Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex
No Thumbnail
Authors
Drakulić, Dunja R.Velickovic, N.
Stanojlović, Miloš R.
Grković, Ivana
Mitrović, Nataša Lj.
Lavrnja, I.
Horvat, Anica
Article
Metadata
Show full item recordAbstract
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 (100g/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 1day 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.
Keywords:
dexamethasone / rat / prefrontal cortex / apoptosisSource:
Journal of Neuroendocrinology, 2013, 25, 7, 605-616Funding / projects:
- Molecular mechanisms of cellular responses on pathological changes in central neuronal system and peripheral organs of mammals (RS-MESTD-Basic Research (BR or ON)-173044)
- Cellular and molecular basis of neuroinflamation: potential targets for translational medicine and therapy (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41014)
DOI: 10.1111/jne.12037
ISSN: 0953-8194
PubMed: 23551329
WoS: 000320402900002
Scopus: 2-s2.0-84879158644
Collections
Institution/Community
VinčaTY - JOUR AU - Drakulić, Dunja R. AU - Velickovic, N. AU - Stanojlović, Miloš R. AU - Grković, Ivana AU - Mitrović, Nataša Lj. AU - Lavrnja, I. AU - Horvat, Anica PY - 2013 UR - https://vinar.vin.bg.ac.rs/handle/123456789/5549 AB - 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 (100g/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 1day 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. T2 - Journal of Neuroendocrinology T1 - Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex VL - 25 IS - 7 SP - 605 EP - 616 DO - 10.1111/jne.12037 ER -
@article{ author = "Drakulić, Dunja R. and Velickovic, N. and Stanojlović, Miloš R. and Grković, Ivana and Mitrović, Nataša Lj. and Lavrnja, I. and Horvat, Anica", year = "2013", 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 (100g/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 1day 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.", journal = "Journal of Neuroendocrinology", title = "Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex", volume = "25", number = "7", pages = "605-616", doi = "10.1111/jne.12037" }
Drakulić, D. R., Velickovic, N., Stanojlović, M. R., Grković, I., Mitrović, N. Lj., Lavrnja, I.,& Horvat, A.. (2013). Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex. in Journal of Neuroendocrinology, 25(7), 605-616. https://doi.org/10.1111/jne.12037
Drakulić DR, Velickovic N, Stanojlović MR, Grković I, Mitrović NL, Lavrnja I, Horvat A. Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex. in Journal of Neuroendocrinology. 2013;25(7):605-616. doi:10.1111/jne.12037 .
Drakulić, Dunja R., Velickovic, N., Stanojlović, Miloš R., Grković, Ivana, Mitrović, Nataša Lj., Lavrnja, I., Horvat, Anica, "Low-Dose Dexamethasone Treatment Promotes the Pro-Survival Signalling Pathway in the Adult Rat Prefrontal Cortex" in Journal of Neuroendocrinology, 25, no. 7 (2013):605-616, https://doi.org/10.1111/jne.12037 . .