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Pharmaceuticals
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Pharmacotherapy for Alzheimer’s Disease
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Pharmacotherapy for Alzheimer’s Disease

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

Deadline for manuscript submissions: 5 October 2025 | Viewed by 3604

Special Issue Editor

Dr. Gabriela Dumitrița Stanciu

E-Mail Website1 Website2
Guest Editor
Advanced Research and Development Center for Experimental Medicine “Prof. Ostin C. Mungiu”, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, Iasi, Romania
Interests: neuroscience; Alzheimer’s disease; in vivo studies; drug development; cannabinoid-based pharmaceuticals; repurposing current therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A large body of studies highlight that Alzheimer’s disease (AD), described as a complex neurodegenerative disorder with a multilayered nature leading to a progressive decline in cognitive function and irreversible neuronal loss, continues to present a significant and escalating challenge to global health. As the frequency of cases rises and conventional pharmaceutical treatments, which primarily alleviate symptoms and come with numerous side effects, continue to exhibit a high rate of ineffectiveness, there arises a pressing demand for alternative approaches. Despite extensive knowledge on the molecular basis of AD, advancements in developing therapies that truly modify the progression of the disease have proven to be elusive. The ability of the editing system tools, repurposing current therapeutics or utilizing multi-target-directed ligands, presents a promising opportunity to elucidate the fundamental mechanisms driving AD pathogenesis and to discover new therapeutic pathways. This strategy has the potential to facilitate the identification of target molecules and the development of innovative preclinical disease models, thus providing hopeful prospects for therapeutic intervention.

Authors are invited to submit original research and review articles highlighting recent findings in the pharmacotherapy of Alzheimer’s disease. These includes, but are not limited to, novel molecular mechanisms and potential therapeutic targets, developing or repurposing drugs with the ability to target multiple disease features or exploring the risks and benefits of cannabinoid-based drugs.

Dr. Gabriela Dumitrița Stanciu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • pharmacotherapy
  • therapeutic editing tools
  • repurposing existing therapeutics
  • multi-target-directed ligands
  • preclinical studies
  • neurodegeneration
  • drug development
  • neuroprotection
  • cannabinoid-based pharmaceuticals
  • single-molecule drugs or whole-plant extracts of Cannabis sativa L.

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Published Papers (3 papers)

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Research

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17 pages, 3728 KiB  
Article
Further In Vitro and Ex Vivo Pharmacological and Kinetic Characterizations of CCF219B: A Positive Allosteric Modulator of the α1A-Adrenergic Receptor
by Robert S. Papay and Dianne M. Perez
Pharmaceuticals 2025, 18(4), 476; https://doi.org/10.3390/ph18040476 - 27 Mar 2025
Viewed by 298
Abstract
Background: Alterations in the adrenergic system have been associated with the pathophysiology of Alzheimer’s disease (AD). A novel α1A-adrenergic receptor (AR)-positive allosteric modulator (PAM), CCF219B, has been shown to outperform donepezil with rescue of AD cognition/memory deficits with a reduction in [...] Read more.
Background: Alterations in the adrenergic system have been associated with the pathophysiology of Alzheimer’s disease (AD). A novel α1A-adrenergic receptor (AR)-positive allosteric modulator (PAM), CCF219B, has been shown to outperform donepezil with rescue of AD cognition/memory deficits with a reduction in amyloid biomarkers and without cardiovascular side effects. Initial pharmacological analysis in transfected cell lines revealed a signal bias with increased efficacy (but not potency) of cAMP signaling and ligand selectivity for norepinephrine (NE). As most GPCR allosteric modulators change the potency of agonists, we hypothesized and now report that CCF219B induced additional aspects of its allosteric interactions with NE that may provide mechanistic insight. Methods: Using Rat-1 fibroblasts stably transfected with α1A-AR, we determined the activation profile of pERK and p38 messengers by CCF219B in the presence of NE. Using membranes prepared from the stably transfected fibroblasts or from the brain of WT mice or the AD mouse model, hAPP(lon), equilibrium or kinetic radioligand-binding analyses were performed. Results: We identified p-ERK1/2 but not p38 as an additional signal pathway that is potentiated by CCF219B in the presence of NE. An analysis of binding studies of CCF219B in membranes derived from the brains of WT or hAPP(lon) mice revealed profiles that were time-dependent and resulted in an increase in α1A-AR expression that was unaltered in the presence of cycloheximide or when performed at 37 °C. hAPP(lon) mice displayed a reduction in α1A-AR-binding sites that were rescued upon prolonged incubation with CCF219B but also displayed a compensatory increase in α1B/D-AR subtype expression. Binding kinetics reveal that CCF219B can decrease the association rate of 3H-NE but only in the presence of GTP. The association rate increased for the radiolabeled antagonist, 125I-HEAT. There were no changes in the dissociation rate of either radiolabel. Conclusions: CCF219B affects the association but not the dissociation rate of NE and explains its ability to increase the active state of the receptor by promoting a pre-coupled conformation, consistent with increasing efficacy but not potency. Potentiation of pERK may contribute to CCF219B’s ability to confer neuroprotection and be pro-cognitive in AD. CCF219B’s ability to increase the expression of α1A-AR provides a positive feedback loop and strengthens the hypothesis that α1-AR subtypes may be involved in AD etiology and/or progression. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease)
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17 pages, 4701 KiB  
Article
Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment
by Gabriela Dumitrita Stanciu, Daniela-Carmen Ababei, Carmen Solcan, Cristina-Mariana Uritu, Vlad-Constantin Craciun, Cosmin-Vasilica Pricope, Andrei Szilagyi and Bogdan-Ionel Tamba
Pharmaceuticals 2024, 17(4), 530; https://doi.org/10.3390/ph17040530 - 19 Apr 2024
Cited by 1 | Viewed by 2182
Abstract
Despite decades of rigorous research and numerous clinical trials, Alzheimer’s disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory [...] Read more.
Despite decades of rigorous research and numerous clinical trials, Alzheimer’s disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease)
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Review

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12 pages, 1044 KiB  
Review
A Review of the Clinical Progress of CT1812, a Novel Sigma-2 Receptor Antagonist for the Treatment of Alzheimer’s Disease
by Sara R. Steinfield, Daniel F. Stenn, Helen Chen and Bettina E. Kalisch
Pharmaceuticals 2025, 18(5), 659; https://doi.org/10.3390/ph18050659 - 30 Apr 2025
Viewed by 306
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease marked by the accumulation of toxic amyloid-beta (Aβ) oligomers. These oligomers are thought to cause synaptic dysfunction and contribute to neurodegeneration. CT1812 is a small-molecule sigma-2 receptor antagonist that is currently being investigated and tested as [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease marked by the accumulation of toxic amyloid-beta (Aβ) oligomers. These oligomers are thought to cause synaptic dysfunction and contribute to neurodegeneration. CT1812 is a small-molecule sigma-2 receptor antagonist that is currently being investigated and tested as a potential disease-modifying treatment for AD. CT1812 acts by displacing Aβ oligomers into the cerebrospinal fluid and preventing their interaction with receptors on neurons. Preclinical studies and early clinical trials of CT1812 show promising results and provide evidence for its potential to slow AD progression. This review outlines the role of Aβ oligomers in AD, CT1812’s mechanism of action, and the effectiveness and limitations of CT1812 based on preclinical and clinical studies. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease)
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