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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 A?(1-42) self-induced aggregation and exerted cytoprotective effect against A? 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.

SUBMITTER: Sestito S

PROVIDER: S-EPMC6420495 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Sestito Simona S Daniele Simona S Pietrobono Deborah D Citi Valentina V Bellusci Lorenza L Chiellini Grazia G Calderone Vincenzo V Martini Claudia C Rapposelli Simona S

Scientific reports 20190315 1

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<sub>2</sub>S 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<sub>2</sub>S-donor moiety. The new chemical entity, named memit, was then tested in ...[more]

PMID: 30874573

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Project description:BackgroundAlzheimer's disease (AD) is a severe, varied, and complex brain condition that gradually impairs memory and cognitive function. Epidemiological studies have shown that patients who have a history of long-term NSAID use have a decreased risk of developing AD. The objective of this study is to conduct the structural analysis of a novel ibuprofen prodrug and test its anti-Alzheimer's properties.MethodsComputational and docking studies were conducted using AMBER 18 package. The in-vivo studies were performed using aluminum chloride-induced experimental AD in rats. Adult Wistar rats of either sex were used and treated with aluminum chloride (32.5 mg/kg, p.o) and ibuprofen prodrug (50 mg/kg, p.o) daily for 30 days. The hole-board test and elevated plus maze were conducted on 10th, 20th and 30th day. Further, on 31st day, animals were euthanized and the brain tissue was used for histopathology. The results obtained were subjected to statistical analysis by one-way ANOVA and Dunnet's test, p < 0.05 was considered to indicate the significance.ResultsThe structural configuration of the novel compound indicated the presence of several structures such as aliphatic, aromatic, and asymmetry in the compound. The geometrical analysis indicated that the ibuprofen conjugate has dreiding energy of 51.22 kcal/mol with a van der waals radius of 62.56 A. The Huckel analysis confirmed the presence of aromatic rings in the compound. The molecular docking studies suggested affinity towards beta-secretase and acetylcholinesterase, besides indicating that the compound has ideal characteristics for the oral route (Log P = 2.33), cellular absorption (TPSA = 95.50), and oral bioavailability (number of rotatable bonds = 10). The toxicity profile indicated devoid of major systemic toxicity with mild possibility of cytotoxicity. The in-vivo analysis showed that the Ibu-prodrug significantly (P < 0.001) reversed the changes induced by aluminum chloride and restored histomorphological features in brain tissue.ConclusionThe findings suggested that the ibuprofen conjugate might possess the potential to manage the complications of AD. The action appears to be mediated through inhibition of beta-secretase and acetylcholinesterase activities. More studies might aid in identifying a specific therapeutic intervention that is still lacking in the treatment of AD.

Project description:BackgroundWe performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer's disease (AD).MethodsThe meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes.ResultsNine studies including 2433 patients that met the study's inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=-0.27, 95% confidence interval (CI)=-0.39 to -0.14, p=0.0001], behavioral disturbances (SMD=-0.12, 95% CI=-0.22 to -0.01, p=0.03), activities of daily living (SMD=-0.09, 95% CI=-0.19 to -0.00, p=0.05), global function assessment (SMD=-0.18, 95% CI=-0.27 to -0.09, p=0.0001), and stage of dementia (SMD=-0.23, 95% CI=-0.33 to -0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups.ConclusionsMemantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.

Project description:Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer.To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results.Systematic review and meta-analysis of randomised controlled trials.The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011.Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine.Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=-0.29, 95% CI -0.45 to -0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=-0.20, 95% CI -0.31 to -0.09), cognition (SMD=-0.25, 95% CI -0.36 to -0.14) and behaviour and mood (SMD=-0.17, 95% CI -0.32 to -0.03) but not on function (SMD=-0.04, 95% CI -0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found 'no significant benefit' on any clinical measures at 1 year.These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.

Project description:BackgroundThe donepezil-memantine combination is a US Food and Drug Administration (FDA)-approved medication to treat Alzheimer's disease (AD). Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7nAChR). Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice.AimThe objective of this review was to critically examine the mechanisms by which the galantamine-memantine combination may be superior to the donepezil-memantine combination in AD by targeting the cholinergic-nicotinic and glutamatergic systems concurrently.MethodPubMed and Google Scholar were searched using the keywords Alzheimer's disease, cholinergic, glutamatergic, α7nAChR, N-methyl-D-aspartate (NMDA) receptors, donepezil, galantamine, memantine, clinical trials, and biomarkers.ResultsAD is associated with several biomarkers such as kynurenine pathway (KP) metabolites, mismatch negativity (MMN), brain-derived neurotrophic factor (BDNF), and oxidative stress. In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued. However, in an RCT in AD, cognition did not significantly improve with the galantamine-memantine combination compared to galantamine alone. In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination. Galantamine and memantine via the α7nACh and NMDA receptors can counteract the effects of kynurenic acid and enhance MMN and BDNF.ConclusionFuture studies with the galantamine-memantine combination with KP metabolites, MMN, and BDNF as biomarkers are warranted. Positive RCTs in AD may lead to FDA approval of the combination, resulting in greater utilization in clinical practice. In the meantime, clinicians may continue to use the galantamine-memantine combination to treat patients with AD.

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

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

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