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Sci Rep. 2019 Mar 15;9(1):4612. doi: 10.1038/s41598-019-40925-8.

Memantine prodrug as a new agent for Alzheimer's Disease.

Author information

1
Department of Pharmacy, University of Pisa, Pisa, 56126, Italy.
2
Department of Pathology, University of Pisa, Pisa, 56126, Italy.
3
Interdepartmental Research Centre for Biology and Pathology of Aging, University of Pisa, Pisa, Italy.
4
Department of Pharmacy, University of Pisa, Pisa, 56126, Italy. simona.rapposelli@unipi.it.
5
Interdepartmental Research Centre for Biology and Pathology of Aging, University of Pisa, Pisa, Italy. simona.rapposelli@unipi.it.

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 H2S 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 H2S-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 H2S in the CNS. Indeed, Memit showed the ability to release H2S 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 H2S-releasing moiety and the native drug.

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