Treatment during a vulnerable developmental period rescues a genetic epilepsy

Autor: Anton Ivanov, Vu Thao Quyen Le-Schulte, Christophe Bernard, Fabio Morellini, Ronny Eichler, Axel Neu, Stephan Lawrence Marguet, Igor Jakovcevski, Ileana L. Hanganu-Opatz, Dirk Isbrandt, Andrea Merseburg
Rok vydání: 2015
Předmět:
therapeutic use [Bumetanide]
Male
Nervous system
drug effects [Body Weight]
Time Factors
pathology [Nerve Net]
Hippocampus
Hippocampal formation
Bioinformatics
pathology [Epilepsy]
Epilepsy
Cognition
drug effects [Behavior
Animal]
Solute Carrier Family 12
Member 2
Premovement neuronal activity
Bumetanide
Neurons
Behavior
Animal
KCNQ Potassium Channels
genetics [KCNQ Potassium Channels]
Electroencephalography
pathology [CA1 Region
Hippocampal]
metabolism [Solute Carrier Family 12
Member 2]
General Medicine
medicine.anatomical_structure
metabolism [Neurons]
drug effects [Cognition]
drug effects [Growth and Development]
Female
Growth and Development
medicine.symptom
Proto-Oncogene Proteins c-fos
medicine.drug
drug effects [Embryo
Mammalian]
medicine.medical_specialty
pathology [Embryo
Mammalian]
genetics [Epilepsy]
genetics [Mutation]
Inflammation
drug therapy [Epilepsy]
Biology
metabolism [RNA
Messenger]
General Biochemistry
Genetics and Molecular Biology
genetics [RNA
Messenger]
Internal medicine
drug effects [Nerve Net]
medicine
drug effects [Neurons]
Animals
ddc:610
RNA
Messenger
pharmacology [Bumetanide]
metabolism [Embryo
Mammalian]
CA1 Region
Hippocampal
pathology [Inflammation]
metabolism [KCNQ Potassium Channels]
Body Weight
Antagonist
Embryo
Mammalian
medicine.disease
Mice
Inbred C57BL
Endocrinology
Animals
Newborn
metabolism [Proto-Oncogene Proteins c-fos]
Mutation
Nerve Net
Zdroj: Nature medicine 21(12), 1436-1444 (2015). doi:10.1038/nm.3987
ISSN: 1546-170X
1078-8956
DOI: 10.1038/nm.3987
Popis: The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.
Databáze: OpenAIRE
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