Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats
Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats
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DOI：
10.1007/s00213-020-05545-5
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发表时间：
2020-06-07
影响因子：
3.4
通讯作者：
Dalla, Christina
中科院分区：
文献类型：
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作者：
Kokras, Nikolaos;Dioli, Chrysoula;Dalla, Christina
神经类固醇，如脱氢表雄酮(DHEA)，在神经退行性变和神经保护中发挥重要作用，但它们在雄激素、雌激素或其他活性代谢物中代谢。新开发的脱氢表雄酮类似物BNN27((20R)-3β，21-二羟基-17R，20-环氧基-5-孕烯)具有神经营养和神经保护作用，没有雌激素或雄激素的作用。目的研究BNN27的抗焦虑或抗抑郁作用。方法成年雄性和雌性Wistar大鼠灌胃给予BNN27(10、30、90 mg/kg)。并接受了测量运动、探索和类似抑郁行为的行为测试(开阔场地、明/暗盒子、洞板和强迫游泳测试)。采集海马区和前额叶皮质进行谷氨酸和GABA测定，并采集躯干血液进行性腺激素分析。结果急性大剂量BNN27使男女小鼠的运动和探索行为减少。中等急性剂量(30毫克/公斤)的BNN27只降低了男性的探索和睾酮水平，并提高了两性的孕激素水平。值得注意的是，在目前的设计中，BNN27既没有缓解焦虑的作用，也没有抗抑郁的作用，也不影响雌激素水平。有趣的是，急性给予低剂量BNN27(10 mg/kg)可增加海马区谷氨酸周转、GABA和谷氨酰胺水平。同样的剂量也只增加了男性前额叶皮质中的谷氨酸水平。正如预期的那样，在行为、激素和神经化学参数的基础水平上，性别差异明显。结论BNN27以性别依赖的方式影响运动、孕酮和睾酮水平，并影响海马和前额叶皮质的谷氨酸能系统和GABA能系统。
Rationale & x39d;eurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3 beta,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects. Objectives This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27. Methods Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis. Results Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected. Conclusions BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.