Fabres Rafael Bandeira, Montes Nathalia Lima, Camboim Yahi de Menezes, de Souza Samir Khal, Nicola Fabrício, Tassinari Isadora D'Ávila, Ribeiro Maria Flavia Marques, Netto Carlos Alexandre, de Fraga Luciano Stürmer
Departamento de Fisiologia, Federal University of Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre, 90050-170, Brazil.
Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Federal University of Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre, 90050-170, Brazil.
Cell Mol Neurobiol. 2020 Nov;40(8):1417-1428. doi: 10.1007/s10571-020-00827-0. Epub 2020 Mar 13.
Neonatal hypoxia-ischemia (HI) is the leading cause of mortality and morbidity in newborns, occurring in approximately 2% of live births. Neuroprotective actions of progesterone (PROG) have already been described in animal models of brain lesions. However, PROG actions on neonates are still controversial. Here, we treated male Wistar rats exposed to HI with PROG. Five experimental groups were defined (n = 6/group) according to the scheme of PROG administration (10 mg/kg): SHAM (animals submitted to a fictitious surgery, without ischemia induction, and maintained under normoxia), HI (animals undergoing HI), BEFORE (animals undergoing HI and receiving PROG immediately before HI), AFTER (animals undergoing HI and receiving PROG at 6 and 24 h after HI) and BEFORE/AFTER (animals undergoing HI and receiving PROG immediately before and 6 and 24 h after HI). At P14 (7 days following HI), the volumes of lesion of the cerebral hemisphere and the hippocampus ipsilateral to the cerebral ischemia were evaluated, along with p-Akt, cleaved caspase-3 and GFAP expression in the hippocampus. PROG reduces the loss of brain tissue caused by HI. Moreover, when administered after HI, PROG was able to increase p-Akt expression and reduce both cleaved caspase-3 and GFAP expression in the hippocampus. In summary, it was possible to observe a neuroprotective action of PROG on the brain of neonatal animals exposed to experimental HI. This is the first study suggesting PROG-dependent Akt activation is able to regulate negatively cleaved caspase-3 and GFAP expression protecting neonatal hypoxic-ischemic brain tissue from apoptosis and reactive gliosis.
新生儿缺氧缺血（HI）是新生儿死亡和发病的主要原因，约占活产儿的2%。孕酮（PROG）的神经保护作用已在脑损伤动物模型中得到描述。然而，PROG对新生儿的作用仍存在争议。在此，我们用PROG治疗暴露于HI的雄性Wistar大鼠。根据PROG给药方案（10mg/kg）定义了五个实验组（每组n = 6）：假手术组（接受假手术，未诱导缺血，维持在常氧状态下的动物）、HI组（经历HI的动物）、术前组（经历HI并在HI前立即接受PROG的动物）、术后组（经历HI并在HI后6小时和24小时接受PROG的动物）和术前/术后组（经历HI并在HI前以及HI后6小时和24小时接受PROG的动物）。在出生后第14天（HI后7天）评估脑缺血同侧大脑半球和海马的损伤体积，以及海马中p-Akt、裂解的半胱天冬酶-3和胶质纤维酸性蛋白（GFAP）的表达。PROG减少了HI引起的脑组织损失。此外，在HI后给药时，PROG能够增加海马中p-Akt的表达，并降低裂解的半胱天冬酶-3和GFAP的表达。总之，有可能观察到PROG对暴露于实验性HI的新生动物大脑具有神经保护作用。这是第一项表明PROG依赖的Akt激活能够负向调节裂解的半胱天冬酶-3和GFAP表达，从而保护新生儿缺氧缺血性脑组织免受凋亡和反应性胶质增生的研究。
