Normandy University, Neuronal and Neuroendocrine Differentiation and Communication, Inserm U1239, Rouen, France.
Normandy University, Neuronal and Neuroendocrine Differentiation and Communication, Inserm U1239, Rouen, France; Normandy University, Regional Platform for Cell Imaging of Normandy (PRIMACEN), Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
Pharmacol Ther. 2020 Apr;208:107386. doi: 10.1016/j.pharmthera.2019.06.008. Epub 2019 Jul 5.
The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discuss the physiopathological implications of these regulatory gliopeptides.
脑内存在苯二氮䓬（BZs）的特异性结合位点，促使人们寻找内源性 BZ 受体配体，通用术语为“内源性苯二氮䓬”。这导致了一种 86 个氨基酸多肽的鉴定，该多肽能够置换 [H]地西泮与脑膜的结合，因此称为地西泮结合抑制剂（DBI）。随后发现，DBI 的序列与一种称为酰基辅酶 A 结合蛋白（ACBP）的脂质载体蛋白相同。DBI/ACBP 的一级结构保存完好，表明内源性苯二氮䓬发挥着重要的功能。DBI/ACBP 基因由中枢神经系统的星形胶质细胞和外周器官的各种细胞类型表达。DBI/ACBP 的内切蛋白酶切割产生几种生物活性肽，包括一种作为外周 BZ 受体/转位蛋白选择性配体的三烷十六肽，和一种十八烷肽，它激活 G 蛋白偶联受体并作为 GABA 受体的变构调节剂。尽管 DBI/ACBP 没有信号肽，但星形胶质细胞以受调控的方式释放内源性苯二氮䓬。与 BZ 结合位点的多样性和广泛分布一致，内源性苯二氮䓬似乎发挥着大量的生物学功能和药理作用。因此，脑室给药 DBI 或衍生肽可诱导冲突和焦虑样行为，并减少食物摄入。相反，DBI/ACBP mRNA 的表达受应激和代谢信号的调节。在体外，内源性苯二氮䓬刺激星形胶质细胞增殖，并保护神经元和星形胶质细胞免受细胞凋亡。内源性苯二氮䓬还调节神经甾体生物合成和神经肽表达，并促进神经发生。在外周器官中，内源性苯二氮䓬激活类固醇激素产生，刺激酰基辅酶 A 神经酰胺合成并引发促炎细胞因子分泌。DBI/ACBP 基因的表达在成瘾/戒断动物模型、神经退行性疾病患者和各种类型的肿瘤中增强。我们在此综述了关于内源性苯二氮䓬的各种作用的最新知识，并讨论了这些调节性神经肽的生理病理意义。
