Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone.
Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.
Lai
Ming-Chi
MC
Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.
Holmes
Gregory L
GL
Lee
Ko-Hung
KH
Yang
San-Nan
SN
Wang
Chien-An
CA
Wu
Chia-Lu
CL
Tiao
Mao-Meng
MM
Hsieh
Chih-Sung
CS
Lee
Chiang-Hsuan
CH
Huang
Li-Tung
LT
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D003292:Convulsants; D003345:Corticosterone / Q000097:blood* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007696:Kindling, Neurologic; D008094:Lithium; D008297:Male; D008426:Maternal Deprivation; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008797:Metyrapone / Q000494:pharmacology; D010766:Phosphorylation; D010862:Pilocarpine; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012934:Social Isolation / Q000523:psychology*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced
D003292:Convulsants; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D010862:Pilocarpine; D008094:Lithium; D003345:Corticosterone; D008797:Metyrapone