Dexamethasone decreases insulin-like growth factor-I and -II via a glucocorticoid receptor dependent mechanism in developing rat brain.
OBJECTIVE
Dexamethasone (Dex) causes neurodegeneration in developing brain. Insulin-like growth factor-I (IGF-I) and -II (IGF-II) are potent neurotrophic and differentiation factors and play key roles in the regulation of growth and development of CNS. Current project evaluated the effects of Dex on IGF-I and -II in developing rat brains.


METHODS
Sprague-Dawley rat pups in each litter were divided into vehicle (n=230) or Dex-treated (n=234) groups. Rat pups in the Dex group received one of the 3 different regimens of i.p. Dex: tapering doses (DexTD) on postnatal days (PD) 3 to PD 6 or repeated doses on PD 4 to PD 6 or single dose on PD 6. To quantify the glucocorticoid receptor (GR) blockade effect, rat pups in the DexTD group on PD 3 and 5 received vehicle or RU486 (GR blocker, 60 mg/kg) s.c., twenty minutes prior to Dex treatment.


RESULTS
Dex decreased the gain of body and brain weight while RU486 inhibited these effects. RU486 also prevented the DexTD-induced increase in caspase-3 activity and reduction in IGF-I and -II proteins. Compared to the vehicle, the expression of mRNA of IGF-I and -II decreased at 24 h after DexTD treatment, while RU486 prevented this decrease on IGF-II but not IGF-I.


CONCLUSIONS
Our findings indicate that Dex via GR decreases IGF-I and -II and causes neurodegeneration in the neonatal rat brain.
Division of Newborn Medicine, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA. abhatt@umc.edu.
Yangzheng
Y
Feng
Division of Newborn Medicine, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
Mobolaji
M
Famuyide
Division of Newborn Medicine, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA. abhatt@umc.edu.
Abhay J
AJ
Bhatt
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity; D006727:Hormone Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; C548904:insulin-like growth factor-1, rat; D015735:Mifepristone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone; D020932:Nerve Growth Factor