TY - JOUR
T1 - Basic mechanisms of catastrophic epilepsy - Overview from animal models
AU - Galanopoulou, Aristea S.
N1 - Funding Information:
This presentation was presented at the International Symposium on Surgery for Catastrophic Epilepsy in Infants (Tokyo, Japan, February 18th, 2012). I would like to acknowledge the support and experimental contributions of my collaborators in the published articles on the multiple-hit model of infantile spasms and particularly of Solomon L. Moshé, Tomonori Ono, Morris Scantlebury, Lenka Chudomelova, Stephen Briggs, Ozlem Akman, Antonietta Coppola, Emmanuel Raffo and David Betancourth. I am grateful for the expert technical assistance of Ms Qianyun Li, Wei Liu, and Hong Wang. Research grants supporting the studies in the multiple-hit model were received from NIH NINDS/NICHD NS62947, NINDS 20253, NS58303 and NS078333, Autism Speaks, People Against Childhood Epilepsy, the Heffer Family Foundation, the Siegel Family Foundation, and P30HD071593 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) at the National Institutes of Health. A research grant from Johnson & Johnson Pharmaceutical Research & Development, LLC (Raritan NJ USA) supported the carisbamate study in the multiple-hit model. The author has received speaker’s honorarium from Novartis and royalties from Morgan & Claypool Publishers. The Albert Einstein College of Medicine holds a patent on the multiple-hit model of IS (#7863499).
PY - 2013/9
Y1 - 2013/9
N2 - Infantile spasms are age-specific seizures of infantile epileptic encephalopathies that are usually associated with poor epilepsy and neurodevelopmental outcomes. The current treatments are not always effective and may be associated with significant side effects. Various mechanisms have been proposed as pathogenic for infantile spasms, including cortical or brainstem dysfunction, disruption of normal cortical-subcortical communications, genetic defects, inflammation, stress, developmental abnormalities. Many of these have been recently tested experimentally, resulting into the emergence of several animal models of infantile spasms. The stress theory of spasms yielded the corticotropin releasing hormone (CRH)-induced model, which showed the higher proconvulsant potency of CRH in developing rats, although only limbic seizures were observed. Models of acute induction of infantile spasms in rodents include the N-methyl-. d-aspartate (NMDA) model of emprosthotonic seizures, the prenatal betamethasone and prenatal stress variants of the NMDA model, and the γ-butyrolactone induced spasms in a Down's syndrome mouse model. Chronic rodent models of infantile spasms include the tetrodotoxin model and the multiple-hit models in rats, as well as two genetic mouse models of interneuronopathies with infantile spasms due to loss of function of the aristaless X-linked homeobox-related gene (ARX). This review discusses the emerging mechanisms for generation of infantile spasms and their associated chronic epileptic and dyscognitive phenotype as well as the recent progress in identifying pathways to better treat this epileptic encephalopathy.
AB - Infantile spasms are age-specific seizures of infantile epileptic encephalopathies that are usually associated with poor epilepsy and neurodevelopmental outcomes. The current treatments are not always effective and may be associated with significant side effects. Various mechanisms have been proposed as pathogenic for infantile spasms, including cortical or brainstem dysfunction, disruption of normal cortical-subcortical communications, genetic defects, inflammation, stress, developmental abnormalities. Many of these have been recently tested experimentally, resulting into the emergence of several animal models of infantile spasms. The stress theory of spasms yielded the corticotropin releasing hormone (CRH)-induced model, which showed the higher proconvulsant potency of CRH in developing rats, although only limbic seizures were observed. Models of acute induction of infantile spasms in rodents include the N-methyl-. d-aspartate (NMDA) model of emprosthotonic seizures, the prenatal betamethasone and prenatal stress variants of the NMDA model, and the γ-butyrolactone induced spasms in a Down's syndrome mouse model. Chronic rodent models of infantile spasms include the tetrodotoxin model and the multiple-hit models in rats, as well as two genetic mouse models of interneuronopathies with infantile spasms due to loss of function of the aristaless X-linked homeobox-related gene (ARX). This review discusses the emerging mechanisms for generation of infantile spasms and their associated chronic epileptic and dyscognitive phenotype as well as the recent progress in identifying pathways to better treat this epileptic encephalopathy.
KW - ACTH
KW - ARX
KW - Carisbamate
KW - Cognitive
KW - Infantile spasms
KW - MTOR
KW - NMDA
KW - Rapamycin
KW - Vigabatrin
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U2 - 10.1016/j.braindev.2012.12.005
DO - 10.1016/j.braindev.2012.12.005
M3 - Review article
C2 - 23312951
AN - SCOPUS:84881370025
SN - 0387-7604
VL - 35
SP - 748
EP - 756
JO - Brain and Development
JF - Brain and Development
IS - 8
ER -