The Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal, Canada.
J Neuroendocrinol. 2012 Jan;24(1):93-101. doi: 10.1111/j.1365-2826.2011.02167.x.
The overall ability of the brain to synthesise neuroactive steroids led us to the identification of compounds that would reproduce aspects of neurosteroid pharmacology. The rate-determining step in neurosteroid biosynthesis is the import of the substrate cholesterol into the mitochondria, where it is metabolised into pregnenolone via the intermediate 22R-hydroxycholesterol. The levels of translocator protein 18-kDa, mediating the import of cholesterol into mitochondria, correlated with increased pregnenolone formation and reduced levels of 22R-hydroxycholesterol in biopsies from Alzheimer's disease (AD), but not age-matched control, brains. 22R-hydroxycholesterol was shown to protect against β-amyloid (Aβ(42) )-induced neurotoxicity. In search of 22R-hydroxycholesterol stable analogues, we identified the naturally occurring heterospirostenol, (22R,25R)-20α-spirost-5-en-3β-yl hexanoate (caprospinol) and derivatives that protect neuronal cells against Aβ(1-42) neurotoxicity. The neuroprotective effect of caprospinol is the result of a combination of overlapping properties, including: (i) the ability to bind to Aβ(42) and reduce plaque formation in the brain in vivo; (ii) interaction with components of the mitochondria respiratory chain resulting in an anti-uncoupling effect; (iii) the capacity to scavenge Aβ(42) monomers present in mitochondria; and (iv) the property of being a sigma-1 receptor ligand. In vivo, caprospinol crosses the blood-brain barrier, accumulates in the brain, and restores cognitive impairment in a pharmacological rat model of AD. Caprospinol is stable, does not bind to known steroid receptors, is devoid of mutagenic and genotoxic properties, and is devoid of acute toxicity in rodents. The pharmacokinetics and pharmacodynamics of caprospinol were studied, and long-term toxicity studies are under investigation, aiming to develop this compound as a disease-modifying drug for the treatment of AD.
大脑合成神经活性甾体的整体能力使我们能够识别出能够再现神经甾体药理学方面的化合物。神经甾体生物合成的限速步骤是将底物胆固醇导入线粒体，在那里它通过中间产物 22R-羟胆固醇代谢为孕烯醇酮。在阿尔茨海默病（AD）患者的活检组织中，介导胆固醇导入线粒体的转位蛋白 18kDa 的水平与增加的孕烯醇酮形成和降低的 22R-羟胆固醇水平相关，但与年龄匹配的对照脑无关。22R-羟胆固醇被证明可以抵抗β-淀粉样蛋白（Aβ（42））诱导的神经毒性。在寻找 22R-羟胆固醇稳定类似物的过程中，我们鉴定了天然存在的异雄甾烷醇，（22R，25R）-20α-螺甾-5-烯-3β-基己酸酯（己酸卡泊醇）及其衍生物，可保护神经元细胞免受 Aβ（1-42）神经毒性的影响。己酸卡泊醇的神经保护作用是多种重叠特性的结果，包括：（i）与 Aβ（42）结合的能力，并减少体内大脑中的斑块形成；（ii）与线粒体呼吸链的成分相互作用，导致抗解偶联作用；（iii）能够清除线粒体中存在的 Aβ（42）单体；以及（iv）作为 sigma-1 受体配体的特性。在体内，己酸卡泊醇可穿过血脑屏障，在大脑中积累，并在 AD 的药理学大鼠模型中恢复认知障碍。己酸卡泊醇稳定，不与已知的甾体受体结合，无致突变和遗传毒性，在啮齿动物中无急性毒性。已研究了己酸卡泊醇的药代动力学和药效动力学，并且正在进行长期毒性研究，旨在将该化合物开发为用于治疗 AD 的疾病修饰药物。
