Imidazoline Receptors Research Articles

Medically induced bradycardia in the elderly and senile patients

Abstract Background Elderly and senile people are most likely to develop cardiovascular diseases, while they have a higher risk of adverse drug reactions. Systemic analysis of medically induced bradycardia (MIB) has not been performed. Aim To analyze the clinical features of MIB in patients ≥65 and ≥75 years according to the Hospital Register of Cardiac Drug Overdoses (storm) data. Materials and methods Analyzed 17,826 cases of hospitalization in the Regional Vascular Center from 01 Jan 2017 to 31 Dec 2019, of them with all types of cardiac drug overdoses – 363, of them with MIB – 52.6% (n=191). Results Average age of those hospitalized with MIB – 74.0 [65.0; 80.0] years: 76.0% were ≥65 years, 49.4% – ≥75 years. Among the cohort ≥65 years, there were more women – 74.3% (vs 52.3%, p=0.003), ≥75 years – 74.4% vs 65.5% (p=0.107). The ratio of absolute and relative overdoses did not depend on age and was 1:9. The frequency of pulse-reducing drug admission before hospitalization did not differ in age groups. In General, in the cohort with MIB: 68.4% – beta-blockers, 25.8% – digoxin, 38.9% – antiarrhythmic drugs with pulse-reducing action (PRA), 9.5% – imidazoline receptor agonists, 10.5% – calcium channel blockers with PRA, 7.4% – other drugs with PRA, while 54.5% of patients received a combination of ≥2 drugs with PRA, 15.7% – ≥3, and even 3.1% – ≥4. In older age groups, a Glomerular Filtration Rate (GFR) decrease in was more often: among ≥65 years GFR <60 ml/min × 1.73 m2 – 83.2% (vs 40.0% in younger patients, p<0.001), <45 ml/min × 1.73 m2 – 61.5% (vs 22.5%, p<0.001), <30 ml/min × 1.73 m2 – 34.5% (vs 15.0%, p<0.001), <15 ml/min × 1.73 m2 – 11.1% (vs 7.5%, p<0.264); among patients ≥75 years: GFR <60 ml/min × 1.73 m2 – 87.4% (vs 60.8%, p<0.001), <45 ml/min × 1.73 m2 – 66.0% (vs 40.2%, p<0.001), <30 ml/min × 1.73 m2 – 37.1% (vs 23.4%, p<0.018), <15 ml/min × 1.73 m2 – 12.0% (vs 8.4%, p<0.357). Patients ≥65 and ≥75 years were more likely to require: emergency hospitalization (97.0% vs 84.1% in younger patients, p<0.001 and 97.0% vs 91.1%, p=0.033), treatment in the intensive care unit (44.7% vs 20.5%, p=0.003 and 48.8% vs 29.2%, p=0.001), temporary pacemaker (58.3% vs 20.0%, p=0.107 and 57.1% vs 40.0%, p=0.284). Hospital mortality in persons ≥75 was 7.7% (vs 1.8% in younger patients, p=0.047), ≥65 – 3.8% (vs 4.6%, p=0.814). Conclusions Older age groups predominate among those hospitalized for MIB. They are characterized by a more pronounced lesion of glomerular filtration, a more severe condition, and a higher risk of death. Practical physicians underestimate the danger of prescribing drugs with PRA, especially in the form of combined therapy, in patients of older age groups, with impaired glomerular filtration, which requires drawing attention to this problem. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Ryazan State Medical University

I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway.

Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I2-IRs) are increased in the brain in Alzheimer's disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I2-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for 4weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-D aspartate 2A and 2B receptor subunit protein levels. Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), was increased in B06-treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I2 imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP8 mice.

The role of selective imidazoline receptor agonists in modern hypertension management: an international real-world survey (STRAIGHT)

Background Multiple pharmacologic strategies are currently available to lower blood pressure (BP). Renin-angiotensin system (RAS)-inhibitors, calcium channel blockers and diuretics are widely recommended as first line therapies. Sympathetic activation is an important contributor to BP elevation but remains unopposed or is even increased by some of these drug classes. Selective imidazoline receptor agonists (SIRAs) reduce increased central sympathetic outflow and are considered as add-on therapy in most guidelines. We conducted an international survey to evaluate contemporary hypertension management strategies in countries with high prescription rates of SIRAs to better understand the rationale and practical indications for their use in a real-world setting. Methods Physicians from seven countries (India, Jordan, Lebanon, Russia, Saudi Arabia, South Africa, United Arab Emirates) were asked to complete a web-based questionnaire and comment on clinical case scenarios to provide information on their current practice regarding antihypertension strategies, underlying rationale for their choices, and adherence to relevant guidelines. Results 281 physicians completed the questionnaire including mainly cardiologists (35%) and general practitioners (32%). 96% reported using European (60%) or local (56%) guidelines in their daily practices. The majority of responding physicians (83%) had knowledge of SIRAs and 70% prescribed SIRAs regularly typically as a third line antihypertensive strategy (63%). The preferred combination partners for SIRAs were RAS-inhibitors (72%). Conclusions Contemporary hypertension management varies between countries and therapeutic approaches in a real-world setting are not always in line with recommendations from available guidelines. In the countries selected for this survey prescription of SIRAs was common and appeared to be guided predominantly by considerations relating to the underlying pathophysiologic mechanism of sympathetic inhibition.

Effective strategies for prevention of cardiovascular complications in elderly patients with arterial hypertension and obesity (clinical example)

The frequency of arterial hypertension has a clear tendency to increase with age. The presence of obesity imposes additional difficulties on the choice of antihypertensive therapy regimen due to the variety of pathophysiological mechanisms of raising blood pressure in patients with a combination of hypertension and obesity. This article presents the clinical case of a 68-year-old patient with hypertension and obesity, discusses a comprehensive approach that includes diet, regular physical activity, cognitive training and pharmacotherapy with the fixed combination of amlodipine with telmisartan and the imidazoline receptor agonist moxonidine. The choice of this combination is due to the following reasons: the ultra-prolonged action of both drugs, which allows you to control blood pressure during the day, including in the morning, when there is the greatest number of cardiovascular events; organoprotective properties; improving carbohydrate metabolism; reducing the risk of diabetes; antiatherosclerotic properties. The choice of moxonidine is due to the need of effective control of blood pressure, reduction of the activity of the sympathetic nervous system, because hypersympathicotonia is one of the central pathogenetic mechanisms for raising blood pressure in patients with hypertension and obesity, and the decrease in resting heart rate less than 80 bpm (an independent risk factor for cardiovascular complications in hypertension). Dietary recommendations will help to reduce body weight and blood pressure, slow the progression of atherosclerosis, prevent the development of cardiovascular catastrophes, and improve the quality of life. The aim of physical activity is reducing body weight, improve cognitive functions and reduce cardiovascular risks. Cognitive training will help improve cognitive function and, consequently, increase patient adherence to treatment. After six weeks of complex treatment, the patient noted the achievement of the target blood pressure, weight loss, improved mood, increased exercise tolerance, improved quality of life, as well as a decrease in proteinuria, which completely disappeared after another three months of therapy.

PHARMACOEPIDEMIOLOGY OF USING OF ANTIHYPERTENSIVE DRUGS BY FAMILY PHYSICIANS

The purpose of the study: to study the features of the rational use of antihypertensive drugs (AHP) by family doctors on an outpatient basis and their analysis of compliance with current international recommendations.Materials and methods: According to questionnaires specially developed for studying the pharmacoepidemiology of hypertension, interviews were conducted with family doctors working in health houses located in different regions of the country and the specifics of their appointment of hypertension to patients with hypertension were studied. The duration of medical experience of doctors is on average 22.6 ± 11.0 years.Results: The main drugs in the prescription structure were ACE inhibitors (19.7%), beta-blockers (19.6%), calcium antagonists (19.1%, diuretics (18.9%) ARBs (12.8%). central action drugs – 8.5%, alpha-adrenergic blockers – 1.4%. ACE inhibitor administration structure: enalapril – 33.8%, lisinopril – 26.3%, captopril – 23.3%, perindopril – 10.1 %, ramipril – 4.7%, the rest - 1.3% Of the beta-blockers: atenolol – 35.7%, bisoprolol – 34.7%, propranolol -15.7%, metoprolol - 8.0%, nebivolol – 4.3% and carvedilol 1.7%. The structure of the appointment of calcium antagonists: amlodipine – 38,3%, nifedipine – 29.6%, verapamil 16.8%, nifedipine SR and verapamil SR 5.7% each, diltheazem 2.1%, the share of all the others no more than 1.8%. Diuretic structure: hydrochlorothiazide – 36.0 %, furosemide – 28.8%, spironolactone – 18.6%, indapamide – 13.5%, torasemide – 2.1%, acetazolamide – 0.9%. The main proportion of ARB was losartan (84.0%) valsartan (8.7%), candesartan (4.2%), all the rest – 3.1%. 38.1% of family doctors still prescribe a centrally acting drug – clofellin, an imidazoline receptor agonist moxonidine (physiotens) is prescribed by family doctors very rarely (1.8%).73.2% of respondents seek to reduce blood pressure to 140/90 mm Hg. Art., and the rest are limited to lowering blood pressure to a «working» level. 33.7% of family doctors start hypertension with monotherapy with the selection of an effective dose of one drug. 40.6% of doctors prefer free combination of AHP, 54.7% consider fixed combinations to be convenient, the rest are low-dose combinations.Conclusion: Our study confirms the need for further improvement of the rational use of AHP by family doctors

Adverse effects of sympathetic activation should not be neglected during the coronavirus disease 2019 pandemic.

Adverse effects of sympathetic activation should not be neglected during the coronavirus disease 2019 pandemic.

Drug-induced bradycardia as a medical and social problem: data from the Cardiac Drug Overdoses Hospital Registry (STORM)

Aim.To analyze hospitalizations due to drug-induced bradyarrhythmia (DIB) over a 5-year period (2014-2018), its clinical characteristics, causes and outcomes.Material and methods. The analysis included all hospitalizations due to DIB at the Ryazan Regional Vascular Center in 2017 and 2018 and retrospectively in 2014.Results.A total of 325 cases of DIB were included in the analysis (age 76,0 [68.0; 82.0] years; men — 26,1%). The proportion of DIB as a hospitalization cause in 2017 increased by 4,3 times compared to 2014 (p<0,001), in 2018 compared to 2014 — by 6,3 times (p<0,001) and compared to 2017 — by 46,2% (p=0,001). We recorded the following manifestations of DIB: bradycardia (<40 bpm — 51,4%), atrioventricular (31,7%) and sinoatrial (29,2%) block, syncope (36,0%), Frederick’s syndrome (8,6%), pauses >3 s (5,9%). Management in intensive care was required in 42,2% of patients, temporary cardiac pacing — in 7,7%, permanent pacemaker — in 6,2%. Mortality rate was 6,2%. Before hospitalization, patients took beta-blockers (65,1%), antiarrhythmic agents (39,6%), cardiac glycosides (23,0%), ^-imidazoline receptor agonist moxonidine (13,5%, its prescription rate increased 8,9 times over 5 years, p=0,004), nondihydropyridine calcium channel blockers (7,9%), and other drugs (15,4%). In 60,1% of patients, ≥2 drugs with bradycardic action were used, in 22,0% — ≥3, in 8,1% — ≥4, in 10,6% — with an excessive single/daily dose.Conclusion.The medical and social significance of DIB have been demonstrated. DIB due to exceeding the recommended dose was associated with independent try of patients to manage the deterioration. In other cases, DIB was due to the summation/ potentiation of several drugs’ action, the comorbidities contributing to the development of bradyarrhythmia and/or changes in pharmacokinetic properties of drugs.

Exploring the antidepressant-like potential of the selective I2-imidazoline receptor ligand LSL 60101 in adult male rats.

While the alteration of I2 receptors has been associated with neurodegenerative and psychiatric disorders, among other brain dysfunctions, I2 selective agonists are also capable of inducing analgesia in models of chronic pain, improving cognition and inducing hypothermia and neuroprotection. However, the literature evaluating the antidepressant-like potential of I2 ligands is scarce and showed mixed results, whereas some studies reported antidepressant-like effects for certain I2 ligands others denied them. In this context, we evaluated the antidepressant-like potential of a highly selective I2-receptor ligand, LSL 60101 ([2-(2-benzofuranyl)-2-imidazole]). LSL 60101 was administered in adult male Sprague-Dawley rats daily during 16days (doses of 10 and 20mg/kg, ip) and its antidepressant-like potential was assessed through the course of treatment in the forced-swim test, novelty-suppressed feeding test and two-bottle choice test (sucrose preference). The regulation of several key neuroplasticity markers (i.e., FADD, p-ERK1/2, ERK1/2, p-JNK1/2, JNK1/2, mBDNF) was evaluated 24-h post-treatment by western blot analysis in the right hippocampus and the proliferation of neural progenitors was quantified in the left hippocampus by immunohistochemistry. The results showed that LSL 60101 did not induce an antidepressant-like effect over the course of treatment in any of the behavioral tests conducted, and it did not alter any of the hippocampal neuroplasticity markers evaluated. These results add to the existing literature by suggesting that not all I2 ligands might be capable of displaying an antidepressant-like potential, and that particularities in the chemical structure of each compound might help explain these discrepancies and deserve future studies.

Results of the pilot part of the cardiac drug overdoses hospital registry (storm): focus on drug-induced bradycardia

Aim. Analysis of the relevance of drug-induced bradycardia (DIB) as a medical and social problem, its main regularities and determination of the need for further study of this issue.
 Materials and Methods. The register study was performed on 01 Jan 2017-30 Jun 2018 (18 months) at the clinical base of the Ryazan Regional Clinical Cardiology Dispensary. Inclusion criteria were: 1) bradycardia/bradyarrhythmia syndrome with intake of at least one drug with a bradycardic effect (BCE), 2) signing Informed consent to the processing of personal and clinical data. No additional interventions were performed in the diagnosis or treatment of patients within the registry.
 Results. During 18 months, 191 patients (age 77.0 [69.0;82.0] years, 26.7% of men) were hospitalized with a verified diagnosis of DIB, which accounted for 52.6% of all cases of hospitalization for drug overdose. During the analyzed period, there was an increase in both the total number of drug overdoses (1.7 times, p0.001) and overdoses of drugs with BCE (1.8 times, p0.001). Main clinical manifestations of DIB: reduced heart rate (50 beats/min 80.0%, 40 beats/min 51.1%), sinoatrial (30.4%) and atrioventricular blocks (1st degree 8.2%, 2nd degree 10.4%, 3rd degree 14.1%), syncope (32.6%) and cardiac pauses 3 s (7.4%). Almost all (94.8%) the patients were hospitalized by ambulance, 40.7% to the intensive care unit; 17.8% required pacemaker implantation; hospital mortality was 5.2%. More than half (54.5%) of hospitalized patients took 2 drugs with BCE, 15.7% 3 and 3.14% 4 (both in monotherapy and as a part of a combination): beta-blockers 68.4%, antiarrhythmic preparations 38.9%, digoxin 25.8%, non-dihydropyridine calcium antagonists 10.5%, I1-imidazoline receptor agonist 9.5%, and other drugs with BCE 7.4%. To analyze the cause of DIB, we used clinical data of 135 patients (age 77.0 [69.0;82.0] years, 20.7% of men), who could indicate the exact dose of a taken drug with BCE. Among them, the absolute exceedance of the recommended dose of drugs with BCE was found in 14.1% of cases, while in 85.9% of cases summation/potentiation effect of several drugs with ВСЕ was observed, with intake of each in a therapeutic dose.
 Conclusion. The study confirmed high medical and social significance of the problem of DIB, which requires attention of practitioners, pharmacologists and clinical pharmacologists, health care providers, and also continuation of its study.

Agmatine reverses memory deficits induced by Aβ1–42 peptide in mice: A key role of imidazoline receptors

Agmatine is a biogenic amine synthesized following decarboxylation of L-arginine by the enzyme arginine decarboxylase and exhibits favourable outcome in neurodegenerative disorders. Present study was designed to examine the relationship between agmatine and the imidazoline receptors in memory deficits induced by Aβ1-42 peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (3μg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aβ1-42, TNF-α and IL-6 and BDNF immunocontent analysis within the hippocampus. While the learning and memory impairment was evident in the mice subjected to MWM test following Aβ1-42 peptide administration, there was a significant increase in Aβ1-42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20mg/kg); imidazoline I1 receptor agonist, moxonidine and imidazoline I2 receptor agonist, 2-BFI starting from day 8 to 27 post-Aβ1-42 injection, significantly prevented the cognitive deficits and normalized the Aβ1-42 peptide, IL-6, TNF-α and BDNF immunocontent in hippocampus. On the other hand, pre-treatment with imidazoline I1 receptor antagonist, efaroxan and imidazoline I2 receptor antagonist, BU 224 attenuated the effects of agmatine on learning and memory in MWM, IL-6, TNF-α and BDNF content. In conclusion, the present study provides functional evidence for the involvement of the imidazoline receptors in agmatine induced reversal of Aβ1-42 induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.

The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity.

Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient's quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I1 receptor (I1-R) and in particular on the selective I1-R agonist 2-(1-([1,1'-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1-10mgkg-1), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I1-R antagonist 3 or the I1/α2 receptor antagonist efaroxan, confirming the I1-R-dependent mechanism. Conversely, pre-treatment with the I2-R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1mgkg-1) for 14days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I1-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.

Predictability study of the pharmacodynamic properties of drugs <i>in silico</i> by the example of comparing data on the naphazoline clinical use and the results of computer modeling

The forecast of naphazoline pharmacological properties has been made using the PASS computer program and the ADVER-Pred web resource of the Way2Drug information and computing platform. Biological activity, mechanisms of action, toxic and side effects, as well as other types of activity of the studied drug associated with interaction with antitargets, metabolism and gene expression regulation have been determined. The results of the naphazoline pharmacological properties forecast obtained in silico have been compared with the information available in the literature about its systemic effects in clinical use and poisoning.It has been established that the studied chemical compound has a very wide spectrum of action, which is primarily associated with the stimulation of adrenoreceptors and imidazoline receptors located in many organs and tissues of the body. At the same time, other mechanisms of naphazoline action forecasted in silico allow us to determine possible directions for further research of its clinical use. Among the toxic and side effects, along with such known adverse events as effect on the central nervous system and arterial hypertension, in the clinical use of naphazoline special attention should be paid to the cardio-, hepato- and nephrotoxic effects forecasted with a high degree of probability. The prominent toxic effect of naphazoline can cause the occurrence of life- threatening conditions - acute cerebrovascular disorder, myocardial infarction, cardiac rhythm disorders, acute left ventricular failure. The obtained data confirm that the use of modern computer methods that provide an assessment of biological activity based on the drug-like compound graphic formula allows us to obtain a forecast with a high degree of confidence for both new pharmacological substances and for drugs approved for clinical use in order to clarify their pharmacological properties.

THE DAILY EXCRETION OF CATECHOLAMINES IN THE URINE OF NORMOTENSIVE PATIENTS WITH DIABETES WITHOUT HYPERTENSION

As you know, judge the state of the tone and reactivity of SAS allows the study of the excretion of the catecholamines (KA), of metabolic products of biogenic amines and enzymes involved in their metabolism. More informative and appropriate for clinical trials is a systematic approach to the study of SAS, including simultaneous determination of excretion of the precursor of the synthesis of KA - DOPA and its spectrum: dopamine (DA), noradrenaline (NA) and adrenaline (A) [8]. In available for us literature data on this problem is quite contradictory and relates to certain aspects of these studies. Installed as the decrease or increase in the level of CA in blood and urine, as in type 2 diabetes [4,5] and in hypertension [7,8,9]. There are no works devoted to the study of the qualitative and quantitative assessment of the functional state of the sympathetic-adrenal system, i.e. excretion of KA and their precursors and activity of monoamine oxidase (MAO) when combined with diabetes 2-type with AG. It is known that one of the processes that lead to the disruption of the cell membrane is the activation of processes of peroxide oxidation of lipids (Pol). Excessive formation of free radicals, accumulation of primary and secondary products of lipoperoxidation weakens the hydrophobic membrane when the body's cells, in particular β-cells of the islets of Langerhans, which leads ultimately to the suppression of proinsulin synthesis and cell death [5]. From the foregoing it is obvious that the state of the sympathetic-adrenal system and processes of lipid peroxidation in type 2 diabetes with hypertension has been insufficiently studied, and the available results are contradictory. Accordingly, this issue remains controversial. An urgent task is the development of optimal approaches to the treatment of hypertension in patients with type 2 diabetes. Ideally, such a drug should have a good antihypertensive effect, but must be at least metabolically neutral. In this regard, of great interest is the class of imidazoline receptor agonists, which not only reduce sympathetic activity and blood pressure (BP), but also have a positive effect on insulin resistance, lipid and glucose metabolism [6,7]. However, the influence of treatment with moxonidine on the functional activity of the sympathetic-adrenal system studied, not studied and the processes of lipid peroxidation on the background of treatment with agonists of imidazoline receptors. On this basis, undertaken the present study

Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I2-Imidazoline Receptor Ligand MCR5.

Behavioural and psychological symptoms of dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer’s disease (AD), together with memory decline. I2-imidazoline receptors (I2-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I2-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I2-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I2-IR ligand MCR5 (5 mg/kg/day for four weeks) in 10-month SAMP8 mice ameliorated both BPSD-like phenotype and cognitive decline by attenuating depressive-like behaviour, reducing fear-anxiety-like behaviour and improving cognitive performance using different tasks. Interaction of I2-IR ligand MCR5 with serotoninergic system did not account for behavioural or cognitive improvement, although changes in molecular pathways underlying depression and anxiety phenotype were observed. MCR5 increased levels of p-AKT, phosphorylated glycogen synthase kinase 3 β (GSK3β) at Ser9 and phosphorylated mammalian target of rapamycin complex 1 (mTORC1) levels in SAMP8 treated mice compared to SAMP8 control. Moreover, MCR5 treatment altered N-methyl-d-aspartate receptor (NMDA) 2B phosphorylation, and decreased the protein levels of phosphorylated cyclin-dependent kinase 5 (p-CDK5) and dopamine- and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein of Mr 32 kDa phosphorylated at Thr75 (p-DARPP32), with a parallel increase in protein kinase A (PKA) and p-cAMP response element-binding (pCREB) levels. Consistent with these changes MCR5 attenuated neuroinflammation by decreasing expression of pro-inflammatory markers such as Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6), and promoted synaptic plasticity by increasing levels of postsynaptic density protein 95 (PSD95) as well as ameliorating tropomyosin-related kinase B (TrkB) and nerve growth factor receptor (NGFR) signalling. Collectively, these results increase the potential of highly selective I2-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations.

1-Benzyl-2-(thien-2-yl)-4,5-dihydro-1H-imidazole

Imidazolines are a valuable class of organic compounds, namely ligands of imidazoline receptors, chiral ligands for metal catalysis, synthetic intermediates. The title compound has been prepared through a modified procedure, employing N-benzylethylenediamine and thiophene-2-carbaldehyde under the action of N-bromosuccinimide (NBS) in dichloromethane (DCM) in a good 78% yield.

Agmatine ameliorates manifestation of depression-like behavior and hippocampal neuroinflammation in mouse model of Alzheimer’s disease

Extensive clinical and experimental studies established that depression and mood disorders are highly prevalent neuropsychiatric conditions in Alzheimer’s disease (AD). However, its neurochemical basis is not clearly understood. Thus, understanding the neural mechanisms involved in mediating the co-morbidity of depression and AD may be crucial in exploring new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in β-amyloid (Aββ1−42) peptide-induced depression using forced swim test (FST) in mice. Following the 28th days of its administration, Aβ1−42 peptide produced depression-like behavior in mice as evidenced by increased immobility time in FST and increased expression of pro-inflammatory cytokines like IL-6 and TNF-α compared to the control animals. The Aβ1−42 peptide-induced depression and neuroinflammatory markers were significantly inhibited by agmatine −, moxonidine, 2-BFI and l-arginine by once-daily administration during day 8–27 of the protocol. The antidepressant-like effect of agmatine in Aβ1−42 peptide in mice was potentiated by imidazoline receptor I1 agonist, moxonidine and imidazoline receptor I2 agonist 2-BFI at their sub-effective doses. On the other hand, it was completely blocked by imidazoline receptor I1 antagonist, efaroxan and imidazoline receptor I2 antagonist, idazoxan Also, agmatine levels were significantly reduced in brain samples of β-amyloid injected mice as compared to the control animals. In conclusion, the present study suggests the importance of endogenous agmatinergic system and imidazoline receptors system in β-amyloid induced a depressive-like behavior in mice. The data projects agmatine as a potential therapeutic target for the AD-associated depression and comorbidities.

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

Background and PurposeProlonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I2 receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056–opioid interaction.Experimental ApproachWe 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 (naloxone‐induced withdrawal), and abuse (conditioned place preference‐associated reward). Chemiluminescence assays tested CR4056 as allosteric modulator of μ‐opioid receptors.Key ResultsCR4056 (ED50 = 4.88 mg·kg−1) and morphine (ED50 = 2.07 mg·kg−1) synergized in reducing CFA‐induced hyperalgesia (ED50 = 0.52 mg·kg−1; 1:1 combination). Consistently, low doses of CR4056 (1 mg·kg−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.Conclusion and ImplicationsWe showed selective synergism between CR4056 and morphine as analgesics. Their combination showed an improved safety and abuse liability profile over morphine alone. CR4056 could be developed as an opioid‐sparing drug in multimodal analgesia.

Deciphering Imidazoline Off-targets by Fishing in the Class A of GPCR field.

Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors - rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2 - adrenoceptors.

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease.

Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore, bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions.

Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography

The mixed-mode chromatographic behavior was estimated for imidazoline and serotonin receptor ligands, and their related compounds on dual hydrophilic/reversed phase stationary phase. The Box-Cox transformation was used to obtain the most suitable mathematical equations which describe the mixed-mode retention. Optimal equations were found for the optimization parameter (λ): λ = -1, λ = -0.5, λ = 0, λ = 0.5, and λ = 1. The proposed equations show satisfactory characteristics compared to standard multimodal and quadratic approaches.For a wide range of volume fractions of the mobile phase modifier, crossing between hydrophilic and reversed phase interactions (the turning point) was defined in terms of the minimal retention and the minimum value of the volume fraction of the aqueous eluent in the mobile phase. The cubic spline interpolation was used as a reference method for estimation of the turning point. It was found out that the newly proposed equations can be used as alternative mathematical forms for the description of the dual retention mechanism and for the evaluation of the turning point.Three new experimental descriptors of the mixed-mode retention were proposed. Two descriptors quantitatively characterize hydrophilic (log kH) and reversed phase (log kR) interactions, while the third one (log kA) refers to the average retention for the whole HILIC/RP range. It was established that the main factors which control dual nature of the mixed-mode retention are lipophilicity, dipol-dipol, van der Waals and hydrogen bonding interactions.It was concluded that the newly proposed estimations of the retention data reliably characterize the mixed-mode chromatographic behavior.