New Insights on Drug Design, Delivery and Targeting in Neurodegeneration

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 23993

Special Issue Editors


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Guest Editor
1. Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
2. UCIBIO—Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: toxicology; pharmacology; ADME/toxicokinetics; membrane transporters; P-glycoprotein; neurodegeneration; drugs of abuse; drug discovery
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Associate Laboratory i4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences—CESPU, 4585-116 Gandra, Portugal
2. UCIBIO—Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal
3. Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
Interests: molecular motors; intracellular transport; cell biology; molecular biology; neurodegeneration; drugs of abuse; pharmacology; toxicology; neurotoxicology; forensic sciences
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases represent a heterogenous group of disorders characterized by progressive degeneration and death of neuronal populations. They affect millions of people worldwide, greatly impacting patient’s quality of life and raising strong economic and health concerns for society. This problem is even more fundamental as the available therapies remain fairly limited and mainly focusing on symptoms relief. Thus, the development of novel drug candidates, based on state-of-the-art chemistry methodologies and/or sparsely explored chemical substances, could help to identify lead compounds with potential pharmaceutical application.

On the other hand, in most cases, the lack of drug efficacy in neurodegeneration treatment comes from a compromised drug delivery to their target sites. Thus, the development of cutting-edge drug delivery systems and approaches would add substantial advance in neurodegeneration treatment.

In this special issue we are interested in reviews and original articles describing novel chemical design-based drug candidates and improved delivery systems to target sites with potential to deal with neurodegeneration.

Prof. Dr. Renata Silva
Prof. Dr. Daniel José Barbosa
Guest Editors

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Keywords

  • drug design and discovery
  • drug delivery
  • drug targeting
  • neurodegeneration
  • new therapeutic strategies
  • in vitro models of neurodegeneration

Published Papers (9 papers)

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Research

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21 pages, 3302 KiB  
Article
New Hybrid Compounds Incorporating Natural Products as Multifunctional Agents against Alzheimer’s Disease
by Lidia Ciccone, Caterina Camodeca, Nicolò Tonali, Lucia Barlettani, Armando Rossello, Carole Fruchart Gaillard, Julia Kaffy, Giovanni Petrarolo, Concettina La Motta, Susanna Nencetti and Elisabetta Orlandini
Pharmaceutics 2023, 15(10), 2369; https://doi.org/10.3390/pharmaceutics15102369 - 22 Sep 2023
Viewed by 974
Abstract
A series of new hybrid derivatives 1ac, 2ac, 3ac, 4ac, 5ac, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer’s disease (AD). [...] Read more.
A series of new hybrid derivatives 1ac, 2ac, 3ac, 4ac, 5ac, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer’s disease (AD). These compounds were designed to merge together the trifluoromethyl benzyloxyaminic bioactive moiety, previously identified, with different acids available in nature. The ability of the synthesized compounds to chelate biometals, such as Cu2+, Zn2+ and Fe2+, was studied by UV–Vis spectrometer, and through a preliminary screening their antioxidant activity was evaluated by DPPH. Then, selected compounds were tested by in vitro ABTS free radical method and ex vivo rat brain TBARS assay. Compounds 2ac, combining the strongest antioxidant and biometal chelators activities, were studied for their ability to contrast Aβ1-40 fibrillization process. Finally, starting from the promising profile obtained for compound 2a, we evaluated if it could be able to induce a positive cross-interaction between transthyretin (TTR) and Aβ in presence and in absence of Cu2+. Full article
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30 pages, 7506 KiB  
Article
An In Vitro Evaluation of the Potential Neuroprotective Effects of Intranasal Lipid Nanoparticles Containing Astaxanthin Obtained from Different Sources: Comparative Studies
by Joana Torres, José Miguel Pereira, Rita Marques-Oliveira, Inês Costa, Eva Gil-Martins, Renata Silva, Fernando Remião, Andreia Filipa Peixoto, José Manuel Sousa Lobo and Ana Catarina Silva
Pharmaceutics 2023, 15(4), 1035; https://doi.org/10.3390/pharmaceutics15041035 - 23 Mar 2023
Cited by 3 | Viewed by 2732
Abstract
The intranasal route has been suggested as a promising alternative to improve the direct transport of molecules to the brain, avoiding the need to cross the blood–brain barrier (BBB). In this area, the use of lipid nanoparticles, namely solid lipid nanoparticles (SLN) and [...] Read more.
The intranasal route has been suggested as a promising alternative to improve the direct transport of molecules to the brain, avoiding the need to cross the blood–brain barrier (BBB). In this area, the use of lipid nanoparticles, namely solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has been highlighted as a promising strategy to improve the treatment of neurodegenerative diseases. In this work, formulations containing SLN and NLC that were loaded with astaxanthin that was obtained from different sources (astaxanthin extract (AE) from the algae Haematococcus pluvialis and pure astaxanthin (PA) from the fungi Blakeslea trispora) were prepared for nose-to-brain administration, and comparative in vitro experiments were performed to evaluate the biocompatibility of the formulations with nasal (RPMI 2650) and neuronal (SH-SY5Y) cells. Afterwards, the antioxidant activity of the formulations was evaluated for its potential neuroprotective effects, using different chemical aggressors. Finally, the cellular uptake of the astaxanthin was evaluated for the formulations that showed the greatest neuroprotection of the neuronal cells against chemical-induced damage. On the production day, all the formulations showed a particle size, a high encapsulation efficiency (EE), the presence of nanoparticles with a typical spherical shape, and a polydispersity index (PDI) and zeta potential (ZP) that are suitable for nose-to-brain administration. After three months of storage at room temperature, no significant changes were observed in the characterization parameters, predicting a good long-term stability. Furthermore, these formulations were shown to be safe with concentrations of up to 100 µg/mL in differentiated SH-SY5Y and RPMI 2650 cells. Regarding neuroprotection studies, the PA-loaded SLN and NLC formulations showed an ability to counteract some mechanisms of neurodegeneration, including oxidative stress. Moreover, when compared with the PA-loaded SLN, the PA-loaded NLC showed greater neuroprotective effects against the cytotoxicity induced by aggressors. In contrast, the AE-loaded SLN and NLC formulations showed no significant neuroprotective effects. Although further studies are needed to confirm these neuroprotective effects, the results of this study suggest that the intranasal administration of PA-loaded NLC may be a promising alternative to improve the treatment of neurodegenerative diseases. Full article
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16 pages, 4014 KiB  
Article
Dose-Effect Determination of a Neuroprotector Fraction Standardized in Coumarins of Tagetes lucida and Bioavailability
by Anislada Santibáñez, Maribel Herrera-Ruiz, Manasés González-Cortazar, Pilar Nicasio-Torres, Ashutosh Sharma and Enrique Jiménez-Ferrer
Pharmaceutics 2023, 15(3), 967; https://doi.org/10.3390/pharmaceutics15030967 - 17 Mar 2023
Cited by 3 | Viewed by 1652
Abstract
Neurodegeneration has been associated with chronic inflammation states in the brain. For this reason, attention has been directed to drugs indicated as anti-inflammatory as possible therapies for the treatment of said conditions. Tagetes lucida has been widely used as a folk remedy in [...] Read more.
Neurodegeneration has been associated with chronic inflammation states in the brain. For this reason, attention has been directed to drugs indicated as anti-inflammatory as possible therapies for the treatment of said conditions. Tagetes lucida has been widely used as a folk remedy in illnesses associated with the central nervous system and inflammatory ailments. Among the compounds that stand out in the plant against these conditions are coumarins, such as 7-O-prenyl scopoletin, scoparone, dimethylfraxetin, herniarin, and 7-O-prenylumbelliferone. Therefore, the relationship between the therapeutic effect and the concentration was evaluated through pharmacokinetic and pharmacodynamic studies, including vascular permeability evaluation by blue Evans and pro- and anti-inflammatory cytokines quantification, under a neuroinflammation model induced by lipopolysaccharide by the oral administration of three different doses (5, 10, and 20 mg/kg) of a bioactive fraction of T. lucida. In the present study, it was found that all doses showed a neuroprotective and immunomodulatory effect, although the doses of 10 and 20 mg/kg were able to exert their effect for a longer time and to a greater extent. The protective effects of the fraction may be mainly associated with the DR, HR, and SC coumarins due to their structural profile and plasmatic and brain tissue bioavailability. Full article
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17 pages, 761 KiB  
Article
Synthesis of Schiff Bases Containing Phenol Rings and Investigation of Their Antioxidant Capacity, Anticholinesterase, Butyrylcholinesterase, and Carbonic Anhydrase Inhibition Properties
by Sertan Aytac, Ozlem Gundogdu, Zeynebe Bingol and İlhami Gulcin
Pharmaceutics 2023, 15(3), 779; https://doi.org/10.3390/pharmaceutics15030779 - 26 Feb 2023
Cited by 27 | Viewed by 3155
Abstract
The widespread usage of Schiff bases in chemistry, industry, medicine, and pharmacy has increased interest in these compounds. Schiff bases and derivative compounds have important bioactive properties. Heterocyclic compounds containing phenol derivative groups in their structure have the potential to capture free radicals [...] Read more.
The widespread usage of Schiff bases in chemistry, industry, medicine, and pharmacy has increased interest in these compounds. Schiff bases and derivative compounds have important bioactive properties. Heterocyclic compounds containing phenol derivative groups in their structure have the potential to capture free radicals that can cause diseases. In this study, we designed and synthesized eight Schiff bases (1015) and hydrazineylidene derivatives (1617), which contain phenol moieties and have the potential to be used as synthetic antioxidants, for the first time using microwave energy. Additionally, the antioxidant effects of Schiff bases (1015) and hydrazineylidene derivatives (1617) were studied using by the bioanalytical methods of 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical (ABTS•+) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activities, and Fe3+, Cu2+, and Fe3+-TPTZ complex reducing capacities. In the context of studies on antioxidants, Schiff bases (1015) and hydrazineylidene derivatives (1617) were found to be as powerful DPPH (IC50: 12.15–99.01 μg/mL) and ABTS•+ (IC50: 4.30–34.65 μg/mL). Additionally, the inhibition abilities of Schiff bases (1015) and hydrazineylidene derivatives (1617) were determined towards some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCAs I and II), enzymes that are linked to some global disorders including Alzheimer’s disease (AD), epilepsy, and glaucoma. In the context of studies on enzyme inhibition, it was observed that the synthesized Schiff bases (1015) and hydrazineylidene derivatives (1617) inhibited AChE, BChE, hCAs I, and hCA II enzymes with IC50 values in ranges of 16.11–57.75 nM, 19.80–53.31 nM, 26.08 ± 8.53 nM, and 85.79 ± 24.80 nM, respectively. In addition, in light of the results obtained, we hope that this study will be useful and guiding for the evaluation of biological activities in the fields of the food, medical, and pharmaceutical industries in the future. Full article
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11 pages, 1186 KiB  
Article
Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimer’s: Design, Synthesis, and Biological Evaluation
by Shraddha Manish Gupta, Ashok Behera, Neetesh K. Jain, Devendra Kumar, Avanish Tripathi, Shailesh Mani Tripathi, Somdutt Mujwar, Jeevan Patra and Arvind Negi
Pharmaceutics 2023, 15(1), 94; https://doi.org/10.3390/pharmaceutics15010094 - 28 Dec 2022
Cited by 8 | Viewed by 2619
Abstract
As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer’s disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. [...] Read more.
As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer’s disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aβ aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines. Full article
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16 pages, 3570 KiB  
Article
Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease
by Akshatha Ganne, Meenakshisundaram Balasubramaniam, W. Sue T. Griffin, Robert J. Shmookler Reis and Srinivas Ayyadevara
Pharmaceutics 2022, 14(7), 1354; https://doi.org/10.3390/pharmaceutics14071354 - 26 Jun 2022
Cited by 17 | Viewed by 3360
Abstract
Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a [...] Read more.
Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer’s disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [ε4, ε4] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington’s disease) and of Alzheimer’s-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD. Full article
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Review

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36 pages, 4880 KiB  
Review
Research Models to Study Ferroptosis’s Impact in Neurodegenerative Diseases
by Inês Costa, Daniel José Barbosa, Vera Silva, Sofia Benfeito, Fernanda Borges, Fernando Remião and Renata Silva
Pharmaceutics 2023, 15(5), 1369; https://doi.org/10.3390/pharmaceutics15051369 - 29 Apr 2023
Cited by 11 | Viewed by 2176
Abstract
Ferroptosis is a type of regulated cell death promoted by the appearance of oxidative perturbations in the intracellular microenvironment constitutively controlled by glutathione peroxidase 4 (GPX4). It is characterized by increased production of reactive oxygen species, intracellular iron accumulation, lipid peroxidation, inhibition of [...] Read more.
Ferroptosis is a type of regulated cell death promoted by the appearance of oxidative perturbations in the intracellular microenvironment constitutively controlled by glutathione peroxidase 4 (GPX4). It is characterized by increased production of reactive oxygen species, intracellular iron accumulation, lipid peroxidation, inhibition of system Xc-, glutathione depletion, and decreased GPX4 activity. Several pieces of evidence support the involvement of ferroptosis in distinct neurodegenerative diseases. In vitro and in vivo models allow a reliable transition to clinical studies. Several in vitro models, including differentiated SH-SY5Y and PC12 cells, among others, have been used to investigate the pathophysiological mechanisms of distinct neurodegenerative diseases, including ferroptosis. In addition, they can be useful in the development of potential ferroptosis inhibitors that can be used as disease-modifying drugs for the treatment of such diseases. On the other hand, in vivo models based on the manipulation of rodents and invertebrate animals, such as Drosophila melanogaster, Caenorhabditis elegans, and zebrafish, have been increasingly used for research in neurodegeneration. This work provides an up-to-date review of the main in vitro and in vivo models that can be used to evaluate ferroptosis in the most prevalent neurodegenerative diseases, and to explore potential new drug targets and novel drug candidates for effective disease-modifying therapies. Full article
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25 pages, 4570 KiB  
Review
Stimuli-Responsive Nanotherapeutics for Treatment and Diagnosis of Stroke
by Manisha Choudhary, Sayali Chaudhari, Tanisha Gupta, Dnyaneshwar Kalyane, Bhagwat Sirsat, Umesh Kathar, Pinaki Sengupta and Rakesh K. Tekade
Pharmaceutics 2023, 15(4), 1036; https://doi.org/10.3390/pharmaceutics15041036 - 23 Mar 2023
Cited by 2 | Viewed by 1704
Abstract
Stroke is the second most common medical emergency and constitutes a significant cause of global morbidity. The conventional stroke treatment strategies, including thrombolysis, antiplatelet therapy, endovascular thrombectomy, neuroprotection, neurogenesis, reducing neuroinflammation, oxidative stress, excitotoxicity, hemostatic treatment, do not provide efficient relief to the [...] Read more.
Stroke is the second most common medical emergency and constitutes a significant cause of global morbidity. The conventional stroke treatment strategies, including thrombolysis, antiplatelet therapy, endovascular thrombectomy, neuroprotection, neurogenesis, reducing neuroinflammation, oxidative stress, excitotoxicity, hemostatic treatment, do not provide efficient relief to the patients due to lack of appropriate delivery systems, large doses, systemic toxicity. In this context, guiding the nanoparticles toward the ischemic tissues by making them stimuli-responsive can be a turning point in managing stroke. Hence, in this review, we first outline the basics of stroke, including its pathophysiology, factors affecting its development, current treatment therapies, and their limitations. Further, we have discussed stimuli-responsive nanotherapeutics used for diagnosing and treating stroke with challenges ahead for the safe use of nanotherapeutics. Full article
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24 pages, 3299 KiB  
Review
Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases
by Luis Alberto Bravo-Vázquez, Erick Octavio Mora-Hernández, Alma L. Rodríguez, Padmavati Sahare, Anindya Bandyopadhyay, Asim K. Duttaroy and Sujay Paul
Pharmaceutics 2023, 15(2), 711; https://doi.org/10.3390/pharmaceutics15020711 - 20 Feb 2023
Cited by 2 | Viewed by 4332
Abstract
Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration and/or loss of neurons belonging to the central nervous system, and represent one of the major global health issues. Therefore, a number of immunotherapeutic approaches targeting the non-functional or toxic proteins that induce neurodegeneration [...] Read more.
Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration and/or loss of neurons belonging to the central nervous system, and represent one of the major global health issues. Therefore, a number of immunotherapeutic approaches targeting the non-functional or toxic proteins that induce neurodegeneration in NDDs have been designed in the last decades. In this context, due to unprecedented advances in genetic engineering techniques and molecular farming technology, pioneering plant-based immunogenic antigen expression systems have been developed aiming to offer reliable alternatives to deal with important NDDs, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Diverse reports have evidenced that plant-made vaccines trigger significant immune responses in model animals, supported by the production of antibodies against the aberrant proteins expressed in the aforementioned NDDs. Moreover, these immunogenic tools have various advantages that make them a viable alternative for preventing and treating NDDs, such as high scalability, no risk of contamination with human pathogens, cold chain free production, and lower production costs. Hence, this article presents an overview of the current progress on plant-manufactured vaccines for NDDs and discusses its future prospects. Full article
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