Ronchetti Santiago, Labombarda Florencia, Roig Paulina, De Nicola Alejandro F, Pietranera Luciana
Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina.
Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
J Neuroendocrinol. 2023 Jan;35(1):e13228. doi: 10.1111/jne.13228. Epub 2023 Jan 23.
Hippocampal neuropathology is a recognized feature of the spontaneously hypertensive rat (SHR). The hippocampal alterations associate with cognitive impairment. We have shown that hippocampal abnormalities are reversed by 17β-estradiol, a steroid binding to intracellular receptors (estrogen receptor α and β subtypes) or the membrane-located G-protein coupled estradiol receptor. Genistein (GEN) is a neuroprotective phytoestrogen which binds to estrogen receptor β and G-protein coupled estradiol receptor. Here, we investigated whether GEN neuroprotection extends to SHR. For this purpose, we treated 5-month-old SHR for 2 weeks with 10 mg kg daily s.c injections of GEN. We analyzed the expression of doublecortin+ neuronal progenitors, glial fibrillary acidic protein+ astrocytes and ionized calcium-binding adapter molecule 1+ microglia in the CA1 region and dentate gyrus of the hippocampus using immunocytochemistry, whereas a quantitative real-time polymerase chain reaction was used to measure the expression of pro- and anti-inflammatory factors tumor necrosis factor α, cyclooxygenase-2 and transforming growth factor β. We also evaluated hippocampal dependent memory using the novel object recognition test. The results showed a decreased number of doublecortin+ neural progenitors in the dentate gyrus of SHR that was reversed with GEN. The number of glial fibrillary acidic protein+ astrocytes in the dentate gyrus and CA1 was increased in SHR but significantly decreased by GEN treatment. Additionally, GEN shifted microglial morphology from the predominantly activated phenotype present in SHR, to the more surveillance phenotype found in normotensive rats. Furthermore, treatment with GEN decreased the mRNA of the pro-inflammatory factors tumor necrosis factor α and cyclooxygenase-2 and increased the mRNA of the anti-inflammatory factor transforming growth factor β. Discrimination index in the novel object recognition test was decreased in SHR and treatment with GEN increased this parameter. Our results indicate important neuroprotective effects of GEN at the neurochemical and behavioral level in SHR. Our data open an interesting possibility for proposing this phytoestrogen as an alternative therapy in hypertensive encephalopathy.
海马神经病理学是自发性高血压大鼠（SHR）的一个公认特征。海马改变与认知障碍相关。我们已经表明，海马异常可被17β-雌二醇逆转，17β-雌二醇是一种与细胞内受体（雌激素受体α和β亚型）或膜定位的G蛋白偶联雌二醇受体结合的类固醇。染料木黄酮（GEN）是一种神经保护性植物雌激素，它与雌激素受体β和G蛋白偶联雌二醇受体结合。在此，我们研究了GEN的神经保护作用是否也适用于SHR。为此，我们对5月龄的SHR进行为期2周的每日10 mg/kg皮下注射GEN治疗。我们使用免疫细胞化学分析了海马CA1区和齿状回中双皮质素阳性神经元祖细胞、胶质纤维酸性蛋白阳性星形胶质细胞和离子钙结合衔接分子1阳性小胶质细胞的表达，同时使用定量实时聚合酶链反应测量促炎和抗炎因子肿瘤坏死因子α、环氧化酶-2和转化生长因子β的表达。我们还使用新物体识别试验评估了海马依赖性记忆。结果显示，SHR齿状回中双皮质素阳性神经祖细胞数量减少，而GEN可使其逆转。SHR齿状回和CA1区中胶质纤维酸性蛋白阳性星形胶质细胞数量增加，但GEN治疗可使其显著减少。此外，GEN使小胶质细胞形态从SHR中主要的活化表型转变为正常血压大鼠中更具监视性的表型。此外，GEN治疗可降低促炎因子肿瘤坏死因子α和环氧化酶-2的mRNA水平，并增加抗炎因子转化生长因子β的mRNA水平。SHR在新物体识别试验中的辨别指数降低，而GEN治疗可提高该参数。我们的结果表明，GEN在SHR的神经化学和行为水平上具有重要的神经保护作用。我们的数据为将这种植物雌激素作为高血压脑病的替代疗法提供了一个有趣的可能性。
