Imidazoline Receptors Research Articles

Assessment of naphazoline effect on erythrocyte superoxide dismutase activity in rats under experimental modeling of acute radiation sickness

Aim to assess the activity of superoxide dismutase in erythrocytes of rats after a single intramuscular injection of naphazoline in radiofrequency dose and in experimental simulation of acute radiation sickness.
 Material and methods. The activity of erythrocytes superoxide dismutase (SOD) after single intramuscular injection of nafazoline in experimental modeling of acute radiation sickness was investigated. The pharmacological properties and mechanisms of radioprotective action of nafazoline were clarified based on the dynamics of activity of erythrocytes SOD in intact and irradiated animals with the dose of 7,4 Gy.
 Results. The superoxide dismutase activity was found to increase significantly 60 min after single intramuscular administration of nafazolin at a dose of 5 mg/kg. Under experimental conditions of acute radiation disease modeling, a decrease in superoxide dismutase activity was observed within the first hour after exposure, evidencing the direct involvement of the antioxidant system components in the inactivation of free-radical reaction products.
 Conclusion. The radioprotective properties of naphazoline may be due not only to reduction of oxygen delivery to the cells of radiosensitive tissues and inhibition of their metabolism by effect on 2-adreno- and imidazoline receptors, but also by activation of antioxidant system links.

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females.

Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor.

Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.

Multi-Regulatory Effects of Agmatine on Akt/GSK-3β/β-Catenin Signaling Pathway in SH-SY5Y cells: A Potential Explanation for its Conflicting Roles in Schizophrenia

Objectives: Schizophrenia is a common psychiatric disease with its complex neurobiology. The current knowledge about the neurobiology of schizophrenia is based on dopaminergic and glutamatergic dysregulation of the central nervous system. The facts that all current antipsychotic drugs act on dopaminergic D2 receptor antagonism and glutamatergic N-Methyl D-Aspartate (NMDA) receptor antagonists reveal schizophrenia-like behavioral and structural alteration in rodents and humans are the major evidences of these hypotheses. However, they are not sufficient to explain the disease neurobiology and lead novel therapeutics. In recent years, it has been shown that the functions of certain intracellular pathways are disrupted in schizophrenia, especially Akt/glycogen synthase kinase 3beta (GSK-3β)/β-catenin signaling pathway. Certain studies showed that GSK-3β inhibition accompanied to the effects of antipsychotic drugs and specific inhibition of the GSK-3β might be a valuable approach for the novel treatments for schizophrenia. Agmatine is an endogenous amine that interacts with many receptors and enzymes including adrenergic, glutamatergic, cholinergic, serotonergic and imidazoline receptors and nitric oxide synthase enzyme. The limited number of studies showed conflicting results about the role of agmatine on schizophrenia and there was no study to evaluate the intracellular molecular mechanisms of agmatine`s schizophrenia-related effects. Herein, we aimed to investigate the effects of agmatine on MK-801 induced neurotoxicity and the disruption of the Akt/GSK-3β/β-catenin signaling pathway in SH-SY5Y human neuroblastoma cells. Methods: SH-SY5Y cells were grouped as the medium, agmatine (50μM), agmatine (100μM), olanzapine (10μM), MK-801 (100μM), MK-801+Agmatine (50μM), MK-801+Agmatine (100μM) and MK-801+Olanzapine (10μM). Real-time cell analysis (RTCA), real-time polymerase chain reaction (Rt-PCR) and western blot (WB) were used for monitoring the cell viabilities, quantifying gene and protein expressions, respectively. Cell viabilities monitored for the 24 hours and comparative viabilities (%) were calculated at the 6th, 12th and 24th hours of treatments. Akt, GSK-3β and β-Catenin gene expressions phosphorylated (p) and non-phosphorylated protein expressions were investigated at the 24th hour of treatments. Results: In RTCA, MK-801 administration decreased cell viabilities at the 6th (p<0.01) and 24th (p<0.001) hours compared to medium in cells. Agmatine (50μM) and agmatine (100μM) pre-treatments increased the cell viabilities at the 6th (p<0.05), 12th (p<0.01), and 24th (p<0.05) hours while olanzapine at 24th (p<0.05) compared to MK-801. In Rt-PCR, MK-801 administration increased GSK-3B decreased CTNNB1 gene expressions (p<0.001) compared to the medium. Agmatine (50μM) and olanzapine reversed (p<0.001) the effects of MK-801 for both gene expressions while agmatine (100μM) reversed (p<0.001) only GSK-3B. In WB, MK-801 administration decreased the p-GSK-3β/GSK-3β ratio compared to medium while only agmatine (50μM) increased the ratio compared to MK-801 administration. Conclusion: Herein, it has been shown that agmatine had a neuroprotective effect on MK-801 induced cell toxicity in SH-SY5Y cells. Our results have suggested a low dose (50μM) agmatine shows antipsychotic like effects on Akt/GSK-3β/β-catenin signaling pathway in SH-SY5Y cells bot, not high dose (100μM). We have suggested that these doses dependent regulatory effects of agmatine might be a possible explanation for its conflicting role in schizophrenia.

Treatment of prolonged clonidine-induced autonomic instability with midodrine: a case report about a new approach or a cautionary tale?

Abstract Background Clonidine is a centrally acting α2 adrenergic and imidazoline-1 receptor agonist that can cause somnolence, bradycardia, and hypotension within several hours of ingestion. Less well-described but observed by us locally is the observation that patients presenting after large overdoses including clonidine can have prolonged autonomic instability. As a result, they may require many days in hospital before recovery. We have previously used midodrine as an indirect antagonist with good effect; however, there are no previous reports of its use for this indication. Case presentation We present the case of a young female patient who developed prolonged autonomic instability following a large overdose of clonidine (coingested with smaller doses of escitalopram + lisdexamfetamine) that was treated with midodrine but complicated by a type 2 non-ST segment elevated myocardial infarction. Conclusion Midodrine seems to ameliorate this protracted instability and may provide a means to decrease hospital length of stay in appropriate individuals.

Moxonidine ameliorates cardiac injury in rats with metabolic syndrome by regulating autophagy

AimsReduced cardiac autophagy, ischemic injury, sympathetic overactivity, and apoptosis all contribute to metabolic syndrome (MetS)-associated cardiovascular risks. NR4A2, an orphan nuclear receptor NR4A family member, induces autophagy while suppressing apoptosis in myocardial infarction. Moxonidine, a sympathoinhibitor imidazoline1 receptor (I1R) agonist, has beneficial metabolic and hemodynamic effects; however, whether autophagy and/or NR4A2 signaling are involved in moxonidine's cardiovascular effects via I1R activation, is unknown, and is the aim of this study. Materials and methodsTo induce MetS, rats were fed 3 % salt in their diet and 10 % fructose in their drinking water for 12 weeks. MetS-rats were given either moxonidine (6 mg/kg/day, gavage), efaroxan (I1R antagonist, 0.6 mg/kg/day, i.p), both treatments, or vehicles for the last two weeks. Blood pressure, lipid profile, and glycemic control were evaluated. Histopathological examination, circulating cardiac troponin I (c-TnI), proinflammatory interleukin-6 (IL-6), apoptosis (active caspase-3 and Fas-immunostaining), interstitial fibrosis [transforming growth factor-β1 (TGF-β1), Mallory's trichrome staining], and extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], were used to assess cardiac pathology. Cardiac NR4A2 and its downstream factor, p53, as well as autophagic flux markers, SQSTM1/p62, LC3, and Beclin-1 were also determined. Key findingsMoxonidine significantly ameliorated MetS-induced metabolic and hemodynamic derangements and the associated cardiac pathology. Moxonidine restored NR4A2 and p53 myocardial levels and enhanced autophagic flux via modulating SQSTM1/p62, LC3, and Beclin-1. Efaroxan reversed the majority of the moxonidine-induced improvements. SignificanceThe current study suggests that autophagy modulation via I1R activation is involved in moxonidine-mediated cardiac beneficial effects in MetS.

Effects of Dexmedetomidine on the Localization of α2A-Adrenergic and Imidazoline Receptors in Mouse Testis

Dexmedetomidine (DEX) used for sedation was reported to have organ-protecting effects in ischemia–reperfusion injury model animals. However, no testicular cell-protecting effect was observed with DEX treatment. The effects of DEX on a normal testis in vivo have not been reported. Therefore, DEX was administered to mice for 14 days to investigate the reproductive toxicology of DEX on the testis and the localization of DEX-responsive receptors. The testes, pituitary glands, and serum were examined and analyzed using real-time PCR, immunofluorescence staining, and liquid chromatography–mass spectrometry. In the testis, α2A-adrenergic receptors were observed in the cytoplasm of Leydig cells, while imidazoline receptors were observed in germ cells and Leydig cell cytoplasm. The levels of luteinizing hormone and follicle-stimulating hormone mRNA in the pituitary gland significantly temporarily decreased. Serum DEX could not be detected 26 h after DEX administration. DEX administration did not affect serum testosterone levels, some testicular mRNA related to spermatogenesis, and oxidative stress factors. Therefore, although DEX receptors are present in the testis, DEX is metabolized relatively quickly, and DEX administration has no damaging effects on the testis. This study is the first in vivo report about the effects of DEX administration on the testis.

Live cell screening identifies glycosides as enhancers of cardiomyocyte cell cycle activity.

Promoting cardiomyocyte proliferation is a promising strategy to regenerate the heart. Yet, so far, it is poorly understood how cardiomyocyte proliferation is regulated, and no factor identified to promote mammalian cardiomyocyte proliferation has been translated into medical practice. Therefore, finding a novel factor will be vital. Here, we established a live cell screening based on mouse embryonic stem cell-derived cardiomyocytes expressing a non-functional human geminin deletion mutant fused to Azami Green (CM7/1-hgem-derived cardiomyocytes). We screened for a subset of compounds of the small molecule library Spectrum Collection and identified 19 potential inducers of stem cell-derived cardiomyocyte proliferation. Furthermore, the pro-proliferative potential of identified candidate compounds was validated in neonatal and adult rat cardiomyocytes as well as human induced pluripotent stem cell-derived cardiomyocytes. 18 of these compounds promoted mitosis and cytokinesis in neonatal rat cardiomyocytes. Among the top four candidates were two cardiac glycosides, peruvoside and convallatoxin, the flavonoid osajin, and the selective α-adrenoceptor antagonist and imidazoline I1 receptor ligand efaroxan hydrochloride. Inhibition of PTEN and GSK-3β enhanced cell cycle re-entry and progression upon stimulation with cardiac glycosides and osajin, while inhibition of IP3 receptors inhibited the cell cycle-promoting effect of cardiac glycosides. Collectively, we established a screening system and identified potential compounds to promote cardiomyocyte proliferation. Our data suggest that modulation of calcium handling and metabolism promotes cardiomyocyte proliferation, and cardiac glycosides might, besides increasing myocardial contraction force, contribute to cardiac repair by inducing cardiomyocyte proliferation.

Over-Prescription of the Imidazoline Receptor Agonists: Evidence for Restriction of the Therapeutic Indication

Major antihypertensive drug classes (but not Imidazoline Receptor Agonists) have been demonstrated to reduce cardiovascular morbidity and mortality. In 2017, Latvia and Lithuania had the highest cardiovascular mortality among the Eastern, Central, Northern, and Western Member States of the European Union (EU). Cardiovascular mortality in Estonia is much lower than in Lithuania and Latvia. To evaluate the consumption of Imidazoline Receptor Agonists in the Baltic States and its potential implications. The study included data on the sales of Imidazoline Receptor Agonists in Lithuania, Latvia, and Estonia; the marketing authorization databases of the competent authorities; the guidelines on the treatment of hypertension, and the reimbursement conditions. The study showed a very high consumption of the Imidazoline Receptor Agonists in Lithuania and Latvia. From 2016 to 2019, the average consumption of Imidazoline Receptor Agonists in Lithuania was 15.5 times higher than in Estonia; in Latvia, it was 8.9 times higher than in Estonia. The guidelines recommend the use of the Imidazoline Receptors Agonists as one of the last options in hypertension therapy, but the marketing authorizations do not restrict their line of therapy. Consumption of IRAs in Lithuania and Latvia is very high. The authorized use of the IRAs in the EU Member States is not in line with the guidelines on the management of arterial hypertension and therefore patients might be deprived of therapies that reduce the cardiovascular risk. The drug regulatory authorities of the EU should review the data on the safety and efficacy of the IRAs and restrict their therapeutic indications if necessary.

IRAS/Nischarin modulates morphine reward by glutamate receptor activation in the nucleus accumbens of mouse brain

The I1 imidazoline receptor and its candidate protein imidazoline receptor antisera-selected (IRAS)/Nischarin are linked to μ opioid receptor (MOR) functions associated with MOR trafficking. We previously demonstrated that IRAS may play an important role in the development of morphine tolerance and physical dependence in vivo. However, the effects of IRAS on morphine psychological dependence are not fully understood. To extend these studies, we investigated the impact of IRAS on morphine dependence in conditioned place preference (CPP) experiments and explored the underlying mechanisms. Knockout of IRAS enhanced the acquisition and reinstatement of morphine-induced CPP. Conditional-knockout of IRAS in the nucleus accumbens (NAc) reproduced higher CPP, and overexpression of IRAS in the NAc rescued the increased morphine-induced CPP in IRAS-/- mice. IRAS-/- mice showed dramatic cAMP-dependent protein kinase (PKA) activation, upregulation of the phosphorylation of the AMPA receptor GluR1-S845 and NMDA receptor NR1-S897 in the NAc after CPP experiment. Moreover, knockout of IRAS induced an increase in spontaneous excitatory postsynaptic current (sEPSC) frequency and a decrease in the AMPA/NMDA ratio in the NAc after chronic morphine treatment. The selective AMPA receptor antagonist NBQX could inhibit morphine CPP in WT mice, while its effect was significantly reduced in IRAS-/- mice. Together, our results demonstrate that IRAS contributes to the regulation of morphine dependence and that the alteration of glutamatergic transmission in the NAc may participate in the effect of IRAS.

Retention mechanisms of imidazoline and piperazine-related compounds in non-aqueous hydrophilic interaction and supercritical fluid chromatography based on chemometric design and analysis

The experimental design methodology based on central composite design of experiments was applied to compare the retention mechanisms in supercritical fluid chromatography (SFC) and non-aqueous hydrophilic interaction liquid chromatography (NA-HILIC). The selected set consists of 26 compounds that belong to imidazoline and serotonin receptor ligands. The different chemometric tools (multiple linear regression, principal component analysis, parallel factor analysis) were used to examine the retention, as well as to identify the most significant retention mechanisms. The retention mechanism was investigated on two different stationary phases (diol, and mixed-mode diol). In NA-HILIC, the mobile phase contains acetonitrile as a main component, and methanolic solution of ammonium formate (+ 0.1% of formic acid) as a modifier. The same mobile phase modifier was used in SFC, with a difference in the main component of the mobile phase which was CO2.The retention behaviour differs significantly between HILIC and SFC conditions. The retention pattern in HILIC mode was more partition-like, while in SFC the solute-sorbent interactions allowed retention. The retention mechanism between mixed-mode diol and the diol phases varies depending on the applied chromatographic mode, e.g., in HILIC the type of stationary phase significantly affects the elution order, while in SFC this was not the case. The HILIC retention behaviour was influenced by the number of tertiary amines-aliphatic, and N atom-centred fragments in tested compounds. On the other hand, the number of pyrrole and pyridine rings in the structure of the compound showed correlation with their SFC retention, simultaneously increasing the molecular weight and rapid elution of larger compounds. It was found that temperature surprisingly plays a major role in SFC mode. The increase in temperature reduces the relative contribution of enthalpy factors to total retention, so the separation in SFC was more entropy-controlled. For further pharmaceutical research and optimization, the SFC would be considered more beneficial compared to HILIC since it gives good selectivity in separation of chosen impurities.

Abstract 3463: Nischarin agonist rilmenidine inhibits pancreatic ductal adenocarcinoma cell migration and invasion

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy due to the lack of early diagnosis and limited response to all treatment modalities. Early metastatic dissemination, rich desmoplastic stroma and immunosuppressive infiltrate are some of the features contributing to the poor prognosis of PDAC patients (5-year survival rate of less than 10%). Despite scientific progress in the development of new therapeutic regimes, PDAC patients in low- and middle-income countries have restricted access to high-cost innovative drugs. Recently, attention has been given to the concept of drug repurposing that could meet the need for novel but affordable and widely accessible therapies. Imidazoline receptor 1 Nischarin (NISCH, IR1, IRAS) is an integrin α5-interacting protein that acts as a tumor suppressor in breast cancer through modulation of cancer cell motility and survival. Importantly, NISCH has several clinically approved agonists that are used for the treatment of hypertension and are shown to modulate autophagy and reduce inflammation and fibrosis, which makes NISCH a potentially good therapeutic target for defying PDAC progression. Based on our GSEA analysis of NISCH expression in PDAC patient samples, NISCH was predicted to have an effect on cancer cell focal adhesion assembly and cytoskeletal organization. Therefore, we examined the effects of NISCH agonists on PDAC cells fitness in vitro. A panel of PDAC cell lines was tested in MTT assay to determine the effects of NISCH agonists rilmenidine, clonidine and moxonidine on cell viability. Flow cytometry, western blot and immunofluorescence were used to examine the effects of NISCH agonists on PDAC cell metabolism, migration and cytoskeletal organization. Tg(fli1:EGFP) zebrafish model was used to examine the effects of NISCH agonists on PDAC cell growth and invasion. We found that NISCH was expressed in PDAC cell lines, and that out of the three tested agonists, rilmenidine most potently inhibited cancer cell viability. Treatment with rilmenidine significantly reduced PANC-1, MIA PaCa-2 and BxPC-3 cell attachment to extracellular matrix (collagen type I and fibronectin) and migratory potential in wound healing and transwell assays. Furthermore, treatment with rilmenidine altered the organization of actin cytoskeleton and focal adhesion assembly, potentially through the reduction of intracellular reactive oxygen species (ROS) levels. Importantly, treatment with rilmenidine inhibited invasion of PANC-1 cells in Tg(fli1:EGFP) zebrafish model. With these antimigratory and potentially antimetastatic effects of rilmenidine, our study lays the ground for a more extensive examination of the biological role of NISCH in PDAC progression and implies that its agonists may be good candidates for drug repurposing in this type of cancer. Citation Format: Marijana Pavlovic, Marija Ostojic, Kristina Zivic, Aleksandar Pavic, Tatjana Srdic-Rajic, Jelena Grahovac. Nischarin agonist rilmenidine inhibits pancreatic ductal adenocarcinoma cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3463.

Abstract 4101: ADRENALINE, an atlas for drug and breast cancer survival interaction: Comedications at diagnosis and impact on breast cancer mortality of the French breast cancer cohort (n=235,375)

Abstract Background: Breast cancer (BC) incidence increases with age, as well as the incidence of many other chronic diseases. Between 42 and 68% of BC patients suffer from other chronic conditions -comorbidities- at BC diagnosis. Comorbidities may be associated with the intake of chronic medications -comedications. The French health insurance system routinely collects health care reimbursements of almost 98% of the population: hospital abstracts, long-term diseases, outpatient care (medical consults, drug purchases under prescription⋯) and death status. The project ADRENALINE (Atlas for DRug and brEast caNcer survivAL INtEraction) analyzes the impact of comedications at diagnosis on BC survival on a French cohort using data from the French social security system. Methods: We identified all women diagnosed with an incident BC treated with surgery in France from 2011 to 2017 and affiliated to the general health insurance scheme. Women with concomitant cancer or metastases at diagnosis were discarded from the analyses. Comedication intake was defined as the delivery in pharmacy of at least 3 months of full treatment (e.g. 90 pills) the 6 months preceding BC diagnosis. The analysis was restricted to drugs taken by at least 300 women. A Cox proportional hazard model was used to estimate the hazard ratio (HR) for each molecule. The model was adjusted on more than 100 confounding variables: social factors, comorbidities and other comedications. Two adjustment methods were tested: Inverse Probability of Treatment Weighting (IPTW) and matching. We assumed that the adjustment was sufficient to control for confounding if the standardized mean difference of each confounder after adjustment did not exceed 0.1. Molecules which did not pass the adjustment quality test were discarded. Results: 235,375 patients were included in the study. Among 219 selected drugs, 91 and 171 passed the adjustment quality test for IPTW and for matching, respectively. The full set of results is available on a web application. Among main findings, several drugs or drug classes were associated with an improved survival: proton-pump inhibitors (IPTW; HR=0.93; p=0.002); statins (e.g. rosuvastatin, IPTW, HR=0.65, p<0.001); beta-blocking agents (atenolol, IPTW, HR=0.78, p=0.003); alverine (IPTW, HR=0.78, p<0.001). Conversely, imidazoline receptor agonists may be deleterious (moxonidine; matching; HR=2.12; p = 0.001). Conclusion: ADRENALINE reports the impact on BC survival of 219 widely prescribed drugs. It can be used to identify molecules with a potential protective or deleterious effect relative to BC. Some of them are currently under mechanistical investigation within a drug screening program. This atlas highlights candidates to drug-repurposing trials or pharmacovigilance warnings, and will be extended to cancers of other localizations in a near future. Citation Format: Elise Dumas, Beatriz Grandal, Lucie Laot, Eric Daoud, Lidia Delrieu, Marc Espié, Sophie Houzard, Christine Le Bihan-Benjamin, Philippe-Jean Bousquet, Elodie Anthony, Aurélien Latouche, Nadir Sella, Thierry Dubois, Annabelle Ballesta, Amyn Kassara, Elaine Del Nery, Benjamin Marande, Samar Alsafadi, Paul Gougis, Chloé-Agathe Azencott, Fabien Reyal, Anne-Sophie Hamy. ADRENALINE, an atlas for drug and breast cancer survival interaction: Comedications at diagnosis and impact on breast cancer mortality of the French breast cancer cohort (n=235,375) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4101.

Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems

Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems

EFFECT OF CORONAVIRUS INFECTION ON PATIENTS WITH CONTROLLED AND UNCONTROLLED ARTERIAL HYPERTENSION

Objective: To assess the severity of coronavirus infection in patients with hypertension, including resistantand refractory hypertension, and to assess the effect of taking ACE inhibitors and ARBs on the course of COVID-19. Design and method: We called 252 people with an established diagnosis of hypertension, included in the database from November 2018 to July 2021, in order to identify patients who have recently undergone COVID-19. Initially, the patients were divided into groups depending on the number of drugs taken and the achievement of target blood pressure levels. Results: 21 (8.3%) of 252 people had a coronavirus infection. 10 out of 21 patients (48%) noted blood pressure destabilization. 6 (60%) of these 10 initially belonged to the group of uncontrolled hypertension (4 of 6 had refractory hypertension, 2 of 6 had uncontrolled resistant hypertension), however, all of them noted worsening blood pressure control and increased frequency of hypertensive crises compared with the period before COVID-19. In 4 out of 9 patients with initially controlled hypertension, BP was destabilized with subsequent normalization of BP during the recovery period. COVID-19 lasted no more than 14 days in all patients and hypertensive crises was treated by taking short-acting drugs, including an ACE inhibitor (Captopril) and an imidazoline receptor agonist (Moxonidine). 7 (33.3%) and 12 (57.1%) of 21 patients continued to take ACE inhibitors and ARBs, respectively, during coronavirus infection. In 2 (9.6%) of 21 patients, the target BP values were achieved during monotherapy with calcium channel antagonists. All patients with Covid-19 had mild or moderate disease; hospitalization was not required in any of the cases. Conclusions: COVID-19 can destabilize blood pressure in patients with hypertension. Taking an ACE inhibitor / ARB does not worsen the course of coronavirus infection in patients with both controlled and uncontrolled hypertension.

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging.

Imidazoline receptors (IR) are classified into three receptor subtypes (I1R, I2R, and I3R) and previous studies showed that regulation of I2R signaling has neuroprotective potential. In order to know if I2R has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized I2R ligands, diethyl (1RS,3aSR,6aSR)-5-(3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1-phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-months-old) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension. In young mice of both strains, MCR5 induced greater relaxations than either B06 or the high-affinity I2R selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evoked marginal responses. MCR5 relaxations were independent of I2R, as IR ligands did not significantly affect them, involved activation of smooth muscle KATP channels and inhibition of L-type voltage-gated Ca2+ channels, and were only slightly modulated by endothelium-derived nitric oxide (negatively) and prostacyclin (positively). Notably, despite the presence of endothelial dysfunction in old mice, MCR5 relaxations were preserved. In conclusion, the present study provides evidence against a functional contribution of I2R in the modulation of vascular tone in the mouse aorta. Moreover, the I2R ligand MCR5 is an endothelium-independent vasodilator that acts largely via I2R-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly.

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06.

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.

Modulation of sympathetic nervous system activity through various therapeutic approaches in patients with resistant hypertension and heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Agency for Research and Development Purpose The increased activity of the sympathetic nervous system is the pathophysiological key of several pathologies, such as hypertension, heart failure, diabetes, etc., the modulation of its activity can improve the management of these diseases and represents an increased scientific interest. Aim Comparatively evaluation of the effects of modulating SNS activity at different levels through various therapeutic approaches on the NYHA functional class of heart failure and physical capacity to exercise in patients with resistant hypertension. Material and method 75 patients with resistant hypertension and heart failure with the preserved ejection fraction were enrolled in the study. All patients for 21 days underwent standardized ambulatory treatment with Losartan 100 mg, Amlodipine 10 mg and Indapamide 1.5 mg, and were subsequently randomized into three equal groups of 25 patients according to treatment supplemented to the previous treatment: group I M - Moxonidine, group II B - Bisoprolol and group III D – renal denervation. Patients were evaluated clinically, echocardiographically and by the 6-minute walking test at baseline, 3 and 6 months. Results The clinical improvement of NYHA class was confirmed by the progressive increase of the distance traveled in the 6 minute walk test. Thus, the groups being comparable according to the distance traveled at the enrollment stage in the study, noted a statistically authentic dynamic starting with 3 months of continuous medication constituting 392.48 ± 14.88 m in the I M group (+ 20.45% from initial values ) versus 359.84 ± 15.15 m in group II B (+ 15.0% of initial values) and 386.08 ± 11.99 m in group III D (+ 24.33% of initial values), p> 0.05. The increase of the distance traveled continued until 6 months of evaluation in all three observation lots with the following values: 416.12 ± 13.50 m (+ 25.06% from the initial) versus 387.80 ± 12.85 m (+ 21.55% from the initial) and 424.28 ± 10.30 m (+ 31.06% from the initial) in lots I M, II B and III D, respectively. Comparative analysis of the dynamics between groups showed a comparable beneficial effect in improving the distance traveled in the 6 minute walk test in groups of patients treated with Moxonidine and Bisoprolol and the superiority of minimally invasive renal denervation treatment over drug treatment, an event notable starting with 3 months of evaluation and maintained until the end of the supervision period. Conclusions Blockade of the sympathetic nervous system at the central level with the selective imidazoline receptor agonist I1 Moxonidine, at the peripheral level by administration of the β1-cardioselective adrenoblocker Bisoprolol or by the minimally invasive method of renal artery denervation resulted in progresive amelioration of NYHA class and increasing physical capacity to exercise, the pharmacological treatment groups showing a comparable effect, but lower than the group of patients undergoing renal denervation.

The non-adrenergic imidazoline-1 receptor protein nischarin is a key regulator of astrocyte glutamate uptake

SummaryAstrocytic GLT-1 is the main glutamate transporter involved in glutamate buffering in the brain, pivotal for glutamate removal at excitatory synapses to terminate neurotransmission and for preventing excitotoxicity. We show here that the surface expression and function of GLT-1 can be rapidly modulated through the interaction of its N-terminus with the nonadrenergic imidazoline-1 receptor protein, Nischarin. The phox domain of Nischarin is critical for interaction and internalization of surface GLT-1. Using live super-resolution imaging, we found that glutamate accelerated Nischarin-GLT-1 internalization into endosomal structures. The surface GLT-1 level increased in Nischarin knockout astrocytes, and this correlated with a significant increase in transporter uptake current. In addition, Nischarin knockout in astrocytes is neuroprotective against glutamate excitotoxicity. These data provide new molecular insights into regulation of GLT-1 surface level and function and suggest new drug targets for the treatment of neurological disorders.

Place of imidazoline receptor agonists in the treatment of hypertension

The review is devoted to selective I1-imidazoline-receptor agonists. An analysis of Russian and foreign studies is presented, the results of which indicate that this drug class not only provides adequate and long-term control of blood pressure, but also has a number of favorable metabolic effects. Therefore, it contributes to reducing insulin resistance (weight loss) and has organ protective properties (endothelial function improvement, left ventricular hypertrophy regression, microalbuminuria reduction). At the same time, selective I1-imidazoline-receptor agonists are much less likely to cause side effects characteristic of old-generation sympatholytic agents. This class of drugs is invariably included in Russian guidelines for the diagnosis and treatment of hypertension.