I schemia in the neonatal brain is an important cause of ref
ractory seizures. Exact timing of neonatal stroke occurrence is
usually unclear and the diagnosi
s delayed until presentation with seizures a few to several hours later. Developmental profi
of chloride co-transporter expression and function in immature brains have been proposed to underlie the effi
cacy of GABA-
agonists to act as hyperpolarizing agents. To investigate the anti-seizure effi
cacy of the fi
rst line anticonvulsant and GABAA-
agonist phenobarbital (PB) and NKCC1 antagonist bumetanide (BTN) as adjunct treatment on neonatal ischemic-seizures,
we utilized unilateral carotid-ligation to produce ischemi
a and acute ischemic-seizures in postnatal day 7 and 10 CD1 mice.
Quantitative video-EEG and western blot quantifi
cation of the adult-form electroneutral chloride co-transporter KCC2 assessed
cacy of the treatment.
Age and sex dependent susceptibility to ischemic seizure severity was detected. Ineffi
cacy of PB for P7 ischemic seizures
was supported by published studies indicating a chloride co-transport dependent developmental reversal of depolarizing to
hyperpolarizing action of GABA by the age of P8-9 in rodents. Th
e age-dependent increase in the hyperpolarizing eff
the GABAA agonists have been shown to depend on the increasing KCC2 expression profi
le detected in the maturing CD1
mouse brains and was supported by the effi
cacy of PB for P10 seizures. However, this study showed a down regulation of KCC2
er cerebral ischemia that may further decrease the effi
cacy of drug actions that are dependent on a hyperpolarizing chloride
gradient for their anticonvulsant action that failed to be rescued by blocking NKCC1 by BTN.
Dr. Kadam completed her Ph.D. from Colorado State University working with Dr. F.E. Dudek who is a world renowned epilepsy resea rcher. She completed her post-doctoral training at Johns Hopkins University School of Medicine and is now an independent researcher with t he Department of Neurology. She has established a small animal EEG core and begun collaborations investigating epileptogenesis both in models of pediatric acquired and genetic epilepsies. Her current research investigating mechanisms underlying neonatal seizure refractoriness is fu nded by an Epilepsy Foundation research grant. She has published 11 papers in reputed journals and is serving as a scienti fi c program review committee member for the American Epilepsy Society.
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