Belelli Delia, Hogenkamp Derk, Gee Kelvin W, Lambert Jeremy J
Systems Medicine, Neuroscience, Mail Box 6, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom.
Department of Pharmacology, 110C Med Surge1, Mail Code 4625, University of California, Irvine, School of Medicine, Irvine, CA, 92697, USA.
Neurobiol Stress. 2019 Dec 23;12:100207. doi: 10.1016/j.ynstr.2019.100207. eCollection 2020 May.
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA receptor (GABAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
在20世纪80年代，人们发现孕酮和脱氧皮质酮的某些内源性代谢产物是γ-氨基丁酸受体（GABAR）强效、有效、正向变构调节剂（PAMs）。这些报告之后，又有发现表明，此类甾体不仅可在外周内分泌腺合成，还可在中枢神经系统（CNS）局部合成，有可能作为旁分泌或自分泌的“神经甾体”信使，从而精细调节神经元抑制作用。这些发现激发了人们的热情，以阐明此类神经甾体的生理作用，并探究其水平是否会在特定的精神和神经疾病中受到干扰。在临床前研究中，具有GABAR活性的甾体显示出抗焦虑、抗惊厥、镇痛和镇静特性，在相对高剂量时可诱导全身麻醉状态。总体而言，这些发现促使人们努力研究神经甾体及相关合成类似物的治疗潜力。然而，经过30多年的研究，要实现它们可能的医学潜力已被证明具有挑战性。美国食品药品监督管理局（FDA）最近批准天然神经甾体别孕烯醇酮（brexanolone）用于治疗产后抑郁症（PPD），这应该会引发对神经甾体研究的新热情。在此，我们重点关注神经活性甾体对γ-氨基丁酸能信号传导的影响，以及在开发此类甾体作为麻醉剂、镇静剂、镇痛药、抗惊厥药、抗抑郁药以及用于治疗神经退行性疾病时所面临的挑战。
