CR4056, a powerful analgesic imidazoline‐2 receptor ligand, inhibits the inflammation‐induced PKCε phosphorylation and membrane translocation in sensory neurons

Vellani, Vittorio; Sabatini, Chiara; Milia, Chiara; Caselli, Gianfranco; Lanza, Marika; Letari, Ornella; Rovati, Lucio C.; Giacomoni, Chiara

doi:10.1111/bph.14845

Cited by 8 publications

(11 citation statements)

References 66 publications

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“…More recently, many other apoA-I mimetic peptides have been described [ 45 , 46 ]. For example, an amphipathic peptide called FAMP with a single 24 amino acids helix was developed in Fukuoka University [ 47 ].…”

Section: Apoa-imentioning

confidence: 99%

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Wolska

Reimund

Sviridov

et al. 2021

Cells

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Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.

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Section: Apoa-imentioning

confidence: 99%

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Wolska

Reimund

Sviridov

et al. 2021

Cells

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“…In this respect, concurrent findings show that CR4056 inhibits PKCε translocation in rat sensory neurons (Vellani et al, 2020), a cellular event shared with other analgesics (Vellani & Giacomoni, 2017). As challenging as it has been thus far to identify a common mechanism for the many pharmacological properties of I 2 receptor ligands, PKCε translocation may be an important piece of the puzzle.…”

Section: Discussionmentioning

confidence: 77%

“…PKCε translocation in rat sensory neurons (Vellani et al, 2020), a cellular event shared with other analgesics (Vellani & Giacomoni, 2017).…”

Section: Discussionmentioning

confidence: 99%

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models

Sala

Ferrari²,

Lanza³

et al. 2020

British J Pharmacology

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Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I 2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I 2 receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056-opioid interaction. Experimental Approach: We used the complete Freund's adjuvant (CFA) model in rats to study the effects of treatments on hyperalgesia, morphine tolerance and microglia activation as measured by immunofluorescence. Opioid-induced adverse effects were assessed in rodent models of morphine-induced constipation, sedation (open field, sedation rating scale, and rotarod), physical dependence (naloxoneinduced withdrawal), and abuse (conditioned place preference-associated reward). Chemiluminescence assays tested CR4056 as allosteric modulator of μ-opioid receptors. Key Results: CR4056 (ED 50 = 4.88 mgÁkg −1) and morphine (ED 50 = 2.07 mgÁkg −1) synergized in reducing CFA-induced hyperalgesia (ED 50 = 0.52 mgÁkg −1 ; 1:1 combination). Consistently, low doses of CR4056 (1 mgÁkg −1) spared one third of the cumulative morphine dose administered during 4 days and prevented/reversed the development of tolerance to morphine anti-hyperalgesia. These opioid-sparing effects were associated with decreased activation of microglia, independent of CR4056 interactions on μ-opioid receptors. Importantly, the low doses of CR4056 and morphine that synergize in analgesia did not induce constipation, sedation, physical dependence, or place preference.

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“…The pharmacology of I2IRs is more complex than that of most conventional receptors. Indeed, single agents such as idazoxan could behave as putative antagonist towards most of I2 triggered effects, still maintaining some "agonist activity" on others, as discussed, for instance, by Vellani et al [35]. Therefore, a conventional agonist/antagonist pharmacology on I2 receptors is difficult to perform.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 [35,36] in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. It was recently reported that CR4056 has antiinflammatory properties [35,40] and thus we sought to determine whether treatment with this ligand affected the activation profile of microglia, by assessing changes in the morphology and phagocytic profile in 5xFAD mice. In addition, we further explored the potential beneficial effects of I2IR ligands regulating functions controlled by astrocytes, such as BBB maintenance.…”

Section: Introductionmentioning

confidence: 99%

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

Mota

Ashburner

Abelleira-Hervas

et al. 2022

IJMS

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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-NOur 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.

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CR4056, a powerful analgesic imidazoline‐2 receptor ligand, inhibits the inflammation‐induced PKCε phosphorylation and membrane translocation in sensory neurons

Cited by 8 publications

References 66 publications

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

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