Molecular and Cellular Endocrinology ( IF 3.8 ) Pub Date : 2020-08-14 , DOI: 10.1016/j.mce.2020.110985 Ladan Marbouti 1 , Maryam Zahmatkesh 2 , Esmail Riahi 3 , Mahdi Shafiee Sabet 4
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Introduction
The 17β-estradiol (E2) enhances hippocampal dendritic spine synapses, facilitates learning processes, and exerts neuroprotection. Brain estrogen decline has been reported in Alzheimer's disease. The role of GnRH in modulating steroid biosynthesis convinced us to examine whether hippocampal GnRH administration could enhance the local E2 levels and overcome the development of cognition decline in amyloid β (Aβ) neurotoxicity. To explore if GnRH acts through regulating E2 synthesis, letrozole, an aromatase inhibitor, has been applied in combination with GnRH.
Methods
Female rats received an intracerebroventricular injection of Aβ. The GnRH and, or letrozole were injected into the CA1 for 14 consecutive days. Working memory, novel object recognition memory, and anxiety-like behavior were evaluated. Serum and hippocampal E2 levels were measured. Hippocampal mRNA expression of GnRH (GnRH-R) and E2 (ERα and ERβ) receptors was assessed. GnRH effect on the excitability of pyramidal cells was studied by in vivo single-unit recording.
Results
GnRH increased hippocampal E2 levels, evoked an increase in the spontaneous firing of pyramidal neurons, and caused mRNA overexpression of hippocampal GnRH receptors. GnRH prevented the adverse effects of Aβ on working memory, NOR index, and anxiogenic behavior. Letrozole did not reverse GnRH modulatory effects on hippocampal E2 levels and neuroprotection.
Conclusion
GnRH prevented the Aβ-induced memory deficit, which may be mediated through hippocampal E2 levels enhancement. The electrophysiological analysis revealed the enhanced neuronal excitability in the CA1 region. All these data suggest that GnRH might be a promising candidate that reduces anxiety and improves memory indices in the context of Aβ neurotoxicity.
中文翻译：
GnRH对淀粉样β诱导的认知功能下降的保护作用：17β-雌二醇的潜在作用。
介绍
17β-雌二醇（E2）增强海马树突棘突触，促进学习过程，并发挥神经保护作用。据报道，阿尔茨海默氏病患者的大脑雌激素水平下降。GnRH在调节类固醇生物合成中的作用说服我们检查海马GnRH给药是否可以提高局部E2水平并克服淀粉样β（Aβ）神经毒性的认知能力下降。为了研究GnRH是否通过调节E2合成起作用，已将来曲唑（一种芳香酶抑制剂）与GnRH结合使用。
方法
雌性大鼠脑室内注射Aβ。将GnRH和或来曲唑连续14天注射到CA1中。工作记忆，新型对象识别记忆和焦虑样行为进行了评估。测量血清和海马E2水平。评估了GnRH（GnRH-R）和E2（ERα和ERβ）受体的海马mRNA表达。通过体内单单位记录研究了GnRH对锥体细胞兴奋性的影响。
结果
GnRH增加海马E2水平，引起锥体神经元自发放电，并引起海马GnRH受体mRNA过度表达。GnRH预防了Aβ对工作记忆，NOR指数和焦虑行为的不利影响。来曲唑没有逆转GnRH对海马E2水平和神经保护的调节作用。
结论
GnRH预防了Aβ诱导的记忆缺陷，这可能是通过海马E2水平的增强来介导的。电生理分析显示，CA1区神经元兴奋性增强。所有这些数据表明，在Aβ神经毒性的情况下，GnRH可能是减少焦虑和改善记忆指数的有希望的候选者。
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