Carbamoylated erythropoietin produces antidepressant-like effects in male and female mice.
Carbamoylated erythropoietin produces antidepressant-like effects in male and female mice.
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氨基甲酰化促红细胞生成素在雄性和雌性小鼠中产生抗抑郁样作用。
DOI：
10.1016/j.pnpbp.2019.109754
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发表时间：
2020
影响因子：
5.6
通讯作者：
Newton,SamuelS
中科院分区：
文献类型：
--
作者：
Sampath,Dayalan;McWhirt,Joshua;Sathyanesan,Monica;Newton,SamuelS
重度抑郁症和相关疾病在全球范围内普遍存在，如果不治疗，自杀的风险很大。目前处方的抗抑郁药不能使30%的治疗个体受益。此外，在症状减轻之前有3周或更长时间的延迟。临床前研究的结果表明营养因子在调节行为方面发挥着重要作用。促红细胞生成素（Epo），这是广泛规定的贫血，已被证明在中枢神经系统中产生强大的神经营养作用。虽然Epo的抗抑郁活性已在多项临床试验中成功证明，但其固有的提高RBC计数和其他血液学参数的能力排除了其作为主流CNS药物的发展。氨甲酰基化Epo（Cepo）是一种化学工程衍生物，没有血液学活性，但保留了Epo的神经营养作用。因此，Cepo是一种有吸引力的候选抗抑郁药。目的：在已建立的抗抑郁药反应性啮齿动物行为学实验中评价Cepo的抗抑郁作用。方法：成年雄性和雌性BALB/c小鼠用于本研究。Cepo（30 μ g/ kg BWT）或溶剂（PBS）在新奇感诱导的摄食减少测试之前腹腔内施用4天，并且随后在强迫游泳测试（FST）、悬尾测试（TST）和旷场测试（OFT）中测试之前5小时腹腔内施用。为了获得机制的见解，我们检查了转录因子cAMP反应元件结合蛋白（CREB.Results）的磷酸化：Cepo以30 μ g/ kg BWT给药4天，在雄性和雌性小鼠中，在新的环境中消耗可口饮料的潜伏期显著减少。雄性BALB/c小鼠在悬尾和强迫游泳试验中的不动性显著降低，雌性小鼠在强迫游泳试验中表现出较低的不动性。
Major depressive disorder and related illnesses are globally prevalent, with a significant risk for suicidality if untreated. Antidepressant drugs that are currently prescribed do not benefit 30% of treated individuals. Furthermore, there is a delay of 3 or more weeks before a reduction in symptoms. Results from preclinical studies have indicated an important role for trophic factors in regulating behavior. Erythropoietin (Epo), which is widely prescribed for anemia, has been shown to produce robust neurotrophic actions in the CNS. Although Epo's antidepressant activity has been successfully demonstrated in multiple clinical trials, the inherent ability to elevate RBC counts and other hematological parameters preclude its development as a mainstream CNS drug. A chemically engineered derivative, carbamoylated Epo (Cepo) has no hematological activity, but retains the neurotrophic actions of Epo. Cepo is therefore an attractive candidate to be tested as an antidepressant. Objective: To evaluate the antidepressant properties of Cepo in established antidepressant-responsive rodent behavioral assays. Methods: Adult male and female BALB/c mice were used for this study. Cepo (30 μgrams/ kg BWT) or vehicle (PBS) was administered intraperitoneally for 4 days before the test of novelty induced hypophagia and subsequently at five hours before testing in forced swim test (FST), tail suspension test (TST) and open field test (OFT). To obtain mechanistic insight we examined the phosphorylation of the transcription factor cAMP response element binding protein (CREB).Results: Administration of Cepo at 30 μgrams/ kg BWT, for 4 days produced significant reduction in latency to consume a palatable drink in a novel environment in male and female mice. Male BALB/c mice had a significant reduction in immobility in both tail suspension and forced swim tests, and female mice exhibited lower immobility in the forced swim test.