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Imidazoline Receptors in Diseases of the CNS
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Imidazoline Receptors in Diseases of the CNS

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 (25 January 2022) | Viewed by 5437

Special Issue Editor

Prof. Dr. Magdalena Sastre

E-Mail Website
Guest Editor
Department of Brain Sciences, ‎Imperial College London, London, UK
Interests: Alzheimer’s disease; neurodegeneration; neuroinflammation; glia; traumatic brain injury; amyloid; astrocytes; microglia

Special Issue Information

Dear Colleagues,

Imidazoline receptors (IRs) were identified in the 90’s following the observations that some radioligands for α2-adrenoceptors with an imidazoline structure, such as [3H]idazoxan and [3H]clonidine also recognized different entities in various tissues, including the brain. Several subtypes were defined according to the affinity for certain ligands, including I1Rs (with high affinity for clonidine) and I2Rs (high affinity for idazoxan). In the CNS, imidazoline receptors, in particular I2IRs have been linked to in a number of psychiatric and neurodegenerative conditions including depression, addiction, pain, Parkinson's disease, Alzheimer’s disease (AD) and Huntington's Chorea. In spite of the great interest in the IRs during the 90’s, only recently has been a renewed enthusiasm for these receptors, due to the neuroprotective effect  of imidazoline ligands in neurological diseases such as AD and the ability of certain imidazoline tracers to be used as markers for astrocytes. This Special Issue will be dedicated to the study of imidazoline ligands in the CNS, in particular the impact on therapeutics and diagnosis for neurodegenerative, neurological and psychiatric disorders.

Prof. Dr. Magdalena Sastre
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • imidazoline ligands
  • neurodegeneration
  • neuroinflammation
  • psychiatric disorders
  • pain

Published Papers (3 papers)

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Research

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17 pages, 8275 KiB  
Article
I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
by Bibiana C. Mota, Nathan Ashburner, Laura Abelleira-Hervas, Liyueyue Liu, Robertas Aleksynas, Lucio Claudio Rovati, Gianfranco Caselli and Magdalena Sastre
Int. J. Mol. Sci. 2022, 23(13), 7320; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137320 - 30 Jun 2022
Cited by 6 | Viewed by 1884
Abstract
Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β [...] Read more.
Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD. Full article
(This article belongs to the Special Issue Imidazoline Receptors in Diseases of the CNS)
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21 pages, 2102 KiB  
Article
Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06
by Andrea Bagán, José A. Morales-García, Christian Griñán-Ferré, Caridad Díaz, José Pérez del Palacio, Maria C. Ramos, Francisca Vicente, Belén Pérez, José Brea, María Isabel Loza, Mercè Pallàs and Carmen Escolano
Int. J. Mol. Sci. 2022, 23(10), 5408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105408 - 12 May 2022
Cited by 3 | Viewed by 1998
Abstract
The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2-IR) that are widely distributed in the brain and [...] Read more.
The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2-IR as a fresh approach for the therapy of ND. Full article
(This article belongs to the Special Issue Imidazoline Receptors in Diseases of the CNS)
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Review

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15 pages, 2026 KiB  
Review
Imidazoline-I2 PET Tracers in Neuroimaging
by Christine A. Parker, David J. Nutt and Robin J. Tyacke
Int. J. Mol. Sci. 2023, 24(12), 9787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129787 - 06 Jun 2023
Cited by 2 | Viewed by 1075
Abstract
Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such [...] Read more.
Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline2 binding site (I2BS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease. Five PET tracers for the I2BS are described in this review, with only one (11C-BU99008) being currently validated to GMP for clinical use, and data reported from healthy volunteers, Alzheimer’s disease patients, and Parkinson’s disease patients. The clinical data utilising 11C-BU99008 have revealed the potential early involvement of astrogliosis in neurodegeneration that might precede the activation of microglia, which, if confirmed, could provide a vital new means for potentially targeting neurodegeneration earlier in the disease course. Full article
(This article belongs to the Special Issue Imidazoline Receptors in Diseases of the CNS)
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