Recent advances in epilepsy

Manford, Mark

doi:10.1007/s00415-017-8394-2

Cited by 180 publications

(144 citation statements)

References 187 publications

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“…Despite advances in the development of therapies for epilepsy, approximately 40% of patients have seizures that are refractory to treatment and also suffer from various comorbidities and adverse effects of antiepileptic drugs (AEDs) (Perucca et al, 2009;Brodie, 2017;Manford, 2017). The GABA A receptor is a target of commonly used AEDs including benzodiazepines (BDZs), barbiturates, and valproate (VPA) (Greenfield, 2013).…”

Section: Introductionmentioning

confidence: 99%

Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome

Nomura¹,

Hawkins²,

Kearney³

et al. 2018

Preprint

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Acknowledgements:This work was supported by NIH grants R01 NS084959 (J.A.K.) and R01MH099114 (A.C.) and a seed grant from the American Epilepsy Society (A.C.). We thank Nick Brandon from AstraZeneca for providing AZD7325.Abstract GABA A receptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether distinct GABA A receptor subtypes contribute to seizure activity, and whether targeting receptor subtypes will have disproportionate benefit over adverse effects. Here we demonstrate that the α 2 / α 3 selective positive allosteric modulator (PAM) AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons. The effect of AZD7325 on synaptic responses was more prominent in mice on the 129S6/SvEvTac background strain that has been demonstrated to be seizure resistant in the model of Dravet syndrome (Scn1a +/-) and in which the α 2 GABA A receptor subunits are higher relative to in the C57BL/6J strain. Consistent with this, treatment of mice with AZD7325 is associated with a higher temperature threshold for hyperthermia-induced seizures in Scn1a +/mice without apparent sedative effects. Our results in a model system indicate that selective targeting α 2 is a potential therapeutic option for Dravet syndrome. Significance StatementThe GABA A receptor is a target of several antiepileptic drugs (AEDs), but whether specific subtypes of GABA A receptors are critical for seizure suppression is not known. We demonstrated that the α 2 / α 3 selective positive allosteric modulator (PAM) AZD7325 potentiates hippocampal inhibitory synaptic responses in mice in a strain-dependent manner. The results are consistent with our previous findings that uncovered strain dependent differential expression of the α 2 subunit in seizure resistant and protective strains for Scn1a heterozygous deletion, a mouse model of Dravet syndrome. Treatment of mice with AZD7325 was associated with a higher temperature threshold for hyperthermia-induced seizures in Scn1a +/mice indicating α 2 is a potential therapeutic target in Dravet syndrome. Materials & Methods AnimalsAll experimental procedures were carried out in accordance with the policies and protocols approved by the Northwestern University IACUC. Three separate mouse strains were used in the series of experiments; C57BL/6J (Strain # 000664, The Jackson Laboratory), 129S6/SvEvTac (Taconic), and [C57BL/6J x 129S6/SvEvTac] F1 strains. Male Scn1a tm1Kea (Scn1a +/-) mice on the 129S6/SvEvTac background (129.Scn1a +/-)(Miller et al., 2014) were crossed with inbred female C57BL/6J or 129S6/SvEvTac mice to generate Scn1a +/mice with F1 (F1.Scn1a +/-) or 129S6/SvEvTac (129.Scn1a +/-) backgrounds, respectively. Both male and female Scn1a +/or wild-type littermates (Scn1a +/+ ) were used for experiments. Slice preparation for electrophysiologyHorizontal hippocampal slices (350 μm) were prepared from postnatal day 14 -16 (P14 -P16) mice as described previously (Fernandes et al., 2015;Nomura et al., 2016). Briefly, brain ...

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Section: Introductionmentioning

confidence: 99%

Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome

Nomura¹,

Hawkins²,

Kearney³

et al. 2018

Preprint

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“…The activation of voltage-gated potassium channels after the action potential is the main regulatory effect that determines the degree of repolarization and repeated neuronal discharge. Epilepsy is a chronic disease of transient brain dysfunction caused by sudden abnormal discharge of brain neurons (Wittner et al, 2001;Manford, 2017). Potassium channels play an important role in maintaining resting membrane potential and regulating cell excitability of neurons, which can cause neuropathic pain or neurological diseases (such as epilepsy and ataxia) (Wickenden, 2002;Pimentel et al, 2008).…”

Section: Other Pathologiesmentioning

confidence: 99%

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Wang

Guo

et al. 2020

Front. Neurosci.

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“…In addition to superior detection modalities, improvements in epilepsy treatment and management during the study period have likely contributed to the down-trending in mortality despite the increase in prevalence of epilepsy. A review published in the Journal of Neurology suggests that a better utilization of anti-epileptic drugs in conjunction with a broadened view of individual patient characteristics has helped make epilepsy treatment more effective [8]. Currently, there is substantial ongoing research to further improve epilepsy therapy.…”

Section: Discussionmentioning

confidence: 99%

The Trend of In-Hospital Epilepsy and Its Mortality in the USA: A National Analysis During 1997 - 2014

2020

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Background: This study focuses on the trend of prevalence of epilepsy hospital discharges in the USA, and the aim is to find any change in the trend of prevalence of epilepsy in the USA and its in-hospital mortality. Methods:A retrospective cohort study used the Healthcare Cost and Utilization Project (HCUP) national database to analyze trends of epilepsy outcomes between 1997 and 2014.Results: A total of 4,594,213 total epilepsy discharges were documented between 1997 and 2014 in the HCUP database. The prevalence of annual discharges increased significantly during the study period from 209,002 discharges in 1997 to 280,255 in 2014 (P < 0.0001). There were a total of 35,643 in-hospital deaths due to epilepsy within the cohort during the study period. Mortality of epilepsy decreased across the entire cohort and between genders. In 1997, there were 2,256 documented in-hospital deaths, while 1,759 were recorded in 2014 (P = 0.00157). Conclusions:Our data showed that the prevalence of hospital epilepsy discharges is increasing in recent years; however, the inhospital mortality is decreasing. The increase in the prevalence could be due to better detection or increased population, while the improved mortality could be due to better available treatments in recent years. Focusing on designing more accurate and affordable screening tools, as well as targeting further pharmacology-based treatments are an area of research that requires further investigation.

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Recent advances in epilepsy

Cited by 180 publications

References 187 publications

Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome

Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

The Trend of In-Hospital Epilepsy and Its Mortality in the USA: A National Analysis During 1997 - 2014

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Recent advances in epilepsy

Cited by 180 publications

References 187 publications

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

The Trend of In-Hospital Epilepsy and Its Mortality in the USA: A National Analysis During 1997 - 2014

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Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome

Potentiating α₂ subunit containing perisomatic GABA_A receptors protects against seizures in a mouse model of Dravet Syndrome