The kainic acid model of temporal lobe epilepsy

doi:10.1016/J.NEUBIOREV.2013.10.011

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The kainic acid model of temporal lobe epilepsy

Journal Article•DOI•

The kainic acid model of temporal lobe epilepsy

Maxime Lévesque¹, Massimo Avoli², Massimo Avoli¹•Institutions (2)

Montreal Neurological Institute and Hospital¹, Sapienza University of Rome²

01 Dec 2013-Neuroscience & Biobehavioral Reviews (PMC Canada manuscript submission)-Vol. 37, Iss: 10, pp 2887-2899

TL;DR: It is concluded that the kainic acid model is a reliable tool for understanding temporal lobe epilepsy, provided that the differences existing between methodological procedures are taken into account.

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About: This article is published in Neuroscience & Biobehavioral Reviews.The article was published on 2013-12-01 and is currently open access. It has received 413 citations till now. The article focuses on the topics: Epileptogenesis & Epilepsy.

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Journal Article•DOI•

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

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Susanne Krasemann¹, Susanne Krasemann², Charlotte Madore², Ron Cialic², Caroline Baufeld², Narghes Calcagno², Rachid El Fatimy², Lien Beckers², Elaine O’Loughlin², Yang Xu³, Zain Fanek², David J. Greco², Scott T. Smith², George Tweet², Zachary Humulock², Tobias Zrzavy⁴, Patricia Conde-Sanroman⁵, Mar Gacias⁵, Zhiping Weng³, Hao Chen³, Emily C. Tjon², Fargol Mazaheri⁶, Kristin Hartmann¹, Asaf Madi², Jason D. Ulrich⁷, Markus Glatzel¹, Anna Worthmann¹, Joerg Heeren¹, Bogdan Budnik⁸, Cynthia A. Lemere², Tsuneya Ikezu⁹, Frank L. Heppner¹⁰, Vladimir Litvak³, David M. Holtzman⁷, Hans Lassmann⁴, Howard L. Weiner², Jordi Ochando⁵, Christian Haass⁶, Oleg Butovsky² - Show less +35 more•Institutions (10)

University of Hamburg¹, Brigham and Women's Hospital², University of Massachusetts Medical School³, Medical University of Vienna⁴, Icahn School of Medicine at Mount Sinai⁵, German Center for Neurodegenerative Diseases⁶, Washington University in St. Louis⁷, Harvard University⁸, Boston University⁹, Charité¹⁰

19 Sep 2017-Immunity

TL;DR: The TREM2-APOE pathway is identified as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.

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1,535 citations

Cites methods from "The kainic acid model of temporal l..."

...We validated our paradigm of dN-induced MG-dNF phenotype by using kainic acid as a model of acute neuronal cell death (Lévesque and Avoli, 2013)....
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...We validated our paradigm of dN-induced MG-dNF phenotype by using kainic acid as a model of acute neuronal cell death (Lévesque and Avoli, 2013)....
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Journal Article•DOI•

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options.

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Wolfgang Löscher¹, Heidrun Potschka¹, Sanjay M. Sisodiya¹, Annamaria Vezzani¹•Institutions (1)

Mario Negri Institute for Pharmacological Research¹

01 Jul 2020-Pharmacological Reviews

TL;DR: The current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and how the problem might be overcome are reviewed.

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Abstract: Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.

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272 citations

Cites background from "The kainic acid model of temporal l..."

...Though generalized convulsive seizures occur occasionally in this model, nonconvulsive electrographic seizures recorded in the Cornu Ammonis sector 1 (CA1) region typically occur multiple times per hour (Lévesque and Avoli, 2013; Löscher, 2016)....
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Journal Article•DOI•

Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration

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Maxime Lévesque¹, Massimo Avoli², Christophe Bernard³•Institutions (3)

Montreal Neurological Institute and Hospital¹, Sapienza University of Rome², Aix-Marseille University³

15 Feb 2016-Journal of Neuroscience Methods

TL;DR: This paper reviews two chemically-induced TLE models, namely the kainic acid and pilocarpine models, which have been widely employed in basic epilepsy research and takes into consideration their behavioral, electroencephalographic and neuropathologic features.

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195 citations

Cites background from "The kainic acid model of temporal l..."

...In adult animals, the administration of a single ntraperitoneal dose of kainic acid (6–15 mg/kg) or of pilocarpine 360–400 mg/kg) (Curia et al., 2008; Lévesque and Avoli, 2013) can rigger status epilepticus....
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...First, the gender, strain and age of animals affect the response o both kainic acid (Lévesque and Avoli, 2013; Zhang et al., 2008) nd pilocarpine (Curia et al....
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...First, the gender, strain and age of animals affect the response o both kainic acid (Lévesque and Avoli, 2013; Zhang et al., 2008) nd pilocarpine (Curia et al., 2008)....
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Journal Article•DOI•

Microglia-Neuron Communication in Epilepsy.

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Ukpong B. Eyo¹, Madhuvika Murugan¹, Long Jun Wu¹•Institutions (1)

Rutgers University¹

01 Jan 2017-Glia

TL;DR: This review highlights microglial reaction to experimental seizures, discusses microglian control of neuronal activities, and proposes the functions of microglia during acute epileptic phenotypes, delayed neurodegeneration, and aberrant neurogenesis.

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Abstract: Epilepsy has remained a significant social concern and financial burden globally. Current therapeutic strategies are based primarily on neurocentric mechanisms that have not proven successful in at least a third of patients, raising the need for novel alternative and complementary approaches. Recent evidence implicates glial cells and neuroinflammation in the pathogenesis of epilepsy with the promise of targeting these cells to complement existing strategies. Specifically, microglial involvement, as a major inflammatory cell in the epileptic brain, has been poorly studied. In this review, we highlight microglial reaction to experimental seizures, discuss microglial control of neuronal activities, and propose the functions of microglia during acute epileptic phenotypes, delayed neurodegeneration, and aberrant neurogenesis. Future research that would help fill in the current gaps in our knowledge includes epilepsy-induced alterations in basic microglial functions, neuro-microglial interactions during chronic epilepsy, and microglial contribution to developmental seizures. Studying the role of microglia in epilepsy could inform therapies to better alleviate the disease. GLIA 2016;65:5-18.

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177 citations

Cites background from "The kainic acid model of temporal l..."

...Both pilocarpine and kainic acid models of epilepsy result in delayed neurodegeneration beginning at about 24 h after drug treatment (Curia et al., 2008; Levesque and Avoli, 2013)....
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...Although beyond the scope of this review, further details of the mechanics and precise pathological features of these models can be found in several excellent reviews of the kainic acid and pilocarpine models of experimental seizures/ epilepsy (Curia et al., 2008; Levesque and Avoli, 2013; Levesque et al., 2016; Turski et al., 1989)....
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...…further details of the mechanics and precise pathological features of these models can be found in several excellent reviews of the kainic acid and pilocarpine models of experimental seizures/ epilepsy (Curia et al., 2008; Levesque and Avoli, 2013; Levesque et al., 2016; Turski et al., 1989)....
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...Although a complex interplay of kainate and non-kainate glutamate receptors have been implicated in the mechanism of kainic acid induced seizures, the CA3 region of the hippocampus is recognized to be extremely susceptible due to a high density of specific kainate receptors in this region (Levesque and Avoli, 2013)....
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...…interplay of kainate and non-kainate glutamate receptors have been implicated in the mechanism of kainic acid induced seizures, the CA3 region of the hippocampus is recognized to be extremely susceptible due to a high density of specific kainate receptors in this region (Levesque and Avoli, 2013)....
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Journal Article•DOI•

Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia

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Tina Notter¹, Jennifer M. Coughlin², Tilo Gschwind¹, Ulrike Weber-Stadlbauer¹, Yuchuan Wang², Michael Kassiou³, Anthony C. Vernon⁴, Dietmar Benke¹, Martin G. Pomper², Akira Sawa², Urs Meyer¹ - Show less +7 more•Institutions (4)

University of Zurich¹, Johns Hopkins University², University of Sydney³, King's College London⁴

01 Feb 2018-Molecular Psychiatry

TL;DR: It is shown that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels, and the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased T SPO expression or ligand binding is challenged.

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Abstract: Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [11C]DPA-713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis.

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168 citations

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References

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McGill University¹

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"The kainic acid model of temporal l..." refers background in this paper

...Acute seizures are characterized by immobility followed by facial clonus (stage 1 according to (Racine, 1972), masticatory movements and head nodding (stage 2), wet-dog shakes, unilateral or bilateral forelimb clonus (stage 4) and rearing and falling (stage 5)) (Mouri et al., 2008; Pernot et al.,…...
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..., 2007) and they are known to contribute to the generation of hippocampal theta rhythms (Buzsáki, 2002; Goldin et al., 2007; Klausberger et al., 2003)....
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...These neurons are known to receive excitatory glutamatergic inputs that are mediated by KA receptors (Dugladze et al., 2007) and they are known to contribute to the generation of hippocampal theta rhythms (Buzsáki, 2002; Goldin et al., 2007; Klausberger et al., 2003)....
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University of Waterloo¹

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Additional excerpts

...This procedure is known as kindling (Goddard et al., 1969)....
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Journal Article•DOI•

Excitatory actions of gaba during development: the nature of the nurture.

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Yehezkel Ben-Ari¹•Institutions (1)

French Institute of Health and Medical Research¹

01 Sep 2002-Nature Reviews Neuroscience

TL;DR: This work proposes that GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions, and provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation.

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Abstract: In the immature brain, GABA (gamma-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation while avoiding the potentially toxic effects of a mismatch between GABA-mediated inhibition and glutamatergic excitation. As key elements of this cascade are activity dependent, the formation of inhibition adds an element of nurture to the construction of cortical networks.

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2,275 citations

"The kainic acid model of temporal l..." refers background in this paper

...Due to high intracellular concentrations of chloride, the immature brain is more prone to seizures because GABA can exert an excitatory and depolarizing action on neurons (Ben-Ari, 2002; Ben-Ari et al., 2007; Cherubini et al., 1991; Kahle et al., 2008)....
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...For instance, both depolarizing effects of GABA and intense synaptogenesis have been proposed to contribute to the high susceptibility to seizures in immature brains (Ben-Ari, 2002; Ben-Ari and Holmes, 2005; Ben-Ari et al., 1989)....
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Journal Article•DOI•

Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy

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Yehezkel Ben-Ari

01 Feb 1985-Neuroscience

TL;DR: This work has shown that kainate-like endotoxins pose a novel threat to the integrity of the immune system through their role as a “spatially aggregating substance” in the response of epilepsy.

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1,707 citations

"The kainic acid model of temporal l..." refers background in this paper

...Lesions outside the amygdala were however not attributed to the toxin itself but to the SE it induces (Ben-Ari, 1985; BenAri et al., 1979b), since administration of diazepam before the KA administration in the amygdala did not modulate the extent of lesions at the site of injection but prevented…...
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...…a better characterization of glutamatergic structures and pathways, and eventually the development of a new animal model of temporal lobe epilepsy characterized by a latent period followed by refractory spontaneous seizures, as in human TLE (Ben-Ari, 1985; Ben-Ari and Cossart, 2000; Nadler, 1981)....
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...Lesions outside the amygdala were however not attributed to the toxin itself but to the SE it induces (Ben-Ari, 1985; BenAri et al., 1979b), since administration of diazepam before the KA administration in the amygdala did not modulate the extent of lesions at the site of injection but prevented distant hippocampal damage (Ben-Ari et al....
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...This opened the path to the identification of new glutamate receptor subtypes, a better characterization of glutamatergic structures and pathways, and eventually the development of a new animal model of temporal lobe epilepsy characterized by a latent period followed by refractory spontaneous seizures, as in human TLE (Ben-Ari, 1985; Ben-Ari and Cossart, 2000; Nadler, 1981)....
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