Effects of neonatal dexamethasone and CpdA on the expression of genes for apoptosis regulator proteins in the neonatal hippocampus

Abstract

Glucocorticoids (GC) are crucial regulators of homeostasis and function. Despite its negative side effects, glucocorticoid therapy in neonates is widely used antenatally for accelerating fetal lung maturation in cases of preterm birth. GC action is mediated via glucocorticoid receptors -ligandactivated transcription factors. Cell death and viability in the neonatal brain are regulated by many factors, but the glucocorticoid receptor signalling is high above them. The present work studies the changes in the expression of genes for apoptosis regulators with Bcl-2 homology (BH) domains (Bcl-xL, Bax, Bim, Bok, Bid) in the neonatal rat hippocampus after dexamethasone (DEX) and CpdA administration. CpdA is a dissociative ligand -glucocorticoid receptor modulator -that shifts glucocorticoid receptor (GR) activity toward transrepression. Ligands administration to P2 pups caused different patterns of timeline changes in the expression of the studied genes. We observed the first increase in the mRNA level of the genes which have glucocorticoid response element (GRE) (Bcl-xL, Bim) in their promoter 30 min after DEX administration. Activated GR action on cells in the neonatal hippocampus is complex and long-lasting; it could also contain receptor homo-and heterodimerisation. Using rat pheochromocytoma PC12 cells as a test system, we assessed GR-GR and GR-MR (mineralocorticoid receptor) dimerisation with proximity ligation assay (PLA) assay separately in the nucleus and cytoplasm after DEX and CpdA administration. An increase in GR-GR dimers in the cell nucleus was observed only after DEX administration. In the cell cytoplasm, we observed a gradual (DEX more than CpdA) increase in the number of both GR-GR and GR-MR dimers.

Synephrine and Its Derivative Compound A: Common and Specific Biological Effects

“…Inhibited NF-κB signaling [16] Murine L929sa fibrosarcoma cells Increased GR-GR dimerization; Decreased number of MR-GR heterodimers [93] Rat pheochromocytoma PC12 cells…”

“…Reduced level of glucose metabolism genes, G6Pase, and PEPCK [90] Reduced glucose production Human ESCC xenografts in nude mice Synephrine Induced apoptosis in cancer cells via the upregulation of pro-apoptotic members of the B-cell lymphoma (Bcl-2) family [93] P2 rat pups CpdA…”

“…As mentioned above, synephrine is a stable hydrolysis product of CpdA [26], a SEGRA with well-known anti-cancer properties. The anti-cancer effects of both CpdA and GCs are partially mediated by apoptosis induction in cancer cells via the following processes: up-regulation of the pro-apoptotic members of the B-cell lymphoma (Bcl-2) family, such as Bim, Bid and Bad; suppression of the anti-apoptotic members, such as Bcl-2, Mcl-1, and Bcl-xL [93,106,107]; as well as inhibition of pro-proliferative signaling including AP-1 and NF-κB [16]. GCs (rather than CpdA) can also inhibit proliferation by suppressing c-MYC [108,109].…”