Department of Pharmacy, University of Pisa, Pisa, 56126, Italy.
Department of Pathology, University of Pisa, Pisa, 56126, Italy.
Sci Rep. 2019 Mar 15;9(1):4612. doi: 10.1038/s41598-019-40925-8.
Hydrogen sulphide has recently drawn much attention due to its potent anti-inflammatory and neuroprotective roles in brain functions. The purpose of the current study was to exploit these beneficial properties of HS to design a new agent for the treatment of Alzheimer's disease (AD). To pursue our aims, we replaced the free amine group of memantine with an isothiocyanate functionality as a putative HS-donor moiety. The new chemical entity, named memit, was then tested in vitro to determine whether it retains the pharmacological profile of the "native drug", while also providing a source of HS in the CNS. Indeed, Memit showed the ability to release HS through a cysteine-mediated mechanism, thus generating memantine. Moreover, the new hybrid molecule exerts protective effects against neuronal inflammation and induces a drastic fall in ROS production. In addition, memit was also able to reduce the Aβ(1-42) self-induced aggregation and exerted cytoprotective effect against Aβ oligomers-induced damage in both human neurons and rat microglia cells. Finally, similarly to memantine, the new compound promotes autophagy, a complex process required for cellular homeostasis in cell survival that results to be altered in neurodegenerative diseases. In conclusion, our study revealed that memit is a prodrug of memantine. Further in vivo studies will be necessary to fully investigate the synergic or cumulative effects due to the HS-releasing moiety and the native drug.
硫化氢由于其在脑功能中的强大抗炎和神经保护作用，最近引起了广泛关注。本研究的目的是利用 HS 的这些有益特性设计一种治疗阿尔茨海默病（AD）的新药物。为了实现我们的目标，我们将美金刚的游离伯胺基用异硫氰酸酯官能团取代，作为潜在的 HS 供体部分。新的化学实体命名为 memit，然后在体外进行测试，以确定它是否保留了“天然药物”的药理特性，同时也为中枢神经系统提供 HS 来源。事实上，Memit 表现出通过半胱氨酸介导的机制释放 HS 的能力，从而产生美金刚。此外，这种新的混合分子对神经元炎症具有保护作用，并能显著降低 ROS 的产生。此外，Memit 还能够减少 Aβ（1-42）自身诱导的聚集，并对 Aβ 寡聚物诱导的人神经元和大鼠小胶质细胞损伤发挥细胞保护作用。最后，与美金刚类似，这种新化合物促进自噬，这是一种细胞存活过程中细胞内稳态所必需的复杂过程，而在神经退行性疾病中，这种过程会发生改变。总之，我们的研究表明，Memit 是美金刚的前药。进一步的体内研究将有必要充分研究由于 HS 释放部分和天然药物的协同或累积效应。
