Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey.
Department of Pharmacology and Psychopharmacology Research Unit, Faculty of Pharmacy, Marmara University, Haydarpaşa, Istanbul, Turkey.
Chem Biol Interact. 2019 Dec 1;314:108823. doi: 10.1016/j.cbi.2019.108823. Epub 2019 Sep 26.
Schizophrenia cannot be treated sufficiently with existing antipsychotic drugs. Taken into account that increased Glycogen Synthase Kinase 3 Beta (GSK-3β) activity is associated with schizophrenia pathophysiology and certain antipsychotics can be able to decrease GSK3β activity, inhibition of GSK-3β activity could be a novel approach for the treatment of schizophrenia. In the present study MK-801, a widely used chemical for the in vivo/in vitro modeling of schizophrenia was selected to evoke a detrimental effect on cellular survival via GSK3β and related proteins. A limited number of studies have reported the curative effects of famotidine, an antiulcer drug, in schizophrenic patients. To the best of our knowledge, no study investigated the molecular mechanism of the beneficial effect of famotidine in the patients. A recent study based on computerized drug modeling software (docking) indicated that famotidine might inhibit the GSK3β activity due to its chemical structure independent from histaminergic receptors. In this study, we aimed to investigate the effects of famotidine on the Akt/GSK-3β/β-catenin signaling pathway on SH-SY5Y neuroblastoma cells in the presence of MK-801. We investigated the effects of famotidine, olanzapine (an antipsychotic drug), and SB 415286 (specific GSK-3β inhibitor), on the basal cellular survival and MK-801 induced neuronal death beside of Akt/GSK-3β/β-catenin protein and gene expressions in SH-SY5Y cells. Cell viability, protein and gene expressions were determined by the real-time cell analysis (xCELLigence) system, western blotting and real-time polymerase chain reactions (Rt-PCR), respectively. Our findings suggested that MK-801 administration decreased cell survival probably via the increasing GSK-3β gene expression and activity in the SH-SY5Y cells. Pre-treatments with famotidine, olanzapine, and SB 415286 prevented MK-801 induced cell death via inhibitory effects on the MK-801 induced GSK-3β activity. Overall, the present results suggest that famotidine has a neuroprotective effect against MK-801 via modulation of the Akt/GSK-3β/β-catenin signaling pathway, an important mechanism in schizophrenia neurobiology.
精神分裂症不能仅用现有的抗精神病药物充分治疗。考虑到糖原合酶激酶 3β（GSK-3β）活性增加与精神分裂症的病理生理学有关，并且某些抗精神病药能够降低 GSK3β 的活性，因此抑制 GSK-3β 的活性可能是治疗精神分裂症的新方法。在本研究中，选择了广泛用于体内/体外精神分裂症建模的 MK-801，以通过 GSK3β 和相关蛋白来引起细胞存活的有害作用。有限的研究报告了抗溃疡药法莫替丁在精神分裂症患者中的治疗效果。据我们所知，尚无研究调查法莫替丁在患者中的有益作用的分子机制。最近的一项基于计算机药物建模软件（对接）的研究表明，由于其化学结构与组胺能受体无关，法莫替丁可能会抑制 GSK3β 的活性。在这项研究中，我们旨在研究法莫替丁对 SH-SY5Y 神经母细胞瘤细胞中 Akt/GSK-3β/β-catenin 信号通路的影响，MK-801 存在的情况下。我们研究了法莫替丁、奥氮平（一种抗精神病药）和 SB 415286（特异性 GSK-3β 抑制剂）对 SH-SY5Y 细胞中基础细胞存活和 MK-801 诱导的神经元死亡的影响，以及 Akt/GSK-3β/β-catenin 蛋白和基因表达。细胞活力、蛋白质和基因表达分别通过实时细胞分析（xCELLigence）系统、western blot 和实时聚合酶链反应（Rt-PCR）来确定。我们的发现表明，MK-801 的给药可能通过增加 SH-SY5Y 细胞中 GSK-3β 基因的表达和活性来降低细胞存活率。法莫替丁、奥氮平和 SB 415286 的预处理可通过抑制 MK-801 诱导的 GSK-3β 活性来预防 MK-801 诱导的细胞死亡。总的来说，这些结果表明，法莫替丁通过调节 Akt/GSK-3β/β-catenin 信号通路对 MK-801 具有神经保护作用，这是精神分裂症神经生物学中的一个重要机制。
