Multi-target Drug Treatments for Neurodegenerative Disease

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 22 July 2024 | Viewed by 6113

Special Issue Editors


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Guest Editor
Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Interests: amyloid aggregation; autophagy; natural polyphenols; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

Degeneration of the central nervous system (CNS) is characterized by chronic progressive loss of the structure and functions of neuronal materials, resulting in functional and mental impairments. While the causes associated with neuronal degeneration remain poorly understood, the incidence of neurodegeneration increases with age, and it is most common in mid-to-late adult life. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Current therapies for neurodegenerative disorders treat symptoms and final manifestations, including aggregate build-up, memory loss, behavioral changes, and sleep deficits; however, this strategy is not a sustainable approach to the management of disease onset or progression. One promising approach considers the inhibition of amyloid formation by small-molecule inhibitors; however, the failure of multiple clinical therapeutic approaches indicates that the current strategies must be modulated and the importance of targeting pre-symptomatic signs, such as oxidative stress and inflammation, must be emphasized. Both oxidative stress and neuroinflammation precede over the symptomology of neurodegenerative disorders, and each promotes a neurotoxic environment associated with neurodegeneration.

In this scenario, polyphenols represent a promising starting point for new preventive and therapeutic approaches, since they effectively and simultaneously target epigenetic, metabolic, inflammatory, and oxidative pathways, as well as amyloid aggregation. These molecules have global availability, low cost, and low toxicity. Improved knowledge of these topics is essential in promoting the use of natural polyphenols far beyond their known antioxidant, antidiabetic, and antilipidemic effects. Increased information on this topic could be exploited to enrich, from a commercial and nutraceutical point of view, the alimentary and healthy values of natural compounds.

Dr. Manuela Leri
Dr. Marzia Vasarri
Guest Editors

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Keywords

  • neurodegenerative diseases
  • nutraceuticals
  • natural compounds
  • Alzheimer’s disease
  • Parkinson’s disease

Published Papers (4 papers)

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Research

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15 pages, 3327 KiB  
Article
Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases
by Andrea Angarita-Rodríguez, J. Manuel Matiz-González, Andrés Pinzón, Andrés Felipe Aristizabal, David Ramírez, George E. Barreto and Janneth González
Pharmaceuticals 2024, 17(5), 648; https://doi.org/10.3390/ph17050648 - 16 May 2024
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Abstract
Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators [...] Read more.
Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein–protein and drug–protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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18 pages, 8507 KiB  
Article
Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease
by Gabriela Dumitrita Stanciu, Daniela Carmen Ababei, Carmen Solcan, Veronica Bild, Andrei Ciobica, Sorin-Ioan Beschea Chiriac, Loredana Maria Ciobanu and Bogdan-Ionel Tamba
Pharmaceuticals 2023, 16(11), 1620; https://doi.org/10.3390/ph16111620 - 16 Nov 2023
Cited by 1 | Viewed by 1260
Abstract
The incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. The lack of a safe and effective causal therapy in cognitive decline is an aggravating factor and requires investigations into [...] Read more.
The incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. The lack of a safe and effective causal therapy in cognitive decline is an aggravating factor and requires investigations into the repurposing of commonly used drugs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new and efficient class of hypoglycemic drugs and, due to their pleiotropic effects, have indications that go beyond diabetes. There is emerging data from murine studies that SGLT2i can cross the blood–brain barrier and may have neuroprotective effects, such as increasing the brain-derived neurotrophic factor (BDNF), reducing the amyloid burden, inhibiting acetylcholinesterase (AChE) and restoring the circadian rhythm in the mammalian target of rapamycin (mTOR) activation. The current study investigates the effect of an SGLT2i and donepezil, under a separate or combined 21-day treatment on AD-relevant behaviors and brain pathology in mice. The SGLT2i canagliflozin was found to significantly improve the novelty preference index and the percentage of time spent in the open arms of the maze in the novel object recognition and elevated plus maze test, respectively. In addition, canagliflozin therapy decreased AChE activity, mTOR and glial fibrillary acidic protein expression. The results also recorded the acetylcholine M1 receptor in canagliflozin-treated mice compared to the scopolamine group. In the hippocampus, the SGLT2i canagliflozin reduced the microgliosis and astrogliosis in males, but not in female mice. These findings emphasize the value of SGLT2i in clinical practice. By inhibiting AChE activity, canagliflozin represents a compound that resembles AD-registered therapies in this respect, supporting the need for further evaluation in dementia clinical trials. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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21 pages, 3724 KiB  
Article
Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease
by Danish Iqbal, Md Tabish Rehman, Mohamed F. Alajmi, Mohammed Alsaweed, Qazi Mohammad Sajid Jamal, Sharifa M. Alasiry, Awatif B. Albaker, Munerah Hamed, Mehnaz Kamal and Hind Muteb Albadrani
Pharmaceuticals 2023, 16(4), 622; https://doi.org/10.3390/ph16040622 - 20 Apr 2023
Cited by 4 | Viewed by 2264
Abstract
The complexity of Alzheimer’s disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 [...] Read more.
The complexity of Alzheimer’s disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3β, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy −11.7, −10.6, and −12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201’s ability to remain inside target proteins’ binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3β-F1094-0201, and NMDA-F1094-0201 complex formation were −73.78 ± 4.31 kcal mol−1, −72.77 ± 3.43 kcal mol−1, and −52.51 ± 2.85 kcal mol−1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3β. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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Review

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25 pages, 1820 KiB  
Review
Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration
by Mónica Álvarez-Córdoba, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Manuel Munuera-Cabeza, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Manuel Romero-Domínguez, Alejandra López-Cabrera, José Ángel Armengol and José Antonio Sánchez-Alcázar
Pharmaceuticals 2023, 16(10), 1359; https://doi.org/10.3390/ph16101359 - 26 Sep 2023
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Abstract
The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration [...] Read more.
The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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