Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6273133 | Neuroscience | 2015 | 13 Pages |
Abstract
Neonatal seizures caused by perinatal asphyxia and hypoxic-ischemic encephalopathy can be refractory to conventional anticonvulsants. This may be due to the depolarizing effects of gamma-aminobutyric acid (GABA) achieved by the activity of the Na+-K+-2Clâ cotransporter (NKCC1). The aim of this study is to evaluate the long-term effects of bumetanide, a NKCC1 inhibitor, on hippocampal neurogenesis and seizure susceptibility in hypoxia-induced neonatal seizure model. Wistar rats were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Following acute seizures, the rats were treated with intraperitoneal injection (i.p.) of bumetanide at a dose of 0.5Â mg/kg for 3Â weeks. In later adulthood, hypoxia-induced seizures increased the number of newborn dentate gyrus cells (DGCs), promoted mossy fiber sprouting (MFS) and reduced the apical dendritic complexity of newborn DGCs 1Â month after the insults. In addition, these seizures resulted in long-lasting consequences, such as spontaneous electroencephalography (EEG) seizures, though spatial learning impairments were not seen. Bumetanide treatments significantly enhanced cell proliferation and dendritic development of newborn DGCs after neonatal seizures, accompanied by the decreased seizure activity. However, systemic administration of bumetanide resulted in much lower brain concentrations, and was incompatible with NKCC1 inhibition in blood-brain barrier (BBB)-protected brain tissue. Our results suggested that bumetanide might have long-term effects in suppressing seizure activity, and altering the neurogenesis after neonatal seizures. These effects of bumetanide may be mediated by the targets outside the BBB-protected central nerve system (CNS) or CNS-located target(s) other than NKCC1.
Keywords
HYSCRHGFAPhybGCLDcxgamma-aminobutyric acidElectroencephalographyBrdUbromodeoxyuridineanalysis of varianceANOVACNSdoublecortinBlood–brain barrierBBBcentral nerve systemdentate gyrusgranular cell layerHPAEEGcorticotrophin releasing hormonehypothalamic–pituitary–adrenalHypoxiaGlial fibrillary acidic proteinGABA
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Authors
S. Wang, X.Q. Zhang, C.G. Song, T. Xiao, M. Zhao, G. Zhu, C.S. Zhao,