Treatment during a vulnerable developmental period rescues a genetic epilepsy
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Treatment during a vulnerable developmental period rescues a genetic epilepsy. / Marguet, Stephan Lawrence; Le-Schulte, Vu Thao Quyen; Merseburg, Andrea; Neu, Axel; Eichler, Ronny; Jakovcevski, Igor; Ivanov, Anton; Hanganu-Opatz, Ileana Livia; Bernard, Christophe; Morellini, Fabio; Isbrandt, Dirk.
in: NAT MED, Jahrgang 21, Nr. 12, 12.2015, S. 1436-44.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Treatment during a vulnerable developmental period rescues a genetic epilepsy
AU - Marguet, Stephan Lawrence
AU - Le-Schulte, Vu Thao Quyen
AU - Merseburg, Andrea
AU - Neu, Axel
AU - Eichler, Ronny
AU - Jakovcevski, Igor
AU - Ivanov, Anton
AU - Hanganu-Opatz, Ileana Livia
AU - Bernard, Christophe
AU - Morellini, Fabio
AU - Isbrandt, Dirk
PY - 2015/12
Y1 - 2015/12
N2 - 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.
AB - 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.
U2 - 10.1038/nm.3987
DO - 10.1038/nm.3987
M3 - SCORING: Journal article
C2 - 26594844
VL - 21
SP - 1436
EP - 1444
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 12
ER -