A Perspective on Multi-target Drugs for Alzheimer’s Disease

Benek, Ondřej; Korábečný, Jan; Soukup, Ondřej

doi:10.1016/j.tips.2020.04.008

Cited by 161 publications

(111 citation statements)

References 66 publications

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“…Alzheimer’s disease (AD) has become a major concern worldwide as no cure has been found yet. To date, three clinical drugs have been approved by the US Food and Drug Administration (FDA), which are all cholinesterase inhibitors; donepezil, galanthamine, and rivastigmine [ 10 ]. AD is classified as a neurodegenerative disorder.…”

Section: Introductionmentioning

confidence: 99%

Potential Anti-Acetylcholinesterase Activity of Cassia timorensis DC.

et al. 2020

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Seventeen methanol extracts from different plant parts of five different Cassia species, including C. timorensis, C. grandis, C. fistula, C. spectabilis, and C. alata were screened against acetylcholinesterase (AChE). C. timorensis extracts were found to exhibit the highest inhibition towards AChE whereby the leaf, stem, and flower methanol extracts showed 94–97% inhibition. As far as we are aware, C. timorensis is one of the least explored Cassia spp. for bioactivity. Further fractionation led to the identification of six compounds, isolated for the first time from C. timorensis: 3-methoxyquercetin (1), benzenepropanoic acid (2), 9,12,15-octadecatrienoic acid (3), β-sitosterol (4), stigmasterol (5), and 1-octadecanol (6). Compound 1 showed moderate inhibition towards AChE (IC50: 83.71 μM), while the other compounds exhibited poor to slightly moderate AChE inhibitory activity. Molecular docking revealed that the methoxy substitution of 1 formed a hydrogen bond with TYR121 at the peripheral anionic site (PAS) and the hydroxyl group at C5 formed a covalent hydrogen bond with ASP72. Additionally, the OH group at the C3′ position formed an interaction with the protein at the acyl pocket (PHE288). This possibly explains the activity of 1 in blocking the entry of acetylcholine (ACh, the neurotransmitter), thus impeding the hydrolysis of ACh.

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Section: Introductionmentioning

confidence: 99%

Potential Anti-Acetylcholinesterase Activity of Cassia timorensis DC.

et al. 2020

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“…deficiency and neuronal loss of AD are proposed every year (Roberson and Mucke, 2006;Benek et al, 2020). The USA Food and Drug Administration has only approved five drugs for the clinical treatment of AD, and these include the cholinesterase inhibitors tacrine, galantamine, donepezil, rivastigmine, and the glutamate receptor antagonist memantine.…”

Section: Downloaded Frommentioning

confidence: 99%

Stem Cell Therapies in Alzheimer’s Disease: Applications for Disease Modeling

Wang

2021

J Pharmacol Exp Ther

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Alzheimer's disease (AD) is a neurodegenerative disease with complex pathological and biological characteristics. Extracellular β-amyloid deposits, such as senile plaques, and intracellular aggregation of hyperphosphorylated tau, such as neurofibrillary tangles, remain the main neuropathological criteria for the diagnosis of AD. There is currently no effective treatment for the disease, and many clinical trials have failed to prove any benefits of new therapeutics. More recently, there has been increasing interest in harnessing the potential of stem cell technologies for drug discovery, disease modeling, and cell therapies, which have been utilized to study an array of human conditions, including AD. The recently developed and optimized induced pluripotent stem cells (iPSCs) technology is a critical platform for screening anti-AD drugs and understanding mutations that modify AD. Neural stem cells (NSCs) transplantation has been investigated as a new therapeutic approach to treat neurodegenerative diseases. Mesenchymal stem cells (MSCs) also exhibit considerable excitement to treat neurodegenerative diseases by secreting growth factors and exosomes, attenuating neuroinflammation. This review highlights recent progress in stem cell research and the translational applications and challenges of iPSCs, NSCs, and MSCs as treatment strategies for AD. Even though these treatments are still in relative infancy, these developing stem cell technologies hold considerable promise to combat AD and other neurodegenerative disorders.

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“…In summary, a multitarget strategy for AD is emerging, involving a broad spectrum of potential therapeutic strategies from modulating neurotransmission, tau-based therapies, amyloid based therapies, modulating intracellular signalling cascades, oxidative stress reduction, modulation of cellular calcium homeostasis, to anti-inflammatory therapy. Research in the field of application of MTDLs strategy in the field of AD has been extensively reviewed elsewhere [ 118 , 186 , 187 , 188 ].…”

Section: Multi-target Strategy For Admentioning

confidence: 99%

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

Zagórska

Jaromin

2020

Molecules

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Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.

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A Perspective on Multi-target Drugs for Alzheimer’s Disease

Cited by 161 publications

References 66 publications

Potential Anti-Acetylcholinesterase Activity of Cassia timorensis DC.

Potential Anti-Acetylcholinesterase Activity of Cassia timorensis DC.

Stem Cell Therapies in Alzheimer’s Disease: Applications for Disease Modeling

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

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