Cavaliere F, D'Ambrosi N, Ciotti M T, Mancino G, Sancesario G, Bernardi G, Volonté C
Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy.
Neurochem Int. 2001 Mar;38(3):189-97. doi: 10.1016/s0197-0186(00)00088-7.
In this work we investigate cell survival after glucose deprivation and/or chemical hypoxia and we analyse the neuroprotective properties of selected antagonists of P2 ATP receptors. We find that in rat cerebellar granule neurones, the antagonist basilen blue prevents neuronal death under hypoglycaemia. Basilen blue acts through a wide temporal range and it retains its efficacy under chemically induced hypoxic conditions, in the presence of the respiratory inhibitors of mitochondria electron transport chain complexes II (3-nitropropionic acid) and III (antimycin A). In spite of the presence of these compounds, basilen blue maintains normal intracellular ATP levels. It furthermore prevents neuronal death caused by agents blocking the mitochondrial calcium uptake (ruthenium red) or discharging the mitochondrial membrane potential (carbonyl cyanide m-chlorophenylhydrazone). Inhibition of poly (ADP-ribose) polymerase, modulation of the enzyme GAPDH and mitochondrial transport of mono-carboxylic acids are not conceivable targets for the action of basilen blue. Survival is sustained by basilen blue also in CNS primary cultures from hippocampus and in PNS sympathetic-like neurones. Partial neuroprotection is furthermore provided by three additional P2 receptor antagonists: suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid 4-sodium and 4,4'-diisothiocyanatostilbene-2,2'disulphonic acid. Our data suggest the exploitation of selected P2 receptor antagonists as potential neuroprotective agents.
在这项研究中，我们研究了葡萄糖剥夺和/或化学性缺氧后的细胞存活情况，并分析了P2 ATP受体的某些拮抗剂的神经保护特性。我们发现，在大鼠小脑颗粒神经元中，拮抗剂巴西蓝可预防低血糖时的神经元死亡。巴西蓝在较宽的时间范围内起作用，并且在化学诱导的缺氧条件下，在线粒体电子传递链复合物II（3-硝基丙酸）和III（抗霉素A）的呼吸抑制剂存在的情况下，它仍保持其功效。尽管存在这些化合物，巴西蓝仍能维持正常的细胞内ATP水平。此外，它还能预防由阻断线粒体钙摄取的药物（钌红）或消除线粒体膜电位的药物（羰基氰化物间氯苯腙）引起的神经元死亡。抑制聚（ADP-核糖）聚合酶、调节甘油醛-3-磷酸脱氢酶以及单羧酸的线粒体转运不是巴西蓝作用的可能靶点。在来自海马体的中枢神经系统原代培养物和外周神经系统交感样神经元中，巴西蓝也能维持细胞存活。另外三种P2受体拮抗剂：苏拉明、磷酸吡哆醛-6-偶氮苯基-2',4'-二磺酸四钠和4,4'-二异硫氰酸根合芪-2,2'-二磺酸，也提供了部分神经保护作用。我们的数据表明，可将选定的P2受体拮抗剂开发为潜在的神经保护剂。
