Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Neurochem Int. 2018 May;115:61-68. doi: 10.1016/j.neuint.2018.02.002. Epub 2018 Feb 21.
Okadaic acid (OKA) is a protein phosphatase 2A inhibitor that is used to induce neurodegeneration and study disease states such as Alzheimer's disease (AD). Lanthionine ketimine-5-ethyl ester (LKE) is a bioavailable derivative of the naturally occurring brain sulfur metabolite, lanthionine ketimine (LK). In previously conducted studies, LKE exhibited neuroprotective and neurotrophic properties in murine models but its mechanism of action remains to be clarified. In this study, a recently established zebrafish OKA-induced AD model was utilized to further elucidate the neuroprotective and neurotrophic properties of LKE in the context of an AD-like condition. The fish were divided into 3 groups containing 8 fish per group. Group #1 = negative control, Group #2 = 100 nM OKA, Group #3 = 100 nM OKA +500 μM LKE. OKA caused severe cognitive impairments in the zebrafish, but concomitant treatment with LKE protected against cognitive impairments. Further, LKE significantly and substantially reduced the number of apoptotic brain cells, increased brain-derived neurotrophic factor (BDNF), and increased phospho-activation of the pro-survival factors pAkt (Ser 473) and pCREB (Ser133). These findings clarify the neuroprotective and neurotrophic effects of LKE by highlighting particular survival pathways that are bolstered by the experimental therapeutic LKE.
岗田酸（OKA）是一种蛋白磷酸酶 2A 抑制剂，用于诱导神经退行性变并研究阿尔茨海默病（AD）等疾病状态。硫辛酰胺-5-乙酯（LKE）是天然存在的脑硫代谢物硫辛酰胺-酮（LK）的生物可利用衍生物。在之前进行的研究中，LKE 在小鼠模型中表现出神经保护和神经营养特性，但作用机制仍需阐明。在这项研究中，利用最近建立的斑马鱼 OKA 诱导的 AD 模型，进一步阐明 LKE 在 AD 样条件下的神经保护和神经营养特性。将鱼分为 3 组，每组 8 条鱼。第 1 组 = 阴性对照，第 2 组 = 100 nM OKA，第 3 组 = 100 nM OKA + 500 μM LKE。OKA 导致斑马鱼严重的认知障碍，但同时用 LKE 治疗可预防认知障碍。此外，LKE 显著减少了凋亡脑细胞的数量，增加了脑源性神经营养因子（BDNF），并增加了促生存因子 pAkt（Ser473）和 pCREB（Ser133）的磷酸化激活。这些发现通过强调实验治疗性 LKE 增强的特定生存途径，阐明了 LKE 的神经保护和神经营养作用。
