Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions
Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions
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DOI：
10.1111/jnc.12324
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发表时间：
2013-08-01
影响因子：
4.7
通讯作者：
Tasca, Carla I.
中科院分区：
文献类型：
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作者：
Dal-Cim, Tharine;Ludka, Fabiana K.;Tasca, Carla I.
鸟苷（Guanosine，GUO）是一种内源性神经递质兴奋性毒性调节剂，在体内和体外神经毒性模型中具有神经保护作用。本研究旨在了解GUO对氧/糖剥夺和再给氧（OGD）促进的氧化损伤的神经保护作用机制。GUO（100 μ M）减少活性氧的产生，并防止OGD诱导的线粒体膜去极化。GUO还表现出抗炎作用，如抑制核因子κ B活化和减少OGD诱导的诱导型一氧化氮合酶的诱导。GUO的这种神经保护作用是通过腺苷A1受体、磷脂酰肌醇3激酶和MAPK/ERK介导的。此外，GUO恢复了由OGD引起的谷氨酸摄取受损，该作用通过百日咳毒素敏感的G蛋白偶联信号传导、腺苷A（2A）受体（A（2A）R）阻断而不是通过A（1）受体发生。GUO对谷氨酸摄取的调节也涉及MAPK/ERK激活。总之，GUO通过调节腺苷受体功能和激活MAPK/ERK，通过以下机制对OGD海马脑片提供神经保护：（i）预防线粒体膜去极化，（ii）减少氧化应激，（iii）通过抑制核因子κ B和诱导型一氧化氮合酶调节炎症，以及（iv）促进谷氨酸摄取。
Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 mu M) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A(1) receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A(2A) receptors (A(2A)R), but not via A(1) receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.