Pinheiro Helena, Gaspar Rita, Baptista Filipa I, Fontes-Ribeiro Carlos A, Ambrósio António F, Gomes Catarina A
Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Center for Innovation in Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
Front Pharmacol. 2018 Mar 19;9:219. doi: 10.3389/fphar.2018.00219. eCollection 2018.
The exposure to supra-physiological levels of glucocorticoids in prenatal life can lead to a long-term impact in brain cytoarchitecture, increasing the susceptibility to neuropsychiatric disorders. Dexamethasone, an exogenous glucocorticoid widely used in pregnant women in risk of preterm delivery, is associated with higher rates of neuropsychiatric conditions throughout life of the descendants. In animal models, prenatal dexamethasone exposure leads to anxious-like behavior and increased susceptibility to depressive-like behavior in adulthood, concomitant with alterations in neuronal morphology in brain regions implicated in the control of emotions and mood. The pharmacologic blockade of the purinergic adenosine A receptor, which was previously described as anxiolytic, is also able to modulate neuronal morphology, namely in the hippocampus. Additionally, recent observations point to an interaction between glucocorticoid receptors (GRs) and adenosine A receptors. In this work, we explored the impact of dexamethasone on neuronal morphology, and the putative implication of adenosine A receptor in the mediation of dexamethasone effects. We report that hippocampal neurons exposed to dexamethasone (250 nM), in the early phases of development, exhibit a polarized morphology alteration: dendritic atrophy and axonal hypertrophy. While the effect of dexamethasone in the axon is dependent on the activation of adenosine A receptor, the effect in the dendrites relies on the activation of GRs, regardless of the activation of adenosine A receptor. These results support the hypothesis of the interaction between GRs and adenosine A receptors and the potential therapeutic value of modulating adenosine A receptors activation in order to prevent glucocorticoid-induced alterations in developing neurons.
孕期暴露于超生理水平的糖皮质激素会对脑细构造成长期影响，增加患神经精神疾病的易感性。地塞米松是一种广泛用于有早产风险孕妇的外源性糖皮质激素，与后代一生中患神经精神疾病的较高几率相关。在动物模型中，孕期暴露于地塞米松会导致成年期出现焦虑样行为，并增加对抑郁样行为的易感性，同时与参与情绪和心境控制的脑区神经元形态改变有关。嘌呤能腺苷A受体的药理阻断作用（先前被描述为具有抗焦虑作用）也能够调节神经元形态，尤其是在海马体中。此外，最近的观察结果表明糖皮质激素受体（GRs）与腺苷A受体之间存在相互作用。在这项研究中，我们探讨了地塞米松对神经元形态的影响，以及腺苷A受体在介导地塞米松效应中的潜在作用。我们报告称，在发育早期暴露于地塞米松（250 nM）的海马神经元表现出极化形态改变：树突萎缩和轴突肥大。虽然地塞米松对轴突的作用依赖于腺苷A受体的激活，但对树突的作用则依赖于GRs的激活，而与腺苷A受体的激活无关。这些结果支持了GRs与腺苷A受体之间相互作用的假说，以及调节腺苷A受体激活以预防糖皮质激素诱导的发育中神经元改变的潜在治疗价值。
