Institute of Pharmacology, Polish Academy of Sciences, Department of Experimental Neuroendocrinology, Smetna Street 12, 31-343 Krakow, Poland.
Int J Mol Sci. 2017 Nov 11;18(11):2394. doi: 10.3390/ijms18112394.
Apoptosis and autophagy are involved in neural development and in the response of the nervous system to a variety of insults. Apoptosis is responsible for cell elimination, whereas autophagy can eliminate the cells or keep them alive, even in conditions lacking trophic factors. Therefore, both processes may function synergistically or antagonistically. Steroid and xenobiotic receptors are regulators of apoptosis and autophagy; however, their actions in various pathologies are complex. In general, the estrogen (ER), progesterone (PR), and mineralocorticoid (MR) receptors mediate anti-apoptotic signalling, whereas the androgen (AR) and glucocorticoid (GR) receptors participate in pro-apoptotic pathways. ER-mediated neuroprotection is attributed to estrogen and selective ER modulators in apoptosis- and autophagy-related neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, stroke, multiple sclerosis, and retinopathies. PR activation appeared particularly effective in treating traumatic brain and spinal cord injuries and ischemic stroke. Except for in the retina, activated GR is engaged in neuronal cell death, whereas MR signalling appeared to be associated with neuroprotection. In addition to steroid receptors, the aryl hydrocarbon receptor (AHR) mediates the induction and propagation of apoptosis, whereas the peroxisome proliferator-activated receptors (PPARs) inhibit this programmed cell death. Most of the retinoid X receptor-related xenobiotic receptors stimulate apoptotic processes that accompany neural pathologies. Among the possible therapeutic strategies based on targeting apoptosis via steroid and xenobiotic receptors, the most promising are the selective modulators of the ER, AR, AHR, PPARγ agonists, flavonoids, and miRNAs. The prospective therapies to overcome neuronal cell death by targeting autophagy via steroid and xenobiotic receptors are much less recognized.
细胞凋亡和自噬参与神经发育以及神经系统对各种损伤的反应。细胞凋亡负责细胞的清除，而自噬可以清除细胞或使其存活，即使在缺乏营养因子的情况下也是如此。因此，这两个过程可能协同或拮抗作用。甾体激素和外来物质受体是细胞凋亡和自噬的调节剂；然而，它们在各种病理中的作用是复杂的。一般来说，雌激素（ER）、孕激素（PR）和盐皮质激素（MR）受体介导抗凋亡信号，而雄激素（AR）和糖皮质激素（GR）受体参与促凋亡途径。在与细胞凋亡和自噬相关的神经退行性疾病，如阿尔茨海默病和帕金森病、中风、多发性硬化症和视网膜病变中，ER 介导的神经保护归因于雌激素和选择性 ER 调节剂。PR 激活在治疗创伤性脑和脊髓损伤以及缺血性中风方面似乎特别有效。除了在视网膜中，激活的 GR 参与神经元细胞死亡，而 MR 信号似乎与神经保护有关。除了甾体激素受体外，芳香烃受体（AHR）介导细胞凋亡的诱导和传播，而过氧化物酶体增殖物激活受体（PPARs）抑制这种程序性细胞死亡。大多数视黄醇 X 受体相关的外来物质受体刺激伴随神经病变的细胞凋亡过程。在基于通过甾体激素和外来物质受体靶向细胞凋亡的可能治疗策略中，最有前途的是 ER、AR、AHR、PPARγ 激动剂、类黄酮和 miRNA 的选择性调节剂。通过靶向甾体激素和外来物质受体的自噬来克服神经元细胞死亡的潜在治疗方法还远未被认识。
