I1-imidazoline Receptor Agonist Research Articles

Regulation of I1-imidazoline receptors on the sedation effect of dexmedetomidine in mice.

Dexmedetomidine has been used as a sedative drug in the clinic for a long time. Many studies demonstrated that the sedative mechanism of dexmedetomidine might be related to the activation of α2-adrenoceptor (α2AR). In addition, it was reported that dexmedetomidine had some affinity for the I1-imidazoline receptor (I1R); however, the role of I1R in dexmedetomidine-induced sedative effects and its possible mechanism are poorly studied. In the present study, we found that agmatine, an I1R agonist, was able to enhance the sedative effect of dexmedetomidine in mice. Efaroxan, an α2AR and I1R antagonist, could prevent and rescue the sedative action of dexmedetomidine in mice, and its preventive effect was better than atipamezole, the specific α2AR antagonist. Knockout of imidazoline receptor antisera-selected (IRAS), the functional I1R candidate protein, suppressed the dexmedetomidine-induced sedation. Moreover, IRAS knockout led to the inhibition of agmatine and efaroxan in regulating dexmedetomidine-induced sedative effects in mice, but not of atipamezole. We then used CHO cell lines that stably expressed α2AR and IRAS to investigate the possible molecular mechanism of IRAS in regulating the dexmedetomidine-induced sedative effect. The results showed that IRAS expression significantly up-regulated dexmedetomidine-induced ERK phosphorylation, which was enhanced by agmatine and inhibited by efaroxan at low concentrations. Therefore, by taking advantage of pharmacological and genetic approaches, our finding revealed the evidence that IRAS plays an important role in the sedative effects of dexmedetomidine, and the ERK signal pathway may be involved in the mechanism of IRAS in regulating dexmedetomidine-induced sedation. This study may offer valuable insights for the advancement of novel anesthetic adjuvants.

MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

Place of imidazoline receptor agonists in the treatment of arterial hypertension

The review is devoted to one of the most controversial issues of modern antihypertensive therapy — the role of new generation sympatholytics — selective I1-imidazoline receptor agonists (AIRs). In modern European recommendations, AIR (moxonidine rilmenidine), along with other centrally acting drugs (reserpine, alpha-methyldopa, clonidine), are mainly intended for additional therapy in rare cases of resistant hypertension, when other treatment options have been ineffective. Nevertheless, AIR invariably finds its place in Russian recommendations for the treatment of arterial hypertension (AH). This class of drugs is recommended for patients with AH in combination with metabolic syndrome and obesity. It is noted that an important property of AIR is its positive effect on carbohydrate and lipid metabolism. This information is based on an analysis of Russian and foreign studies, which convincingly indicate that this class of drugs not only provides adequate and long-term blood pressure control, but also has the above-mentioned positive metabolic effects. At the same time, AIRs are much less likely to cause side effects characteristic of older generation centrally acting drugs. Thus, AIRs have become firmly established in clinical practice in Russia for the treatment of patients with AH in certain clinical situations.

Modern ideas about the consequences of sympathoadrenal hyperactivation in hypertensive patients with metabolic disorders: modulation possibilities

The prevalence of hypertension (HTN) in the Russian Federation and the world continues to grow. This is largely due to the epidemic of obesity and related conditions — metabolic syndrome and type 2 diabetes. The most common and proven hypothesis of the relationship between hypertension and obesity is the activation of the sympathetic nervous system. However, modern research shows that the consequences of sympathetic hyperactivation are not limited only to hemodynamic effects, but extend to many organs and systems. Long-term sympathetic hyperactivation can lead to insulin resistance and type 2 diabetes. Neurotransmitters affect fat cells by increasing lipolysis and leading to increased fatty acid release, the liver by increasing gluconeogenesis, and pancreatic β-cells by decreasing insulin secretion. The sympathetic nervous system plays an important role in energy management by regulating metabolic rate. Obese individuals have significantly less pronounced postprandial thermogenesis, despite a higher insulin response, while the hemodynamic response to isometric or heterometric exercise is reduced. Chronic stress serves not only as a trigger for behavioral disorders, but also directly leads to various physiological disorders, including through sympathetic activation. However, the choice of antihypertensive agents affecting the sympathetic activity in patients with obesity and metabolic disorders is very limited. According to current guidelines, β-blockers are not the drugs of choice in patients with uncomplicated HTN, since it has a weaker evidence base compared to other classes of drugs and have metabolic and other side effects. Therefore, selective I1-imidazoline receptor agonists, and in particular, moxonidine may be the drugs of choice in this category of patients. Moxonidine in combination therapy of patients with HTN and metabolic disorders, including metabolic disorders in menopause, as well as with a physiological estrogen decrease, significantly improves the effectiveness of antihypertensive therapy and increases the achievement of target blood pressure. In addition, its metabolic effects improve prognosis of such patients.

Hypertension in periand postmenopausal women: mechanisms, management, observation

An important role in the development and evolution of hypertension in females is applied to sex hormones. Estrogen deficiency and hyperandrogenism, characteristic of periand postmenopause, are links in the pathogenesis of hypertension in this period of a woman's life and are accompanied by an increase in sympathetic nervous system activity, renin-angiotensin-aldosterone system activation, salt sensitivity, abdominal obesity and metabolic syndrome, left ventricle hypertrophy, left atrial dilatation with a high risk of atrial fibrillation, stroke and heart failure development. The paper discusses antihypertensive therapy during periand postmenopause, effectiveness and tolerability of different drug classes. Special attention is paid to the mechanism of action of selective I1-imidazoline receptor agonist moxonidine, which in women during this period both effectively reduces high blood pressure and has a beneficial metabolic effect, what is documents in studies of monotherapy, combined antihypertensive therapy with major classes and in combination with menopausal hormone therapy. The paper presents the joint expert opinion concerning above mentioned issues.

Hypertension in peri- and postmenopausal women — pathophysiological mechanisms and approaches to treatment

This review presents epidemiological data on the effect of sex hormones and reproductive status on the level of blood pressure (BP) and the incidence of es­sential hypertension (EHT) in women. The role of estrogen deprivation and hyper­androgenism in the development of EHT in peri- and postmenopause is discussed. The main mechanisms of EHT in periand postmenopausal women: sympathetic and renin-angiotensin-aldosterone system hyperactivity, salt-sensitivity, high prevalence of abdominal obesity, metabolic syndrome, left ventricular hypertrophy, left atrial dilatation and high risk of atrial fibrillation, stroke and heart failure with preserved left ventricle ejection fraction. Data on the efficacy and tolerability of the main classes of antihypertensive drugs in women is presented. We discussed the mechanisms of selective I1-imidazoline receptor agonists and the results of cohort studies of moxonidine monotherapy and its combination with other antihypertensive drugs and hormonal menopausal therapy in peri- and post­menopausal women. Moxonidine reduces high blood pressure in peri- and postmenopausal women and has a beneficial effect on metabolic syndrome components, but is also effective in patients with hypertensive crises, especially with sympathetic hyperactivity.

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.

Features of antihypertensive therapy and real-world prescription of selective imidazoline receptor agonists in Russia vs other countries: STRAIGHT study data analysis

To compare the strategies for hypertension management and features of clinical use of I1-imidazoline receptor (I1-IR) agonists in the Russian Federation and other countries where the STRAIGHT (Selective imidazoline receptor agonists Treatment Recommendation and Action In Global management of HyperTension) study was conducted. It was a cross-sectional online study involving physicians of various specializations. The study was conducted from January 18 to July 1, 2019, in seven countries with a high rate of I1-IR agonist prescription, including Russia. A total of 125 (4.5%) responders filled out the survey in the Russian Federation, which was somewhat lower than in other countries (6.8%). The participants were mostly general practitioners (54.0%) and cardiologists (42.0%), while in other countries greater diversity was seen. Most Russian physicians (83.0%) seemed to rely on national clinical guidelines in their routine practice, while in other countries the US guidelines were more popular (66.0%). The majority of responders stated that they took into account the traditional risk factors of hypertension when initiating the therapy; every second responder noted if sleep apnea was present. Awareness of I1-IR agonists, their prescription rate and their preference were higher in Russia. The main reported benefits of I1-IR agonists were their efficacy, including in resistant hypertension, and their metabolic effects (in Russia). Most participants preferred I1-IR agonists as third-line therapy (65.0% in Russia vs 60.0% in other countries) and in combination with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARB) (55.0% in Russia vs 54.0% in other countries). Compared to responders from other countries, Russian physicians prescribe I1-IR agonists as first-line (15.0% vs 5.0%) and second-line (48.0% vs 21.0%) therapy more often. Russian physicians were the most aware of I1-IR agonists and tended to prescribe drugs of this class for hypertension management more often, and I1-IR agonist combination with ACEi was preferable compared to physician responders from other countries. Antihypertensive efficacy and metabolic effects were reported as the major benefits of I1-IR agonist therapy.

Optimization of Pharmacotherapy Within the Framework of a Patient-oriented Approach in the Treatment of Hypertension in Multimorbidity Patients (Clinical Case and Literature Review)

Arterial hypertension (AH) remains one of the main causes of disability and death worldwide, including in Russia. At the same time, the risks of coronary and cerebrovascular events increase in the presence of additional risk factors. The most common modifiable risk factors are metabolic disorders, including pre-diabetes, dyslipidemia, peripheral arterial atherosclerosis, and obesity, which also imposes certain features on the choice of optimal pharmacotherapy. Currently, the terminology of comorbid conditions continues to be discussed depending on their pathogenesis and the presence or absence of dominance of one disease over others, i.e. polymorbidity, comorbidity and multimorbidity. At the same time, “associative polymorbidity” is distinguished with a certain set of diseases that often occur in conjunction with each other with individual susceptibility of the body. One of the most common phenotypes of polymorbidity occurring in all age groups in both sexes is cardiometabolic, which is based on the formation of insulin resistance, sympathetic overactivity and chronic inflammation. This article provides a clinical example of the use of a fixed combination of angiotensin II receptor blocker telmisartan and calcium channel blocker amlodipine with the addition of an I1-imidazoline receptor agonist moxonidine in real clinical practice in a polymorbid cardiometabolic patient with target organ damage (left ventricular hypertrophy and microalbuminuria). High antihypertensive (favorable effect on 24-hour blood pressure, especially in the early morning) and organoprotective effectiveness of this combination, its possibilities in correcting additional risk factors (reduced heart rate, body weight and a positive effect on metabolic parameters), due to a synergistic effect on the central pathogenetic mechanisms of hypertension and obesity – insulin resistance and sympathetic overactivity.

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.&#x0D; 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.&#x0D; 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.&#x0D; 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.

Moxonidine inhibits excitatory inputs to airway vagal preganglionic neurons via activation of both α2-adrenoceptors and imidazoline I1 receptors

As an imidazoline I1 receptor agonist with very weak binding affinity for α2-adrenoceptors, moxonidine is commonly used in the treatment of hypertension. Moxonidine also has been implicated to act centrally to reduce airway vagal outflow. However, it is unknown at which central sites moxonidine acts to affect airway vagal activity, and how moxonidine takes effect at synaptic and receptor levels. In this study, airway vagal preganglionic neurons (AVPNs) were retrogradely labeled in neonatal rats from the intrathoracic trachea; retrogradely labeled AVPNs in the external formation of the nucleus ambiguus (NA) were identified in rhythmically active medullary slices using whole-cell patch-clamp techniques; and the effects of moxonidine on the spontaneous excitatory postsynaptic currents (EPSCs) of AVPNs were observed at synaptic level. The results show that moxonidine (10 μmol·L−1) significantly inhibited the frequency of spontaneous EPSCs in both inspiratory-activated and inspiratory-inhibited AVPNs. This effect was partially blocked by SKF-86466 (10 μmol·L−1), a highly selective antagonist of α2-adrenoceptors, or AGN-192403, a selective antagonist of imidazoline I1 receptors, and was completely blocked by efaroxan (10 μmol·L−1), an antagonist of both α2-adrenoceptors and imidazoline I1 receptors. These results demonstrate that moxonidine inhibits the excitatory inputs to AVPNs via activation of both α2-adrenoceptors and imidazoline I1 receptors, and suggest that physiologically both of these two types of receptors are involved in the central regulation of airway vagal activity at preganglionic level. Moxonidine might be potentially useful in diseases with aberrant airway vagal activity such as asthma and chronic obstructive diseases.

Agmatine Protects Against the Progression of Sepsis Through the Imidazoline I2 Receptor-Ribosomal S6 Kinase 2-Nuclear Factor-κB Signaling Pathway.

The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis. Clinical/laboratory investigations. Medical centers/University-based research laboratory. Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g. Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation. Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα. Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.

Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats.

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.

Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders.

We previously observed that selective agonists of the sympatho-inhibitory I1 imidazoline receptors (LNP ligands) have favorable effects on several cardiovascular and metabolic disorders defining the metabolic syndrome, including body weight. The objectives of this study were to explore the effects of LNPs on adiposity and the mechanisms involved, and to evaluate their impact on metabolic homeostasis. Young Zucker fa/fa rats were treated with LNP599 (10 mg/kg/day) for 12 weeks. Effects on body weight, adiposity (regional re-distribution, morphology, and function of adipose tissues), cardiovascular and metabolic homeostasis, and liver function were evaluated. Direct effects on insulin and AMP-activated protein kinase (AMPK) signaling were studied in human hepatoma HepG2 cells. LNP599 treatment limited the age-dependent remodeling and inflammation of subcutaneous, epididymal, and visceral adipose tissues, and prevented total fat deposits and the development of obesity. Body-weight stabilization was not related to reduced food intake but rather to enhanced energy expenditure and thermogenesis. Cardiovascular and metabolic parameters were also improved and were significantly correlated with body weight but not with plasma norepinephrine. Insulin and AMPK signaling were enhanced in hepatic tissues of treated animals, whereas blood markers of hepatic disease and pro-inflammatory cytokine levels were reduced. In cultured HepG2 cells, LNP ligands phosphorylated AMPK and the downstream acetyl-CoA carboxylase and prevented oleic acid-induced intracellular lipid accumulation. They also significantly potentiated insulin-mediated AKT activation and this was independent from AMPK. Selective I1 imidazoline receptor agonists protect against the development of adiposity and obesity, and the associated cardio-metabolic disorders. Activation of I1 receptors in the liver, leading to stimulation of the cellular energy sensor AMPK and insulin sensitization, and in adipose tissues, leading to improvement of morphology and function, are identified as peripheral mechanisms involved in the beneficial actions of these ligands.

Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors.

Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice. Mice received daily single intraperitoneal injection of EtOH (2.5g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40μg/mouse), endogenous agmatine enhancers (l-arginine [80μg/mouse], arcaine [50μg/mouse], aminoguanidine [25μg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11. Agmatine (20 to 40μg/mouse) administration for 7days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80μg/mouse) or arcaine (50μg/mouse) and aminoguanidine (25μg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I1 receptor agonist, moxonidine, and I2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I1 receptor antagonist, efaroxan, and I2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization. Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.

Protective effect of the imidazoline I2 receptor agonist 2-BFI on oxidative cytotoxicity in astrocytes

Astrocytes perform a variety of functions that are important for normal neuronal activity and recovery after brain injury. Because astrocytes are very vulnerable to H2O2, protection of astrocytes from oxidative damage in various neurological diseases is important in maintaining brain function and preventing brain damage. In this study, we investigated the characteristics and mechanisms of a specific imidazoline I2 receptor agonist 2-BFI-mediated cytoprotection using a rat astrocyte cultures of H2O2-exposed oxidative stress. Here we show that 2-BFI in H2O2-exposed astrocytes protects cell death through increased lysosomal membrane stability, LC3-II conversion, and subsequently suppresses accumulation of p62. These effects of 2-BFI were significantly reversed after treatment with the lysozyme activity inhibitor Bafilomycin A1. These results suggest that the cytoprotective effects of 2-BFI, which increases lysosomal stability in oxidative stress, may involve regulation of lysosomal-associated membrane protein-dependent autophagy and autolysosome degradation in astrocytes.

Mechanisms of imidazoline I2 receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.

Although the antinociceptive efficacies of imidazoline I2 receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2 receptor agonist-induced antinociception. von Frey filaments were used to assess antinociceptive effects of two I2 receptor agonists, 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Rectal temperature was measured to assess hypothermic effects of 2-BFI. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6mg·kg-1 2-BFI (i.p.) from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. In each experiment, pharmacological mechanisms were investigated by combining 2-BFI or CR4056 with various pharmacological manipulations of the monoaminergic system including selective reuptake inhibition, monoamine depletion and monoamine receptor antagonism. In the CCI model, selective reuptake inhibitors of 5-HT (fluoxetine) or noradrenaline (desipramine), but not dopamine (GBR12909), enhanced 2-BFI-induced antinociception. Selective depletion of 5-HT or noradrenaline almost abolished 2-BFI-induced antinociception. 5-HT1A , 5-HT2A and α1 -adrenoceptor antagonists, but not other monoaminergic antagonists, attenuated 2-BFI and CR4056-induced antinociception in CCI and/or CFA models. However, none of these monoamine receptor antagonists significantly altered 2-BFI-induced hypothermia or discriminative stimulus effects. Antinociception induced by I2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5-HT1A , 5-HT2A and α1 -adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I2 receptor agonists were mediated by distinct, independent mechanisms.

The imidazoline I2 receptor agonist 2-BFI attenuates hypersensitivity and spinal neuroinflammation in a rat model of neuropathic pain

Chronic pain is a large, unmet public health problem. Recent studies have demonstrated the importance of neuroinflammation in the establishment and maintenance of chronic pain. However, pharmacotherapies that reduce neuroinflammation have not been successfully developed to treat chronic pain thus far. Several preclinical studies have established imidazoline I2 receptor (I2R) agonists as novel candidates for chronic pain therapies, and while some I2R ligands appear to modulate neuroinflammation in certain scenarios, whether they exert anti-neuroinflammatory effects in models of chronic pain is unknown. This study examined the effects of the prototypical I2R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) on hypersensitivity and neuroinflammation induced by chronic constriction injury (CCI), a neuropathic pain model in rats. In CCI rats, twice-daily treatment with 10 mg/kg 2-BFI for seven days consistently increased mechanical and thermal nociception thresholds, reduced GFAP and Iba-1 levels in the dorsal horn of the spinal cord, and reduced levels of TNF-α relative to saline treatment. These results were recapitulated in primary mouse cortical astrocyte cultures. Incubation with 2-BFI attenuated GFAP expression and supernatant TNF-α levels in LPS-stimulated cultures. These results suggest that I2R agonists such as 2-BFI may reduce neuroinflammation which may partially account for their antinociceptive effects.