Memantine prodrug as a new agent for Alzheimer’s Disease

Abstract

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 H ₂S 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 H ₂S-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 H ₂S in the CNS. Indeed, Memit showed the ability to release H ₂S 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 H ₂S-releasing moiety and the native drug.