The Antioxidant Additive Approach for Alzheimer’s Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators

Benchekroun, Mohamed; Romero, Alejandro; Egea, Javier; León, Rafael; Michalska, Patrycja; Buendía, Izaskun; Jimeno, M. Luísa; Jun, Daniel; Janočková, Jana; Šepsová, Vendula; Soukup, Ondřej; Aguilera, Óscar; Refouvelet, Bernard; Ouari, Olivier; Marco‐Contelles, José; Ismaïli, Lhassane

doi:10.1021/acs.jmedchem.6b01178

Cited by 85 publications

(69 citation statements)

References 40 publications

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“…Despite extensive evidence of high levels of oxidative stress in AD brains, Nrf2 is predominantly cytoplasmic in neurons, demonstrating the failure of this pathway20. Thus, the Nrf2-EpRE pathway has emerged as a promising pharmacological target for the treatment of AD212223242526. Furthermore, there is evidence that the activities of GSK3β and Nrf2 are negatively correlated, thus increasing neuronal sensitivity to oxidative stress in AD2728.…”

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confidence: 99%

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Gameiro

Michalska

Tenti

et al. 2017

Sci Rep

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The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.

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confidence: 99%

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Gameiro

Michalska

Tenti

et al. 2017

Sci Rep

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“…Previous studies concentrated on the effect of LA on diabetes, obesity, and Alzheimer disease [12,13,15,23]. LA supplementation was found to be a potential treatment for the observed loss of cellular energetics in Alzheimer disease and it could potentiate the antioxidant defense system to prevent or delay the oxidative stress in the progression of this devastating dementing disorder [15,23]. However, few studies were focused on the effect of LA on age-related cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

“…As the strongest anti-oxidant small molecule chemical to date, LA is widely used in the treatment and prevention of various diseases [12,13,14]. Some animal studies have shown that LA may have effect on Alzheimer disease [15]. However, at present, there is no reports about whether LA treatment can prevent or delay the decline of learning and memory caused by aging.…”

Section: Introductionmentioning

confidence: 99%

Lipoic Acid Facilitates Learning and Memory in Aged Mice

Pei¹,

Dong²,

Luo³

et al. 2019

JFNR

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Lipoic acid (LA) is identified as an antioxidant to scavenge and inactivate free radicals. Although LA has been used as a dietary supplement for a long time, the effect of LA supplement on preventing aged-memory loss haven't been studied yet. This study aimed to determine whether LA could promote the ability of learning and memory in the aged mice model. There were four groups in this study: aged control group (20 months old C57BL / 6J mice without any dosage), 0.1% LA dosage group (20 months old C57BL / 6J mice), 0.2% LA dosage group (20 months old C57BL / 6J mice), and young control group(3 months old C57BL / 6J mice without any dosage). Cognitive abilities were tested through behavioral tests, and factors related to synaptic plasticity (BDNF, PSD95, p-NMDAR1, p-CAMK II) were detected by Western Blot. In behavioral test, young control group shown a greater capacity in learning and memory than aged control group. Comparing with aged control group, the abilities of passive avoidance and spatial memory and learning in two LA dosage groups were significantly enhanced by using step-down test and Morris water maze respectively. Up-regulated expression of BDNF and higher levels of PSD95, p-NMDAR1, p-CAMKⅡ were observed in both two LA dosage groups and young control group compared with aged control group. Our findings suggest that long-term LA intervention can effectively delay or prevent the decline of learning and memory associated with aging via altered synaptic plasticity.

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“…Accordingly, several MTDLs have been developed by many research groups [ 5 , 6 , 7 , 8 ]. In the last decade, we have contributed to this area by using multicomponent reactions (MCR) [ 9 , 10 , 11 , 12 , 13 ] as a very suitable and efficient synthetic tool, with its easy performance and its time-saving procedure leading a higher structural diversity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

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The Antioxidant Additive Approach for Alzheimer’s Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators

Cited by 85 publications

References 40 publications

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

Lipoic Acid Facilitates Learning and Memory in Aged Mice

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

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