Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

Abstract

Several growth factors, such as vascular endothelial growth factor, brain-derived neurotrophic factor, and insulin-like growth factor-I are involved in the actions of progesterone in the central nervous system. Previous studies in neuronal and glial cultures have shown that progesterone may regulate growth factor signaling, increasing the phosphorylation of extracellular-signal regulated kinase (ERK) and the phosphorylation of Akt, components of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI3K) signaling pathways, respectively. In this study, we have evaluated whether progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, regulate PI3K and MAPK signaling in the brain of ovariectomized rats in vivo. Significant increases in the phosphorylation of ERK, in the expression of the catalytic (p110) and the regulatory (p85) subunits of PI3K and in the phosphorylation of Akt were observed in the hypothalamus, the hippocampus, and the cerebellum 24 hr after progesterone administration. Progesterone metabolites partially mimicked the effect of progesterone and had a stronger effect on MAPK and PI3K signaling in the hypothalamus than in the other brain regions. These findings suggest that progesterone regulates MAPK and PI3K signaling pathways in the central nervous system in vivo by direct hormonal actions and by mechanisms involving progesterone metabolites.

Variation in Progesterone Receptors and GnRH Expression in the Hypothalamus of the Pregnant South American Plains Vizcacha, Lagostomus maximus (Mammalia, Rodentia)1

“…However, nongenomic actions of PR have been recently described [38]. Cytoplasmic second messenger signaling cascades involving extranuclear PR that interacts with Src kinase via MAPK action can increase the phosphorylation of coactivators that act as transcription factors [39,40]. This rapid, nonclassical progesterone action may converge with classical PR-mediated response to serve as an amplification mechanism to regulate nuclear PR action on gene transcription and translation that facilitate female reproductive behavior [38].…”

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

“…This effect of PROG requires high concentrations and cannot be blocked by the use of a nuclear receptor antagonist, suggesting a mechanism independent of the activation of these receptors [38]. PROG increases the activity of Akt and ERK1/2, both major kinases involved in cell survival [12,39]. PROG also has anti-inflammatory properties, and its action reduces the inflammatory response following brain damage [40,41].…”

Time-Window of Progesterone Neuroprotection After Stroke and Its Underlying Molecular Mechanisms

“…However, our results here showed that the PI3K-mediated neuroprotection by P4 administered at 72 h post-MCAO is P4R-independent. P4 is reportedly to regulate PI3K signaling pathway through its metabolites (Guerra-Araiza et al, 2009), but our data determined that the neuroprotection of P4 at 24-72 h post-MCAO was insensitive to the inhibition of 5α-reductase by fenasteride. P4-binding membrane protein 25-Dx (also known as PGRMC1) in the brain (Krebs et al, 2000;Sakamoto et al, 2004) is involved in the anti-apoptotic actions of P4 (Peluso et al, 2006(Peluso et al, , 2008.…”

“…Because the neuroprotection by P4 at 1 h post-MCAO was P4R-independent, it is proposed that P4 prevents ischemia-increased [Ca 2+ ] i by antagonizing σ 1 receptor, which may stabilize the ERK1/2 activation. 4.3 PI3K signaling is required for P4R-independent and P4R-dependnet neuroprotections P4 has been reported to enhance the phosphorylation of Akt/PKB (Singh et al, 2001;Kuolen et al, 2008) in the hippocampus and cerebellum (Guerra-Araiza et al, 2009). On the other hand, PI3K signaling is believed to suppress apoptotic cell death via its downstream effectors, such as Akt/PKB, to inhibit the Bcl2 family protein Bad (Noshita et al, 2001).…”

“…The membrane-associated P4R component 1 (PGRMC1) has been reported to elevate the level of Akt phosphorylation in breast cancer (Neubauer et al, 2008). P4 increases the phosphorylation of ERK and Akt, and the expression of the regulatory (p85) subunits of phosphoinositide-3 kinase (PI3K) in the brain (Guerra-Araiza et al, 2009). Furthermore, the P4's metabolite allopregnanolone (ALLO) potentiates the GABAergic synapse activity (Ardeshiri et al, 2006).…”