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首页> 外文期刊>The European Journal of Neuroscience >Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.
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Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.

机译：铵改变正在发育的脑细胞的3D培养物中的肌酸转运和合成，导致继发性脑肌酸缺乏。

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Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of the present work was thus to analyse how the genes of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), allowing creatine synthesis, as well as of the creatine transporter SLC6A8, allowing creatine uptake into cells, are regulated in rat brain cells under NH4+ exposure. Reaggregated brain cell three-dimensional cultures exposed to NH4Cl were used as an experimental model of hyperammonemia in the developing central nervous system (CNS). We show here that NH4+ exposure differentially alters AGAT, GAMT and SLC6A8 regulation, in terms of both gene expression and protein activity, in a cell type-specific manner. In particular, we demonstrate that NH4+ exposure decreases both creatine and its synthesis intermediate, guanidinoacetate, in brain cells, probably through the inhibition of AGAT enzymatic activity. Our work also suggests that oligodendrocytes are major actors in the brain in terms of creatine synthesis, trafficking and uptake, which might be affected by hyperammonemia. Finally, we show that NH4+ exposure induces SLC6A8 in astrocytes. This suggests that hyperammonemia increases blood-brain barrier permeability for creatine. This is normally limited due to the absence of SLC6A8 from the astrocyte feet lining microcapillary endothelial cells, and thus creatine supplementation may protect the developing CNS of hyperammonemic patients.
机译：儿科患者的高氨血症会导致对发育中大脑的不可理解的不可逆的影响，这可能危及生命。先前我们已经表明，这些NH4 +诱导的不可逆作用中的某些可能是由于轴突生长受损所致，而轴突生长受损可以通过肌酸共处理而受到铵暴露的保护。因此，本研究的目的是分析精氨酸：甘氨酸a基转移酶（AGAT）和胍基乙酸甲酯甲基转移酶（GAMT）的基因，从而允许肌酸的合成以及允许肌酸摄取进入细胞的肌酸转运蛋白SLC6A8的调控。 NH4 +暴露下的大鼠脑细胞。暴露于NH4Cl的重新聚集的脑细胞三维培养物被用作发展中的中枢神经系统（CNS）中高氨血症的实验模型。我们在这里显示，NH4 +暴露以细胞类型特异性方式在基因表达和蛋白质活性方面差异性地改变了AGAT，GAMT和SLC6A8调控。特别是，我们证明了NH4 +暴露可能会抑制AGAT酶活性，从而降低脑细胞中的肌酸及其合成中间体胍基乙酸盐。我们的工作还表明，就肌酸合成，运输和摄取而言，少突胶质细胞是大脑的主要角色，这可能会受到高氨血症的影响。最后，我们证明了NH4 +暴露会在星形胶质细胞中诱导SLC6A8。这表明高氨血症增加了肌酸的血脑屏障通透性。由于缺乏星形胶质细胞衬里的微毛细血管内皮细胞中SLC6A8的存在，这通常受到限制，因此补充肌酸可以保护高氨血症患者的中枢神经系统。

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