Tarozzi A, Merlicco A, Morroni F, Bolondi C, Di Iorio P, Ciccarelli R, Romano S, Giuliani P, Hrelia P
Department of Pharmacology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
J Biol Regul Homeost Agents. 2010 Jul-Sep;24(3):297-306.
Amyloid-beta (Abeta) peptide aggregation forms such as soluble oligomers (O) have a causal role in neuronal dysfunction and death associated with Alzheimer?s Disease (AD). The main efforts for the development of neuroprotective drugs are therefore focused on preventing Abeta production, aggregation or downstream neurotoxic events. We therefore investigated the effect of guanosine (GUO), a guanine based purine, that exerts neurotrophic and neuroprotective effects. The GUO showed the ability to reduce neuronal death in terms of apoptosis, but not necrosis, elicited by Abeta1-42O in human neuroblastoma SH-SY5Y cells. The neuroprotective effect was recorded only when the GUO was added simultaneously to treatment of the SH-SY5Y cells with Abeta1-42O. By contrast, the GUO treatment of SH-SY5Y cells before and after the appearance of beta1-42O toxicity had no neuroprotective effects. The employment of specific inhibitors showed the involvement of neuronal survival pathways, such as PI3K?Akt and MAPK-ERK for the GUO anti-apoptotic effects observed. In parallel, the SH-SY5Y cells treated with GUO, in experimental conditions similar to those adopted to evaluate neuronal death, showed a marked decrease of the early reactive oxygen species formation induced by Abeta1-42O and pro-oxidant H2O2. In the same neuronal model, GUO was also shown to inhibit the extra- and intra-cellular Abeta1-42 release as well as the beta-secretase activity evoked by H2O2 pro-oxidant action. Based on these findings, GUO and other guanine based purines appear to be a promising class of compounds with neuroprotective properties that may play an important role in the therapy of AD.
淀粉样β（Aβ）肽聚集体形式，如可溶性寡聚体（O），在与阿尔茨海默病（AD）相关的神经元功能障碍和死亡中起因果作用。因此，开发神经保护药物的主要努力集中在预防Aβ的产生、聚集或下游神经毒性事件上。因此，我们研究了鸟苷（GUO）的作用，鸟苷是一种基于鸟嘌呤的嘌呤，具有神经营养和神经保护作用。在人神经母细胞瘤SH-SY5Y细胞中，GUO显示出能够减少由Aβ1-42O引发的凋亡（而非坏死）导致的神经元死亡。仅当将GUO与Aβ1-42O同时添加用于处理SH-SY5Y细胞时，才记录到神经保护作用。相比之下，在β1-42O毒性出现之前和之后对SH-SY5Y细胞进行GUO处理均无神经保护作用。使用特异性抑制剂表明，所观察到的GUO抗凋亡作用涉及神经元存活途径，如PI3K-Akt和MAPK-ERK。同时，在与用于评估神经元死亡的实验条件相似的情况下，用GUO处理的SH-SY5Y细胞显示，由Aβ1-42O和促氧化剂H2O2诱导的早期活性氧形成显著减少。在同一神经元模型中，GUO还显示出能够抑制细胞外和细胞内Aβ1-42的释放以及由H2O2促氧化作用引发的β-分泌酶活性。基于这些发现，GUO和其他基于鸟嘌呤的嘌呤似乎是一类有前景的具有神经保护特性的化合物，可能在AD治疗中发挥重要作用。
