Adenosine A1 receptors control the metabolic recovery after hypoxia in rat hippocampal slices
Adenosine A1 receptors control the metabolic recovery after hypoxia in rat hippocampal slices
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DOI：
10.1111/jnc.13512
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发表时间：
2016-03-01
影响因子：
4.7
通讯作者：
Carvalho, Rui A.
中科院分区：
文献类型：
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作者：
Duarte, Joao M. N.;Cunha, Rodrigo A.;Carvalho, Rui A.
腺苷是一种神经调节剂，可以保护神经元免受缺氧的影响。这种效应归因于腺苷 A(1) 受体 (A(1)R) 抑制兴奋性突触传递的能力。然而，A(1)R 激活还可以通过控制新陈代谢来保护非脑组织免受缺氧损伤。因此，我们现在测试了这样的假设：灌流海马切片缺氧损伤后 A(1)R 介导的神经保护也涉及神经元和星形胶质细胞代谢的控制。 90 分钟的缺氧会增加乳酸、丙氨酸和丙酮酸水平，并降低能量负荷 (EC)、磷酸肌酸/肌酸比率和谷氨酰胺含量。这些代谢改变在复氧3小时后完全恢复。 A(1)R 选择性拮抗剂 1,3-二丙基-8-环戊基黄嘌呤的存在刺激糖酵解，防止缺氧引起的 EC 下降，并增加 GABA 水平。 A(1)R 阻断进一步削弱了缺氧后复氧代谢的恢复，其典型特征是 EC 持续降低和线粒体代谢增加，这一点通过三羧酸循环中更大的 [U-C-13] 葡萄糖氧化得到证实。这些结果表明，A(1)R阻断可防止复氧过程中缺氧诱导的代谢改变的恢复，这表明A(1)R控制脑组织初级代谢的能力可能是迄今为止未被认识的A(1)R介导的神经保护机制。
Adenosine is a neuromodulator that protects neurons from hypoxia. This effect is attributed to the ability of adenosine A(1) receptors (A(1)R) to inhibit excitatory synaptic transmission. However, A(1)R activation also protects non-brain tissues from hypoxic insults by controlling metabolism. Thus, we now tested the hypothesis that A(1)R-mediated neuroprotection after a hypoxic insult in superfused hippocampal slices also involves the control of neuronal and astrocytic metabolism. A 90-min hypoxia insult increased lactate, alanine, and pyruvate levels and decreased energy charge (EC), phosphocreatine/creatine ratio, and glutamine content. These metabolic modifications were fully recovered after reoxygenation for 3h. The presence of the A(1)R-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine stimulated glycolysis, prevented the hypoxia-induced decrease of EC, and increased the levels of GABA. A(1)R blockade further blunted the recovery of metabolism on reoxygenation after hypoxia, as typified by a sustained decreased EC and an increased mitochondrial metabolism, as confirmed by a greater [U-C-13]glucose oxidation through the tricarboxylic acid cycle. These results demonstrate that A(1)R blockade prevents the recovery of hypoxia-induced metabolic alterations during reoxygenation, which indicates that the ability of A(1)R to control primary metabolism in the brain tissue may be a hitherto unrecognized mechanism of A(1)R-mediated neuroprotection.