title: Low-dose dexamethasone treatment promotes the pro-survival signalling pathway in the adult rat prefrontal cortex.
abstract: Synthetic glucocorticoid dexamethasone (DEX), a highly potent anti-inflammatory and immunosuppressive agent, is widely used in the treatment of brain cancer, as well as for inflammatory and autoimmune diseases. The present study aimed to determine whether low-dose subchronic DEX treatment (100 μg/kg for eight consecutive days) exerts long-term effects on apoptosis in the adult rat prefrontal cortex (PFC) by examining the expression of cell death-promoting molecules [poly(ADP-ribose) polymerase (PARP), p53, procaspase 3, cleaved caspase 3, Bax] and cell-survival molecules (AKT, Bcl-2). The results obtained revealed that body, thymus and adrenal gland weights, as well corticosterone levels, in the serum and PFC were reduced 1 day after the last DEX injection. In the PFC, DEX caused activation of AKT, augmentation of pro-survival Bcl-2 protein and an enhanced Bcl-2/Bax protein ratio, as well Bcl-2 translocation to the mitochondria. An unaltered profile with respect to the protein expression of apoptotic molecules PARP, procaspase 3 and Bax was detected, whereas p53 protein was decreased. Reverse transcriptase -polymerase chain reaction analysis showed a decrease of p53 mRNA levels and no significant difference in Bcl-2 and Bax mRNA expression in DEX-treated rats. Finally, a DNA fragmentation assay and Fluoro-Jade staining demonstrated no considerable changes in apoptosis in the rat PFC. Our findings support the concept that low-dose DEX creates a hypocorticoid state in the brain and also indicate that subchronic DEX treatment activates the pro-survival signalling pathway but does not change apoptotic markers in the rat PFC. This mechanism might be relevant for the DEX-induced apoptosis resistance observed during and after chemotherapy of patients with brain tumours.
authors.affiliation: Laboratory of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11001 Belgrade, Serbia. drakulic@vinca.rs
authors.forename: D
authors.initials: D
authors.lastname: Drakulić
authors.forename: N
authors.initials: N
authors.lastname: Veličković
authors.forename: M
authors.initials: M
authors.lastname: Stanojlović
authors.forename: I
authors.initials: I
authors.lastname: Grković
authors.forename: N
authors.initials: N
authors.lastname: Mitrović
authors.forename: I
authors.initials: I
authors.lastname: Lavrnja
authors.forename: A
authors.initials: A
authors.lastname: Horvat
mesh_terms: D000818:Animals; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects*; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D003907:Dexamethasone