The immature brain is susceptible to post-ischemic seizures. Current clinical practice includes empiric treatments with phenobarbital (PB) as first line for confirmed or suspected seizures in the newborn. This proposal will investigate the age and gender dependent differences in KCC2 expression and modulation following ischemic neonatal brains of CD1 mice. In preparation we have established the age-dependent increase in KCC2 expression and the age-dependent efficacy of first line anticonvulsant drug, phenobarbital on neonatal ischemic seizures in-vivo in P7, P10 and P12 pups. We have found phenobarbital to be inefficacious in suppressing ischemic seizures at P7 and significantly efficacious at P10 and P12 using quantitative video-EEG. Our data show a significant biological sex related difference both in the severity of post-ischemic seizures and in the efficacy of phenobarbital to suppress seizures at P7. The following hypotheses will be tested in the CD1 mouse model of neonatal stroke induced by unilateral common carotid ligation only (i.e., no global hypoxia): 1.Ischemic insults downregulate the acute and delay the sub-acute developmental expression profile of the adult-form electroneutral chloride cotransporter KCC2 (chloride-extruding K-Cl cotransporter) at P7 and P10; 2. Early blocking of KCC2 downregulation following ischemia may be a novel strategy to prevent emergence of refractory neonatal seizures. 3. Quantitative video-EEG of acute post-stroke events from P7 and P10 CD1 pups and their response to standard and novel anticonvulsants like PB and bumetanide (BTN; potent NKCC1 antagonist) will help predict the efficacy of combination therapies immediate versus early after blocking KCC2 downregulation following neonatal stroke. The added inefficacy of novel anticonvulsant BTN; a potent NKCC1 antagonist detected in our previously funded study by the EFA (2011) has highlighted the importance of the differential efficacy of BTN in different seizure models. Especially of interest are our preliminary findings that KCC2 is downregulated after ischemia in this model whereas NKCC1 expression remains stable with trends towards upregulation. Therefore the mechanism by which acute seizures are induced in immature brains and the specific effect that protocol has on enhancing or worsening chloride cotransporter function by phosphorylation or degradation of KCC2 may dictate the efficacy of anticonvulsants that depend on the chloride gradient for their anti-seizure effects. Post-ischemic response of preventing KCC2 downregulation to immediate treatment with combination therapy of phenobarbital and NKCC1 antagonist bumetanide will be investigated and compared to early treatment after the occurrence of ischemic seizures and evaluated for sexual dimorphism.
The immature brain, compared to adult, is more susceptible to post-ischemic seizures. Neonatal strokes are a major cause of epilepsy and long-term co-morbidities in infants and children, and are clinically refractory to treatment by commonly used antiepileptic drugs. This study will use a rodent model of neonatal stroke and ischemic seizures to provide novel insights to help design consistent, evidence-based guidelines for the management of seizures, where considerable dilemmas in management protocols still exist.
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