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Drug Delivery to the Central Nervous System: From Design, Synthesis, and Evaluation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 May 2025) | Viewed by 8030

Special Issue Editor

Dr. Masaru Tanaka

E-Mail Website
Guest Editor
Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
Interests: depression; anxiety; dementia pain; and their comorbidities nature; and translational research in neurological diseases and psychiatric disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The central nervous system (CNS) is the most mysterious and fascinating organ system in the human body responsible for regulating a myriad of vital functions and enabling higher cognitive processes. However, the CNS is also highly vulnerable to various disorders that can impair its normal functioning and affect the quality of life of millions of people around the world. Developing effective treatments for these disorders is a daunting task, as most drugs cannot reach the CNS due to the presence of formidable barriers that protect it from harmful substances. These barriers, namely the blood–brain barrier and the blood–cerebrospinal fluid barrier, are selective and tightly regulated, allowing only certain molecules to cross into the CNS.

This Special Issue aims to shed light on the challenges and opportunities in drug design and delivery for the CNS, showcasing innovative strategies and novel materials that can overcome these barriers and deliver drugs to their desired targets with precision and control. This Special Issue covers a wide range of topics, from understanding the mechanisms and dynamics of the barriers, to designing and synthesizing new drugs and carriers, to evaluating their safety and efficacy in preclinical and clinical studies. The ultimate goal is to unravel the secrets of the CNS and enable transformative therapies that can cure or alleviate the symptoms of neurological and neuropsychiatric disorders. We invite you to join us on this exciting journey to explore the borders of drug delivery for the CNS and discover new ways to improve the health and well-being of patients suffering from these debilitating conditions. We welcome original research and comprehensive review articles that contribute to advancing knowledge and practice in this emerging field.

Dr. Masaru Tanaka
Guest Editor

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Keywords

  • central nervous system
  • central nervous system diseases
  • drug delivery systems
  • blood–brain barrier
  • blood–cerebrospinal fluid barrier
  • drug design
  • nanomedicine
  • neuropharmacology
  • neuroprotective agents
  • biomarkers

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Published Papers (3 papers)

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16 pages, 5662 KiB  
Article
Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia
by Sungeun Chung, Yujong Yi, Irfan Ullah, Kunho Chung, Seongjun Park, Jaeyeoung Lim, Chaeyeon Kim, Seon-Hong Pyun, Minkyung Kim, Dokyoung Kim, Minhyung Lee, Taiyoun Rhim and Sang-Kyung Lee
Int. J. Mol. Sci. 2024, 25(1), 661; https://doi.org/10.3390/ijms25010661 - 4 Jan 2024
Cited by 6 | Viewed by 3024
Abstract
Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. [...] Read more.
Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders. Full article
(This article belongs to the Special Issue Drug Delivery to the Central Nervous System: From Design, Synthesis, and Evaluation)
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Review

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33 pages, 1176 KiB  
Review
GLP-1 Analogues in the Neurobiology of Addiction: Translational Insights and Therapeutic Perspectives
by Juan David Marquez-Meneses, Santiago Arturo Olaya-Bonilla, Samuel Barrera-Carreño, Lucía Catalina Tibaduiza-Arévalo, Sara Forero-Cárdenas, Liliana Carrillo-Vaca, Luis Carlos Rojas-Rodríguez, Carlos Alberto Calderon-Ospina and Jesús Rodríguez-Quintana
Int. J. Mol. Sci. 2025, 26(11), 5338; https://doi.org/10.3390/ijms26115338 (registering DOI) - 1 Jun 2025
Abstract
Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction [...] Read more.
Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment. Full article
(This article belongs to the Special Issue Drug Delivery to the Central Nervous System: From Design, Synthesis, and Evaluation)
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25 pages, 1553 KiB  
Review
The Glycocalyx: The Importance of Sugar Coating the Blood-Brain Barrier
by Candis Dancy, Kaitlyn E. Heintzelman and Moriah E. Katt
Int. J. Mol. Sci. 2024, 25(15), 8404; https://doi.org/10.3390/ijms25158404 - 1 Aug 2024
Cited by 4 | Viewed by 3800
Abstract
The endothelial glycocalyx (GCX), located on the luminal surface of vascular endothelial cells, is composed of glycoproteins, proteoglycans, and glycosaminoglycans. It plays a pivotal role in maintaining blood–brain barrier (BBB) integrity and vascular health within the central nervous system (CNS), influencing critical processes [...] Read more.
The endothelial glycocalyx (GCX), located on the luminal surface of vascular endothelial cells, is composed of glycoproteins, proteoglycans, and glycosaminoglycans. It plays a pivotal role in maintaining blood–brain barrier (BBB) integrity and vascular health within the central nervous system (CNS), influencing critical processes such as blood flow regulation, inflammation modulation, and vascular permeability. While the GCX is ubiquitously expressed on the surface of every cell in the body, the GCX at the BBB is highly specialized, with a distinct composition of glycans, physical structure, and surface charge when compared to GCX elsewhere in the body. There is evidence that the GCX at the BBB is disrupted and partially shed in many diseases that impact the CNS. Despite this, the GCX has yet to be a major focus of therapeutic targeting for CNS diseases. This review examines diverse model systems used in cerebrovascular GCX-related research, emphasizing the importance of selecting appropriate models to ensure clinical relevance and translational potential. This review aims to highlight the importance of the GCX in disease and how targeting the GCX at the BBB specifically may be an effective approach for brain specific targeting for therapeutics. Full article
(This article belongs to the Special Issue Drug Delivery to the Central Nervous System: From Design, Synthesis, and Evaluation)
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