Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum.
High-potency glucocorticoids (GC) are used in the prophylaxis and treatment of neonatal bronchopulmonal dysplasia, but there is concern about side effects on the developing brain. Recently, the low-potency GC hydrocortisone (HC) has been suggested as an alternative to high-potency GC. We compared the neurotoxic effects of HC with the high-potency GC dexamethasone (DEX) in chicken cerebellum. A single dose of GC was injected into the egg at embryonic day 16 and the death of granule neurons in histologic sections of the cerebellar cortex was examined 24 h later. DEX and HC showed a similar dose-dependent induction of morphological apoptosis and caspase-3 activation in the internal granular layer. A doubling of the apoptosis rate compared to the basal rate was seen for the highest dose of DEX (5 mg/kg) and medium dose of HC (1 mg/kg). In cultures of embryonic chicken cerebellar granule cells, DEX and HC increased cell death and induced rapid caspase-3 activation in a similar dose-dependent manner. Transfection of granule cells with a luciferase reporter gene revealed that the dose needed for the activation of gene transcription (classical signalling pathway) with DEX was much lower than for HC. In conclusion, HC does not present itself as a safer drug than DEX in this model. In addition, it appears that DEX and HC induce apoptosis in immature granule neurons via a non-genomic (non-classical) mechanism.
Aden
Petra
P
Department of Pathology, Ullevål University Hospital, N-0407 Oslo, Norway. p.k.aden@medisin.uio.no
Goverud
Ingeborg
I
Liestøl
Knut
K
Løberg
Else Marit
EM
Paulsen
Ragnhild E
RE
Maehlen
Jan
J
Lømo
Jon
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D002642:Chick Embryo / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000633:toxicity*; D006854:Hydrocortisone / Q000633:toxicity*; D007211:Indoles; D009474:Neurons / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007211:Indoles; D011965:Receptors, Glucocorticoid; C007293:DAPI; D003907:Dexamethasone; D053148:Caspase 3; D006854:Hydrocortisone