals The Integrated Effects of Brivaracetam, a Selective Analog of Levetiracetam, on Ionic Currents and Neuronal Excitability

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 369
Author(s):  
Te-Yu Hung ◽  
Sheng-Nan Wu ◽  
Chin-Wei Huang
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Ionic Currents ◽  
Delayed Rectifier ◽  
Open Probability ◽  
Acute Seizures ◽  
Dependent Inhibition ◽  
K Current ◽  
Patch Configuration ◽  
Epilepsy Models

Brivaracetam (BRV) is recognized as a novel third-generation antiepileptic drug approved for the treatment of epilepsy. Emerging evidence has demonstrated that it has potentially better efficacy and tolerability than its analog, Levetiracetam (LEV). This, however, cannot be explained by their common synaptic vesicle-binding mechanism. Whether BRV can affect different ionic currents and concert these effects to alter neuronal excitability remains unclear. With the aid of patch clamp technology, we found that BRV concentration dependently inhibited the depolarization-induced M-type K+ current (IK(M)), decreased the delayed-rectifier K+ current (IK(DR)), and decreased the hyperpolarization-activated cation current in GH3 neurons. However, it had a concentration-dependent inhibition on voltage-gated Na+ current (INa). Under an inside-out patch configuration, a bath application of BRV increased the open probability of large-conductance Ca2+-activated K+ channels. Furthermore, in mHippoE-14 hippocampal neurons, the whole-cell INa was effectively depressed by BRV. In simulated modeling of hippocampal neurons, BRV was observed to reduce the firing of the action potentials (APs) concurrently with decreases in the AP amplitude. In animal models, BRV ameliorated acute seizures in both OD-1 and lithium-pilocarpine epilepsy models. However, LEV had effects in the latter only. Collectively, our study demonstrated BRV’s multiple ionic mechanism in electrically excitable cells and a potential concerted effect on neuronal excitability and hyperexcitability disorders.

Microglia depletion exacerbates acute seizures and hippocampal neuronal degeneration in mouse models of epilepsy

2020 ◽  
Vol 319 (3) ◽  
pp. C605-C610
Author(s):  
Mei Liu ◽  
Lijuan Jiang ◽  
Min Wen ◽  
Yue Ke ◽  
Xiangzhen Tong ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neuronal Excitability ◽  
Neuronal Degeneration ◽  
Epileptic Seizures ◽  
Gabaergic Neurons ◽  
Seizure Severity ◽  
Neuronal Excitation ◽  
Acute Seizures ◽  
Models Of Epilepsy

Epileptic seizures are the manifestation of hypersynchronous and excessive neuronal excitation. While the glutamatergic and GABAergic neurons play major roles in shaping fast neuronal excitation/inhibition homeostasis, it is well illustrated that astrocytes profoundly regulate neuronal excitation by controlling glutamate, GABA, cannabinoids, adenosine, and concentration of K+ around neurons. However, little is known about whether microglia take part in the regulation of acute neuronal excitation and ongoing epileptic behaviors. We proposed that if microglia are innately ready to respond to epileptic overexcitation, depletion of microglia might alter neuronal excitability and severity of acute epileptic seizures. We found that microglia depletion by plx3397, an inhibitor of CSF1R, exacerbates seizure severity and excitotoxicity-induced neuronal degeneration, indicating that microglia are rapidly responsive to the change of excitation/inhibition homeostasis and participate in the protection of neurons from overexcitation.

scholarly journals Long-Term Effects of Myoinositol on Behavioural Seizures and Biochemical Changes Evoked by Kainic Acid Induced Epileptogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Lia Tsverava ◽  
Manana Kandashvili ◽  
Giorgi Margvelani ◽  
Tamar Lortkipanidze ◽  
Georgi Gamkrelidze ◽  
...  
Keyword(s):  
Kainic Acid ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Biochemical Changes ◽  
Mrna Levels ◽  
Long Term Effects ◽  
Molecular Changes ◽  
Acute Seizures ◽  
Spontaneous Recurrent Seizures

Epilepsy is one of the most devastating neurological diseases and despite significant efforts there is no cure available. Occurrence of spontaneous seizures in epilepsy is preceded by numerous functional and structural pathophysiological reorganizations in the brain—a process called epileptogenesis. Treatment strategies targeting this process may be efficient for preventing spontaneous recurrent seizures (SRS) in epilepsy, or for modification of disease progression. We have previously shown that (i) myoinositol (MI) pretreatment significantly decreases severity of acute seizures (status epilepticus: SE) induced by kainic acid (KA) in experimental animals and (ii) that daily post-SE administration of MI for 4 weeks prevents certain biochemical changes triggered by SE. However it was not established whether such MI treatment also exerts long-term effects on the frequency of SRS. In the present study we have shown that, in KA-induced post-SE epilepsy model in rats, MI treatment for 28 days reduces frequency and duration of behavioural SRS not only during the treatment, but also after its termination for the following 4 weeks. Moreover, MI has significant effects on molecular changes in the hippocampus, including mi-RNA expression spectrum, as well as mRNA levels of sodium-MI transporter and LRRC8A subunit of the volume regulated anionic channel. Taken together, these data suggest that molecular changes induced by MI treatment may counteract epileptogenesis. Thus, here we provide data indicating antiepileptogenic properties of MI, which further supports the idea of developing new antiepileptogenic and disease modifying drug that targets MI system.

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