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 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.

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

“…In this section, we review studies reported in the recent chemical and biological literature on the miscellaneous memantine derivatives for which AD neuroprotective activity derived by merging two pharmacophores is claimed, but which lie outside the hybrid series described in the other paragraphs of this review. In this regard, a lot of efforts have been made over the years to enhance memantine potency, synthesizing double-acting prodrug or targeting the second region of the same receptor to increase its efficacy [ 6 , 63 ]. Otherwise, merging two well-known NMDAR antagonists has been exploited as a strategy to obtain more efficient channel blockers with potential further clinical applications [ 64 ].…”

“…Particularly, H 2 S combines neuroprotection, antinflammatory and antiapoptotic activities to NMDAR-modulation ability both directly, with sulfhydration of critical cysteine residues, and indirectly, through regulation of intracellular calcium concentration [ 72 , 73 ]. On this basis, the interesting biological outputs of compound 18 , an H 2 S-releasing memantine derivative by Sestito and coworkers, can open a range of possibilities for new MTDL campaign [ 63 ]. Compound 18 bears an isothiocyanate moiety as H 2 S-donating moiety, replacing the characteristic free amino group of memantine ( Figure 11 ).…”

“…Furthermore, compound 18 was able to protect cells from oxidative stress and LPS-TNFα insult, reducing ROS production and stimulating cell proliferation in neuroinflammation in an in vitro model at 10 μM ( Figure 11 ). Antiamyloidogenic properties of memantine were confirmed with compound 18 , which demonstrated to reduce Aβ 42 self-induced aggregation and to reduce Aβ-induced damage in rat microglia cells to roughly the same extent as its parent compound [ 63 ].…”

Anti‐inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2S donors in COVID‐19 therapy

“…Nrf2 is a nuclear factor responsible for promoting the expression of multiple antioxidant genes and preventing oxidative damage. Such a mechanism of action has been described also for synthetic isothiocyanates whose H 2 S donor profile has been widely described (Citi, Corvino, et al, 2020;Citi et al, 2014Citi et al, , 2019Martelli, Piragine, et al, 2020;Martelli et al, 2014;Prawan et al, 2009;Sestito, Daniele, et al, 2019;Sestito, Pruccoli, et al, 2019;Testai et al, 2016). Anethole dithiolethione, another H 2 S donor, has been widely used as H 2 S donor or as a moiety for the development of H 2 S-releasing hybrid drugs, including non-steroidal anti-inflammatory agents, such as H 2 S-aspirin and H 2 S-diclofenac.…”

Schisandra Extract and Ascorbic Acid Synergistically Enhance Cognition in Mice through Modulation of Mitochondrial Respiration

“…FDA-approved drugs, including Aricept (donepezil) and Razadyne (galantamine), both of which are cholinesterase inhibitors, prevent memory deficits, but cause side effects such as nausea, vomiting, and muscle cramps [7]. Other agents include minocycline, a tetracycline antibiotic that targets neuroinflammation in AD [8], and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist that attenuates damage caused by reactive oxygen species (ROS) in the brain [9]. Although mitochondrial dysfunction is a causative factor in memory deficits in AD [3], how mitochondrial modulation by natural compounds alters the expression of key synaptic proteins is not known.…”