Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, TX, USA.
Prog Brain Res. 2010;186:113-37. doi: 10.1016/B978-0-444-53630-3.00008-7.
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
这一章概述了神经甾体，特别是它们对大脑的影响、性别差异及其治疗潜力。神经甾体在大脑内合成，可快速调节神经元兴奋性。它们分为孕烷神经甾体，如别孕烯醇酮和别孕烷四氢皮质酮；雄烷神经甾体，如雄烷二醇和雄烷酮；以及硫酸酯神经甾体，如孕烯醇酮硫酸酯。别孕烯醇酮等神经甾体是 GABA-A 受体的正变构调节剂，在多种动物模型中具有强大的抗惊厥活性。神经甾体增加突触和紧张性抑制。它们是癫痫易感性、焦虑和应激的内源性调节剂。硫酸酯神经甾体如孕烯醇酮硫酸酯，是 GABA-A 受体的负变构调节剂，是增强记忆的物质。对脑部疾病易感性的性别差异可能归因于神经甾体和人类大脑特定结构中的性别二态性。具有更好生物利用度和疗效的合成神经甾体以及增强神经甾体合成的药物，在焦虑、癫痫和其他脑部疾病的治疗中有一定的潜力。合成神经甾体类似物 ganaxolone 在癫痫治疗中的临床试验令人鼓舞。缺乏苯二氮䓬样副作用的神经甾体生成剂在焦虑和抑郁治疗中显示出希望。
