中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (1): 17-21.doi: 10.4103/1673-5374.150640

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

合成神经甾体对脑的保护作用

  

  • 收稿日期:2014-12-17 出版日期:2015-01-15 发布日期:2015-01-15

Synthetic neurosteroids on brain protection

Mariana Rey 1, Héctor Coirini 1, 2, *   

  1. 1 Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Vuelta de Obligado 2490, (C1428ADN)
    Ciudad Autónoma de Buenos Aires, Argentina
    2 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Ciudad Autónoma de Buenos Aires, Argentina
  • Received:2014-12-17 Online:2015-01-15 Published:2015-01-15
  • Contact: Héctor Coirini, Ph.D., hcoirini@ibyme.conicet.gov.ar.
  • Supported by:

    This work was supported by grants from Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCYT, PICT-2006-727) and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP-860). 

摘要:

神经甾体是神经元兴奋性的内源性调节介质。大脑内的神经甾体表达对中枢神经系统活性有重大影响,并且是神经元和神经胶质细胞存活、生长所必需的物质。神经甾体对创伤性脑损伤、缺血性卒中、阿尔茨海默氏病等有神经保护作用。内源性神经甾体合成或合成类固醇类似物可能会构成一些疾病的治疗有前途的新策略。周围神经活性类固醇的当前药物化学的重点是对新的合成类固醇类似物的开发,具有天然的类固醇的绝对构型。一些研究表明,3α羟基配置是关键的结合和活性,但在甾核的修改可能会产生不同药效。在发达国家,合成类固醇GNX和ALPX具有麻醉和抗惊厥特性。另一方面,合成的类固醇ENT-神经甾产生TBPS的更有效的抑制除了ALPX与GABA A受体结合。此外,Héctor Coirini教授发现,一些合成的类固醇环氧化物降低TBPS结合并以剂量依赖性方式促进氟硝西泮和蝇蕈醇结合。在缺氧诱导的脑损伤模型已经展示出合成类固醇的神经保护作用。其中,合成类固醇RU486能够防止创伤性脑损伤导致的兴奋性毒性,5α - 雄甾3β,5,6β三醇在体外的缺血性脑卒中模型中表现出神经保护作用。此外,孕烯醇酮或孕限制类似物对围产期缺氧条件下的脑组织表现出防止胶质和神经元损伤的作用。

Abstract:

Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute promising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3α-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions.

Key words:  allopregnanolone, synthetic steroids, GABAA receptor, neuroprotection, cerebral cortex, hippocampus