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Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor.
Neurobiology of Stress ( IF 5 ) Pub Date : 2019-12-23 , DOI: 10.1016/j.ynstr.2019.100207
Delia Belelli 1 , Derk Hogenkamp 2 , Kelvin W Gee 2 , Jeremy J Lambert 1
Affiliation  

In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). 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 GABAAR-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.



中文翻译:

实现GABAA受体的神经活性类固醇调节剂的治疗潜力。

在1980年代,黄体酮和脱氧皮质酮的特定内源性代谢产物被证明是GABA A受体(GABA A R)的有效,有效,正变构调节剂(PAM )。这些报道之后,发现不仅可以在周围的内分泌腺体中合成类固醇,而且可以在中枢神经系统(CNS)中局部合成类固醇,从而有可能充当旁分泌或自分泌的“神经类固醇”信使,从而微调神经元抑制作用。这些发现激发了人们对阐明这种类固醇的生理作用的热情,并探讨了它们在特定的精神病和神经病中是否可能受到干扰。在临床前研究中,GABA AR-活性类固醇显示出抗焦虑,抗惊厥,镇痛和镇静作用,并且在较高剂量下可引起全身麻醉。总的来说,这些发现鼓励人们努力研究神经甾体和相关合成类似物的治疗潜力。但是,经过30多年的调查,事实证明,实现其可能的医学潜力具有挑战性。FDA最近批准用于治疗产后抑郁症(PPD)的天然神经甾体Allopregnanolone(brexanolone)应该激发人们对神经甾体研究的新热情。在这里,我们重点研究神经活性类固醇对GABA-能信号传导的影响,以及开发类固醇如麻醉剂,镇静剂,镇痛药,抗惊厥药,

更新日期:2019-12-23
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