AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus
AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus
复制标题
DOI：
10.1046/j.1471-4159.2003.02253.x
复制
发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Frenguelli, BG
中科院分区：
文献类型：
--
作者：
Gadalla, AE;Pearson, T;Frenguelli, BG
5-氨基咪唑-4-甲酰胺核苷（AICA 核苷；Acadesine）可激活完整细胞中的 AMP 激活蛋白激酶 (AMPK)，据报道对哺乳动物 CNS 发挥保护作用。在大鼠大脑皮质脑切片中，AMPK 被代谢应激（缺血 > 缺氧 > 血糖不足）和 AICA 核苷 (0.1-10 mM) 激活。 AICA 核苷对 AMPK 的激活被平衡核苷转运抑制剂大大减弱。 AICA 核苷还抑制大鼠海马 CA1 区的兴奋性突触传递，腺苷 A(1) 受体拮抗剂可阻止这种传递，并可通过应用腺苷脱氨酶来逆转。然而，AICA 核苷既不是腺苷脱氨酶的底物，也不是腺苷受体的激动剂。我们得出的结论是，代谢应激和 AICA 核苷都会刺激哺乳动物大脑中的 AMPK 活性，但 AICA 核苷具有额外的作用，即与腺苷竞争核苷转运蛋白的摄取。这导致细胞外腺苷增加并随后激活腺苷受体。 AICA 核苷的神经保护作用可以通过该机制以及或代替 AMPK 激活来介导。因此，在将 AICA 核苷的作用归因于 AMPK 激活时应谨慎，特别是在抑制腺苷再摄取会产生生理后果的系统中。
5-Aminoimidazole-4-carboxamide riboside (AICA riboside; Acadesine) activates AMP-activated protein kinase (AMPK) in intact cells, and is reported to exert protective effects in the mammalian CNS. In rat cerebrocortical brain slices, AMPK was activated by metabolic stress (ischaemia > hypoxia > aglycaemia) and AICA riboside (0.1-10 mM). Activation of AMPK by AICA riboside was greatly attenuated by inhibitors of equilibrative nucleoside transport. AICA riboside also depressed excitatory synaptic transmission in area CA1 of the rat hippocampus, which was prevented by an adenosine A(1) receptor antagonist and reversed by application of adenosine deaminase. However, AICA riboside was neither a substrate for adenosine deaminase nor an agonist at adenosine receptors. We conclude that metabolic stress and AICA riboside both stimulate AMPK activity in mammalian brain, but that AICA riboside has an additional effect, i.e. competition with adenosine for uptake by the nucleoside transporter. This results in an increase in extracellular adenosine and subsequent activation of adenosine receptors. Neuroprotection by AICA riboside could be mediated by this mechanism as well as, or instead of, by AMPK activation. Caution should therefore be exercised in ascribing an effect of AICA riboside to AMPK activation, especially in systems where inhibition of adenosine re-uptake has physiological consequences.