The inhibitors of monoamine oxidase B (MAO B) are effectively used as therapeutic drugs for neuropsychiatric and neurodegenerative diseases. However, their mechanism of action is not clear, since the neuroprotective effect of MAO B inhibitors is associated with the blockage of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-death cascade, rather than the inhibition of MAO B. Here, we provide evidence that GAPDH potentiates the ethanol-induced activity of MAO B and brain cell toxicity. The levels of nuclear GAPDH and MAO B activity are significantly increased in brain-derived cell lines upon 75 mM ethanol-induced cell death. Over-expression of GAPDH in cells enhances ethanol-induced cell death, and also increases the ethanol-induced activation of MAO B. In contrast, the MAO B inhibitors rasagiline and selegiline (0.25 nM) and the rasagiline metabolite, 1-R-aminoindan (1 muM) decreases the ethanol-induced MAO B, prevents nuclear translocation of GAPDH and reduces cell death. In addition, GAPDH interacts with transforming growth factor-beta-inducible early gene (TIEG2), a transcriptional activator for MAO B, and this interaction is increased in the nucleus by ethanol but reduced by MAO B inhibitors and 1-R-aminoindan. Furthermore, silencing TIEG2 using RNAi significantly reduces GAPDH-induced MAO B upregulation and neurotoxicity. In summary, ethanol-induced cell death, attenuated by MAO B inhibitors, may result from disrupting the movement of GAPDH with the transcriptional activator into the nucleus and secondly inhibit MAO B gene expression. Thus, the neuroprotective effects of rasagiline or 1-R-aminoindan on ethanol-induced cell death mediated by a novel GAPDH-MAO B pathway may provide a new insight in the treatment of neurobiological diseases including alcohol-use disorders.

译文

单胺氧化酶B (maob) 抑制剂被有效地用作神经精神和神经退行性疾病的治疗药物。然而,它们的作用机制尚不清楚,因为MAO B抑制剂的神经保护作用与glyceraldehyde-3-phosphate脱氢酶 (GAPDH)-死亡级联的阻断有关,而不是与MAO B的抑制有关。我们提供了GAPDH增强乙醇诱导的MAO B活性和脑细胞毒性的证据。在75 mM乙醇诱导的细胞死亡后,脑源性细胞系中的核GAPDH和MAO B活性水平显着增加。GAPDH在细胞中的过表达增强了乙醇诱导的细胞死亡,也增加了乙醇诱导的MAO B的活化。相反,MAO B抑制剂雷沙吉兰和司来吉兰 (0.25 nM) 和雷沙吉兰代谢物1-r-氨基吲哚 (1 muM) 降低了乙醇诱导的MAO B,防止GAPDH的核易位并减少细胞死亡。此外,GAPDH与转化生长因子-β 诱导的早期基因 (TIEG2) 相互作用,TIEG2是MAO B的转录激活因子,这种相互作用在细胞核中被乙醇增加,但被MAO B抑制剂和1-r-氨基吲哚减少。此外,使用RNAi沉默TIEG2可显着降低GAPDH诱导的MAO B上调和神经毒性。总之,乙醇诱导的细胞死亡,由MAO B抑制剂减弱,可能是由于用转录激活因子破坏GAPDH进入细胞核的运动,其次抑制MAO B基因表达。因此,雷沙吉兰或1-r-氨基吲哚对由新型GAPDH-MAO B途径介导的乙醇诱导的细胞死亡的神经保护作用可能为治疗包括酒精使用障碍在内的神经生物学疾病提供新的见解。

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