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.
Highlights
Alzheimer’s disease (AD) is a progressive age-dependent neurodegenerative brain disorder that slowly destroys memory and thinking skills
A dramatic decrease of CBS activity and a drastic fall in H2S levels have been detected in the brain of patients affected by AD, suggesting that a reduced production of H2S may be involved in the cognitive decline associated to AD4
We found that memit displayed an affinity comparable to that of the native drug only when cysteine was present in the assay medium, while no binding was observed in the absence of cysteine
Summary
Alzheimer’s disease (AD) is a progressive age-dependent neurodegenerative brain disorder that slowly destroys memory and thinking skills. It is the cause of 60% to 70% of cases of dementia and represent one of the main public health issue with a significant impact on the whole society. H2S is a gaseous transmitter that functions as a smooth muscle relaxant and neuromodulator It is produced endogenously from the amino acids L-cysteine and homocysteine (HCy) by several enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and. Growing evidences indicate that NaHS, an exogenous H2S-generating agent, induces neuroprotection against oxidative stress (OS) through at least three main mechanisms: (a) restoration of GSH (glutathione) cellular levels[12]; (b) activation of ATP sensitive potassium channels (KATP); (c) reduction of mitochondrial ROS production[13,14]. It has been demonstrated that H2S has protective effects against Aβ-induced cell injury by inhibiting inflammation, promoting cell growth, and preserving mitochondrial function[2,15]
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