New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (24 February 2025) | Viewed by 42311

Special Issue Editors


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Guest Editor
1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2. Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Interests: Alzheimer’s disease; aging; determinants of longevity; neurodegenerative diseases

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Guest Editor
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: drug screening in silico; protein-protein interactions; bioinformatics

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Guest Editor
1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2. Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
Interests: Alzheimer’s disease; aging; determinants of longevity; neurodegenerative diseases; cardiovascular disease; cachexia
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Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) features two diagnostic types of aggregate: extracellular Aβ amyloids, and intra-neuronal tau tangles.  However, many other proteins have also been identified within AD aggregates and often feature AD-specific phosphorylations or other post-translational modifications [PTMs] 1,2.  The upregulation of several kinases has been implicated as possibly driving AD pathology, but other PTMs (e.g., acetylation, oxidation, glycosylation) can also induce protein misfolding and aggregation.  In this Special Issue of Pharmaceuticals, we welcome papers that describe research addressing any part of the progression from the identification of novel drug targets, the in silico screening of structural libraries, the validation of candidate molecules in cell or animal model systems, and ultimately culminating in human trials.  The highest priority will be given to work presenting novel targets and evidence for their potential utility in preventing or ameliorating Alzheimer’s disease or other neurological diseases, and any other diseases where protein aggregation due to altered proteostasis is noted, and to the identification and validation of early biomarkers associated with cognitive impairment and its progression to AD.

1   Ganne, A., Balasubramaniam, M., Griffin, W. S. T., Shmookler Reis, R. J. & Ayyadevara, S. Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer's Disease. Pharmaceutics 14, doi:10.3390/pharmaceutics14071354 (2022).

2   Ayyadevara, S. et al. Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls. Aging Cell 15, 924-939, doi:10.1111/acel.12501 (2016).

Prof. Dr. Robert Joseph Shmookler Reis
Dr. Meenakshisundaram Balasubramaniam
Dr. Srinivas Ayyadevara
Guest Editors

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Keywords

  • Alzheimer’s disease
  • Parkinson’s disease
  • Huntington’s disease
  • amyotrophic lateral sclerosis
  • neurodegeneration
  • inflammation
  • anti-inflammatory drugs
  • post-translational modifications
  • protein misfolding
  • protein aggregation

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Published Papers (14 papers)

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Research

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28 pages, 13669 KiB  
Article
Central Insulin-like Growth Factor-1 Treatment Enhances Working and Reference Memory by Reducing Neuroinflammation and Amyloid Beta Deposition in a Rat Model of Sporadic Alzheimer’s Disease
by Joanna Dunacka, Beata Grembecka, Irena Majkutewicz and Danuta Wrona
Pharmaceuticals 2025, 18(4), 527; https://doi.org/10.3390/ph18040527 - 4 Apr 2025
Viewed by 387
Abstract
Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer’s disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading [...] Read more.
Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer’s disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading to brain insulin resistance, which may mimic the early pathophysiological changes in sporadic AD (sAD). In this study, we investigated whether restoring insulin signaling through ICV injection of IGF-1 could ameliorate spatial memory deficits during sAD progression in a rat model induced by ICV STZ injection. Methods: Male Wistar rats (n = 40) were subjected to double ICV injections of STZ (0.75 mg/kg/ventricle, days 2 and 4) and IGF-1 (1 μg/single injection, days 1 and 3), and placed at the Morris water maze (MWM) at baseline, 7, 45 and 90 days after injections. Reference (days 1–3 and day 4 MWM)) and working (days 5–8 MWM) memory, microglia activation (CD68+ cells), and amyloid β (Aβ) deposition (immunohistochemistry) were measured. Results: We found that ICVIGF-1 administration protected working memory demonstrated as (1) reduced latency to reach the platform, and reduced swimming distance in trials 3 (p < 0.05) and 4 (p < 0.01) on days 45 and 90 post-injection and (2) a short-term (up to 45 days post-injection) enhancement of reference memory, manifested by a reduction in swimming distance and latency (p < 0.05). Furthermore, IGF-1 treatment reduced neuroinflammation in CA2 (p < 0.05) and Aβ deposition in CA1(p < 0.01) of the hippocampus. Conclusions: Central IGF-1 attenuates spatial memory deficits in the ICVSTZ-induced sAD model by reducing neuroinflammation and Aβ accumulation in the hippocampus. Full article
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15 pages, 1335 KiB  
Article
Elucidating the Synergistic Effect of the PrimeC Combination for Amyotrophic Lateral Sclerosis in Human Induced Pluripotent Stem Cell-Derived Motor Neurons and Mouse Models
by Shiran Salomon-Zimri, Nitai Kerem, Gabriel R. Linares, Niva Russek-Blum, Justin K. Ichida and Ferenc Tracik
Pharmaceuticals 2025, 18(4), 524; https://doi.org/10.3390/ph18040524 - 3 Apr 2025
Viewed by 476
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the involvement of multiple pathways and mechanisms. The complexity of its pathophysiology is reflected in the diverse hypotheses relating to its underlying causes. Given this intricate interplay of processes, a combination [...] Read more.
Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the involvement of multiple pathways and mechanisms. The complexity of its pathophysiology is reflected in the diverse hypotheses relating to its underlying causes. Given this intricate interplay of processes, a combination therapy approach offers a promising strategy. Combination therapies have demonstrated significant success in treating complex diseases, where they aim to achieve synergistic therapeutic effects and reduce drug dosage. PrimeC is an oral combination treatment composed of a patented novel formulation consisting of specific and unique doses of two well-characterized drugs (ciprofloxacin and celecoxib). It aims to synergistically inhibit the progression of ALS by addressing key elements of its pathophysiology. Objectives: Demonstrating the synergistic effect of the PrimeC combination compared to each of its individual components, celecoxib and ciprofloxacin, and assessing its ability to improve the drug concentration profile and efficacy. Methods: The efficacy of the PrimeC combination was assessed in a survival assay using human induced pluripotent stem cell (iPSC)-derived motor neurons. Additionally, a drug profiling study was conducted, measuring drug levels in the brain and serum of C57BL mice treated with a single compound versus the combination. Results: Motor neurons modeling ALS treated with the PrimeC combination exhibited better survival rates compared to treatment with either individual compound alone. The enhanced efficacy of the combination was further supported by a drug concentration profiling study in rodents, demonstrating that the PrimeC combination resulted in increased ciprofloxacin concentrations in both brain tissue and serum—highlighting the optimized interaction and synergistic potential of its two comprising agents. Conclusions: Our findings support the potential of combination therapy as an effective strategy for ALS treatment. Specifically, the PrimeC combination demonstrated promising therapeutic effects, providing a strong rationale for its ongoing development as a targeted treatment for ALS. Full article
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13 pages, 1865 KiB  
Article
Comprehensive Analysis of Drug-Induced Parkinson-like Events
by Mami Kikegawa, Hideko Sone and Yoshihiro Uesawa
Pharmaceuticals 2024, 17(8), 1099; https://doi.org/10.3390/ph17081099 - 22 Aug 2024
Viewed by 1470
Abstract
Specific drugs are well known to have the capacity to induce Parkinson-like symptoms. Parkinson-like events are side effects that may persist for an extended period even after drug administration is discontinued. Although these events can be triggered by various drugs, the mechanisms underlying [...] Read more.
Specific drugs are well known to have the capacity to induce Parkinson-like symptoms. Parkinson-like events are side effects that may persist for an extended period even after drug administration is discontinued. Although these events can be triggered by various drugs, the mechanisms underlying their diverse symptoms remain largely unclear. To investigate this, we used the Japanese Adverse Drug Event Reporting Database, which is maintained by the Pharmaceuticals and Medical Devices Agency, to analyze the risk factors associated with Parkinson-like events along with the associated drug trends and characteristics. Our findings indicate that similar to Parkinson’s disease, age-related differences affect the onset of these reported events, with older individuals being more susceptible. Hierarchical clustering and principal component analysis revealed that the mechanisms triggering these Parkinson-like events are consistent across reports, suggesting a common underlying cause. However, even with a consistent mechanism, the side effects can vary depending on the site of action. These insights underline the importance of the swift identification of the drugs suspected of causing these events and the implementation of measures to reduce their side effects. Full article
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13 pages, 1306 KiB  
Article
Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer’s Disease Risk: A Retrospective Cohort Proof-of-Concept Study
by Tiffany W. Chow, Mark Raupp, Matthew W. Reynolds, Siying Li, Gwendolyn E. Kaeser and Jerold Chun
Pharmaceuticals 2024, 17(4), 408; https://doi.org/10.3390/ph17040408 - 22 Mar 2024
Cited by 1 | Viewed by 8870
Abstract
Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people [...] Read more.
Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted. Full article
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20 pages, 7352 KiB  
Article
Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer’s Candidates
by Yousaf Khan, Shoaib Khan, Rafaqat Hussain, Wajid Rehman, Aneela Maalik, Urooba Gulshan, Mohamed W. Attwa, Hany W. Darwish, Hazem A. Ghabbour and Nawab Ali
Pharmaceuticals 2023, 16(12), 1667; https://doi.org/10.3390/ph16121667 - 30 Nov 2023
Cited by 11 | Viewed by 1746
Abstract
A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (117) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied [...] Read more.
A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (117) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 117, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure–activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data. Full article
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19 pages, 4350 KiB  
Article
Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan
by Samuel Kakraba, Srinivas Ayyadevara, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Suresh Bowroju, Narsimha Reddy Penthala, Ramani Atluri, Steven W. Barger, Sue T. Griffin, Peter A. Crooks and Robert J. Shmookler Reis
Pharmaceuticals 2023, 16(10), 1498; https://doi.org/10.3390/ph16101498 - 20 Oct 2023
Cited by 3 | Viewed by 3380
Abstract
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, [...] Read more.
Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1–42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15–30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality. Full article
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Review

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37 pages, 1537 KiB  
Review
Overview of Metformin and Neurodegeneration: A Comprehensive Review
by Weronika Kruczkowska, Julia Gałęziewska, Paulina Buczek, Elżbieta Płuciennik, Mateusz Kciuk and Agnieszka Śliwińska
Pharmaceuticals 2025, 18(4), 486; https://doi.org/10.3390/ph18040486 - 28 Mar 2025
Viewed by 1143
Abstract
This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin’s effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions [...] Read more.
This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin’s effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and multiple sclerosis. Key findings demonstrate that metformin’s neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin’s association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases. Full article
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24 pages, 3290 KiB  
Review
Targeting Iron Responsive Elements (IREs) of APP mRNA into Novel Therapeutics to Control the Translation of Amyloid-β Precursor Protein in Alzheimer’s Disease
by Mateen A. Khan
Pharmaceuticals 2024, 17(12), 1669; https://doi.org/10.3390/ph17121669 - 11 Dec 2024
Cited by 2 | Viewed by 1516
Abstract
The hallmark of Alzheimer’s disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the [...] Read more.
The hallmark of Alzheimer’s disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the APP 5′-UTR and may be a target for regulating the production of Alzheimer’s amyloid precursor protein. Since modifying Aβ protein expression can give anti-amyloid efficacy and protective brain iron balance, targeted regulation of amyloid protein synthesis through modulation of 5′-UTR sequence function is a novel method for the prospective therapy of Alzheimer’s disease. Numerous mRNA interference strategies target the 2D RNA structure, even though messenger RNAs like tRNAs and rRNAs can fold into complex, three-dimensional structures, adding even another level of complexity. The IRE family is among the few known 3D mRNA regulatory elements. This review seeks to describe the structural and functional aspects of IREs in transcripts, including that of the amyloid precursor protein, that are relevant to neurodegenerative diseases, including AD. The mRNAs encoding the proteins involved in iron metabolism are controlled by this family of similar base sequences. Like ferritin IRE RNA in their 5′-UTR, iron controls the production of APP in their 5′-UTR. Iron misregulation by iron regulatory proteins (IRPs) can also be investigated and contrasted using measurements of the expression levels of tau production, Aβ, and APP. The development of AD is aided by iron binding to Aβ, which promotes Aβ aggregation. The development of small chemical therapeutics to control IRE-modulated expression of APP is increasingly thought to target messenger RNAs. Thus, IRE-modulated APP expression in AD has important therapeutic implications by targeting mRNA structures. Full article
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17 pages, 921 KiB  
Review
Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases
by Yuxuan Li, Jingxuan Fu and Hui Wang
Pharmaceuticals 2024, 17(11), 1462; https://doi.org/10.3390/ph17111462 - 31 Oct 2024
Cited by 1 | Viewed by 2293
Abstract
Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water [...] Read more.
Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels. Full article
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21 pages, 1019 KiB  
Review
Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies
by Jameel M. Al-Khayri, Mamtha Ravindran, Akshatha Banadka, Chendanda Devaiah Vandana, Kushalva Priya, Praveen Nagella and Kowshik Kukkemane
Pharmaceuticals 2024, 17(10), 1391; https://doi.org/10.3390/ph17101391 - 18 Oct 2024
Cited by 6 | Viewed by 6555
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease’s [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease’s complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies. Full article
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24 pages, 2644 KiB  
Review
Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease
by Pontus Forsell, Cristina Parrado Fernández, Boel Nilsson, Johan Sandin, Gunnar Nordvall and Märta Segerdahl
Pharmaceuticals 2024, 17(8), 997; https://doi.org/10.3390/ph17080997 - 28 Jul 2024
Cited by 2 | Viewed by 3239
Abstract
Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer’s disease has been described. [...] Read more.
Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer’s disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer’s disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function. Full article
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19 pages, 1054 KiB  
Review
Non-Apoptotic Programmed Cell Death as Targets for Diabetic Retinal Neurodegeneration
by Yingjia Lin, Shuping Ke, Weiqing Ye, Biyao Xie and Zijing Huang
Pharmaceuticals 2024, 17(7), 837; https://doi.org/10.3390/ph17070837 - 26 Jun 2024
Cited by 2 | Viewed by 2417
Abstract
Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in [...] Read more.
Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in neurotrophic factors are the key determinants in the pathophysiology of DRN. Non-apoptotic programmed cell death (PCD) plays a crucial role in regulating stress response, inflammation, and disease management. Therapeutic modalities targeting PCD have shown promising potential for mitigating DRN. In this review, we highlight recent advances in identifying the role of various PCD types in DRN, with specific emphasis on necroptosis, pyroptosis, ferroptosis, parthanatos, and the more recently characterized PANoptosis. In addition, the therapeutic agents aimed at the regulation of PCD for addressing DRN are discussed. Full article
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33 pages, 7616 KiB  
Review
Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease
by Yiting Zhao, Man Lin, Fengguang Zhai, Jun Chen and Xiaofeng Jin
Pharmaceuticals 2024, 17(6), 782; https://doi.org/10.3390/ph17060782 - 14 Jun 2024
Cited by 3 | Viewed by 2797
Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin–proteasome system (UPS) plays a crucial role in the [...] Read more.
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin–proteasome system (UPS) plays a crucial role in the initiation and progression of PD. Notably, E3 ubiquitin ligases serve as pivotal components determining substrate specificity within UPS and are intimately associated with the regulation of various proteins implicated in PD pathology. This review comprehensively summarizes the mechanisms by which E3 ubiquitin ligases and deubiquitinating enzymes modulate PD-associated proteins and signaling pathways, while exploring the intricate relationship between UPS dysfunctions and PD etiology. Furthermore, this article discusses recent research advancements regarding inhibitors targeting PD-related E3 ubiquitin ligases. Full article
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18 pages, 1187 KiB  
Review
Innovative Therapeutic Strategies in Alzheimer’s Disease: A Synergistic Approach to Neurodegenerative Disorders
by Sarfaraz K. Niazi, Matthias Magoola and Zamara Mariam
Pharmaceuticals 2024, 17(6), 741; https://doi.org/10.3390/ph17060741 - 6 Jun 2024
Cited by 7 | Viewed by 3524
Abstract
Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a [...] Read more.
Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system’s role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions. Full article
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