RESUMO
Prolactin (PRL) is a polypeptide hormone that has been reported to play a significant role in neuroprotection against neuronal excitotoxicity produced by glutamate (Glu) or kainic acid (KA) in both, in vitro and in vivo models. However, the molecular mechanisms involved in PRL's neuroprotective effects in the hippocampus have not been completely elucidated. The aim of the present study was to assess the signaling pathways involved in PRL neuroprotection against excitotoxicity. Primary rat hippocampal neuronal cell cultures were used to assess PRL-induced signaling pathway activation. The effects of PRL on neuronal viability, as well as its effects on activation of key regulatory pathways, phosphoinositide 3-kinases/Protein Kinase B (PI3K/AKT) and glycogen synthase kinase 3ß / nuclear factor kappa B (GSK3ß/NF-κB), were evaluated under conditions of Glutamate-induced excitotoxicity. Additionally, the effect on downstream regulated genes such as Bcl-2 and Nrf2, was assessed. Here, we show that the PI3K/AKT signaling pathway is activated by PRL treatment during excitotoxicity, promoting neuronal survival through upregulation of active AKT and GSK3ß/NF-κB, resulting in induction of Bcl-2 and Nrf2 gene expression. Inhibition of the PI3K/AKT signaling pathway abrogated the protective effect of PRL against Glu-induced neuronal death. Overall, results indicate that the neuroprotective actions of PRL are mediated in part, by the activation of the AKT pathway and survival genes. Our data support the idea that PRL could be useful as a potential neuroprotective agent in different neurological and neurodegenerative diseases.
Assuntos
NF-kappa B , Fármacos Neuroprotetores , Ratos , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neuroproteção , Prolactina/farmacologia , Prolactina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurônios/metabolismo , Ácido Glutâmico/toxicidade , Ácido Glutâmico/metabolismoRESUMO
It has been well recognized that prolactin (PRL), a pleiotropic hormone, has many functions in the brain, such as maternal behavior, neurogenesis, and neuronal plasticity, among others. Recently, it has been reported to have a significant role in neuroprotection against excitotoxicity. Glutamate excitotoxicity is a common alteration in many neurological and neurodegenerative diseases, leading to neuronal death. In this sense, several efforts have been made to decrease the progression of these pathologies. Despite various reports of PRL's neuroprotective effect against excitotoxicity, the signaling pathways that underlie this mechanism remain unclear. This review aims to describe the most recent and relevant studies on the molecular signaling pathways, particularly, PI3K/AKT, NF-κB, and JAK2/STAT5, which are currently under investigation and might be implicated in the molecular mechanisms that explain the PRL effects against excitotoxicity and neuroprotection. Remarkable neuroprotective effects of PRL might be useful in the treatment of some neurological diseases.
Assuntos
Neuroproteção , Fármacos Neuroprotetores , Feminino , Hipocampo , Humanos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/farmacologia , ProlactinaRESUMO
The progesterone receptor (PR) plays a pivotal role in the maturation process of the secretory endometrium, implantation and maintenance of pregnancy in rabbits. To determine the dynamics of PR gene expression and its physiological significance, the endometrial expression of PR and PR mRNA were evaluated and compared with the expression of the progesterone-regulated uteroglobin (UG) gene during 0-5 days post-coitus in rabbits. The results of immunoblot experiments indicated the presence of PR in endometrial cell extracts from days 1-4 of pregnancy with maximum PR immunostaining on day 2, followed by a marked diminution until its complete disappearance on day 5. When endometrial PR mRNA content was assessed by Northern blots, the results were similar to those of PR immunostaining, with maximal concentrations on the second day after mating. However, PR mRNA levels were still high on day 3, despite the concomitant decrease in immunostainable PR. Endometrial UG gene expression, on the other hand, exhibited a different time sequence. Thus, the UG content in uterine flushings progressively increased from day 3 after mating, reaching maximal levels on the fifth day. The endometrial UG mRNA content presented a similar profile, as its maximum concentration occurred on days 4-5. The overall results indicate that endometrial PR is down-regulated at both the mRNA and protein levels, possibly by endogenous progesterone during early pregnancy. The striking observation that maximal expression of endometrial UG gene products occurred when PR and its mRNA are no longer detectable suggests an important role for this progesterone-binding uterine protein during the preimplantation period.