González-Ramírez Mariela, Gavilán Javiera, Silva-Grecchi Tiare, Cajas-Madriaga Daniel, Triviño Sergio, Becerra José, Saez-Orellana Francisco, Pérez Claudia, Fuentealba Jorge
Laboratory of Chemistry of Natural Products, University of Concepción, Concepción, Chile.
Laboratory of Screening of Neuroactive Compounds, University of Concepción, Concepción, Chile.
J Alzheimers Dis. 2018;61(4):1463-1475. doi: 10.3233/JAD-170958.
Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.
阿尔茨海默病（AD）的特征是由于β淀粉样肽（Aβ）聚集增加而形成淀粉样斑块。寻找AD新治疗方法的一种策略集中在能够减少Aβ积累的化合物上。据描述，含有苯并呋喃环的化合物在降低Aβ诱导的毒性方面发挥着重要作用；然而，迄今为止仅对合成苯并呋喃进行了测试。本研究的目的是检测从安第斯-巴塔哥尼亚真菌黄粉盘菌培养物中分离出的天然苯并呋喃福曼诺辛（Fx）的体外神经保护特性，并评估其对Aβ肽的影响。我们在广泛的浓度范围（10-11-10-4 M）下测试了Fx对PC-12细胞的作用，发现该化合物不会改变细胞活力。Fx对PC12细胞中Aβ诱导的毒性也表现出浓度依赖性效应，在10-6 M时细胞活力高于100%。然后，我们测量了Fx（10-7-10-5 M）在急性和慢性（24小时）时对大鼠海马神经元胞质Ca2+瞬变频率的影响。急性孵育Fx会使胞质Ca2+瞬变频率增加至约200%，而慢性孵育Fx会增加Ca2+瞬变频率。最后，当Fx（10-6 M）与Aβ（5×10-6 M）共同孵育时，可防止Aβ诱导的细胞内Ca2+瞬变减少。结果表明，这种天然存在的苯并呋喃对Aβ肽毒性具有强大的神经保护作用，可能是通过干扰其与质膜的结合来介导的，并使Fx作为一种新的化学实体，用于开发对抗Aβ肽神经毒性的药理学工具。
