Adrenalectomy promotes a permanent decrease of plasma corticoid levels and a transient increase of apoptosis and the expression of Transforming Growth Factor beta1 (TGF-beta1) in hippocampus: effect of a TGF-beta1 oligo-antisense.
BACKGROUND
Corticosterone reduction produced by adrenalectomy (ADX) induces apoptosis in dentate gyrus (DG) of the hippocampus, an effect related to an increase in the expression of the pro-apoptotic gene bax. However it has been reported that there is also an increase of the anti-apoptotic gene bcl-2, suggesting the promotion of a neuroprotective phenomenon, perhaps related to the expression of transforming growth factor beta1 (TGF-beta1). Thus, we have investigated whether TGF-beta1 levels are induced by ADX, and whether apoptosis is increased by blocking the expression of TGF-beta1 with an antisense oligonucleotide (ASO) administered intracerebrally in corticosterone depleted rats.


RESULTS
It was observed an increase of apoptosis in DG, 2 and 5 days after ADX, in agreement with a reduction of corticosterone levels. However, the effect of ADX on the number of apoptotic positive cells in DG was decreased 5 days after the lesion. In CA1-CA3 regions, the effect was only observed 2 days after ADX. TGF-beta1 mRNA levels were increased 2 days after ADX. The sustained intracerebro-ventricular administration of a TGF-beta1 ASO via an osmotic mini pump increased apoptosis levels in CA and DG regions 5 days after ADX as well as sham-operated control animals. No significant effect was observed following a scrambled-oligodeoxynucleotide treatment.


CONCLUSIONS
The changes in both the pattern and the magnitude of apoptotic-cell morphology observed 2 and 5 days after ADX suggest that, as a consequence of the reduction of corticosteroids, some trophic mechanisms restricting cell death to a particular time window are elicited. Sustained intracerebral administration of TGF-beta1 ASO increased the apoptosis promoted by ADX, suggesting that TGF-beta1 plays an anti-apoptotic role in vivo in hippocampus.
Bravo
Javier A
JA
Department of Biochemistry and Molecular Biology, Laboratory of Neurobiochemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Chile. jbravo@ciq.uchile.cl
Parra
Claudio S
CS
Arancibia
Sandor
S
Andrés
Sergio
S
Morales
Paola
P
Herrera-Marschitz
Mario
M
Herrera
Luisa
L
Lara
Hernán E
HE
Fiedler
Jenny L
JL
D000315:Adrenalectomy; D000818:Animals; D017209:Apoptosis; D002552:Cerebral Ventricles; D003345:Corticosterone / Q000097:blood*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003345:Corticosterone