Indirect involvement of α2-adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I1 receptor ligand LNP599 in a rat model of experimental neuropathy.

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I1-receptor agonist LNP599 and whether the attenuation involves co-activation of α2-adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb. Additionally, GTPγS radioligand binding assay, ß-arrestin recruitment and intracellular cAMP levels were used for receptor profiling in vitro. LNP599 (imidazoline I1 receptor agonist) and clonidine (α2-adrenoceptor agonist) produced equal dose-related mechanical antihypersensitivity effects in both sexes. LNP599 attenuated heat nociception preferentially in males, while clonidine reduced heat nociception equally in males and females. Carbophenyline (another imidazoline I1 receptor agonist) had no significant effect on mechanical hypersensitivity or heat nociception in males or females. Mechanical antihypersensitivity and heat antinociception induced by LNP599 in SNI males was prevented by pretreatments with yohimbine or atipamezole (two α2-adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I1 receptor/α2-adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α2A- or other subtypes of α2-adrenoceptors. However, LNP599 was a weak partial agonist for 5-HT2B receptors and bound to sigma-1 and sigma-2 receptors that all are involved in modulation of spinal nociception. The results indicate that the suppression of neuropathic pain hypersensitivity by LNP599 is not due to action on spinal imidazoline I1 receptors, but rather due to indirect activation of spinal α2-adrenoceptors.

Agmatine alleviates ethanol withdrawal-associated cognitive impairment and neurochemical imbalance in rats.

The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.

Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis.

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination.

RATIONALE: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. OBJECTIVES: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. RESULTS: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. CONCLUSIONS: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control.

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.

Dexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline Receptors.

ABSTRACT: Dexmedetomidine (DEX), an α2-adrenoreceptor (α2-AR) and imidazoline receptor agonist, is most often used for the sedation of patients in the intensive care unit. Its administration is associated with an increased incidence of bradycardia; however, the precise mechanism of DEX-induced bradycardia has yet to be fully elucidated. This study was undertaken to examine whether DEX modifies pacemaker activity and the underlying ionic channel function through α2-AR and imidazoline receptors. The whole-cell patch-clamp techniques were used to record action potentials and related ionic currents of sinoatrial node cells in guinea pigs. DEX (≥10 nM) reduced sinoatrial node automaticity and the diastolic depolarization rate. DEX reduced the amplitude of hyperpolarization-activated cation current (If or Ih) the pacemaker current, even within the physiological pacemaker potential range. DEX slowed the If current activation kinetics and caused a significant shift in the voltage dependence of channel activation to negative potentials. In addition, efaroxan, an α2-AR and imidazoline I1 receptor antagonist, attenuated the inhibitory effects of DEX on sinoatrial node automaticity and If current activity, whereas yohimbine, an α2-AR-selective antagonist, did not. DEX did not affect the current activities of other channels, including rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs), L-type Ca2+ current (ICa,L), Na+/Ca2+ exchange current (INCX), and muscarinic K+ current (IK,ACh). Our results indicate that DEX, at clinically relevant concentrations, induced a negative chronotropic effect on the sinoatrial node function through the downregulation of If current through an imidazoline I1 receptor other than the α2-AR in the clinical setting.

Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications.

The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently affected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guidance on their use. This review discusses the etiology of hypertension, and more specifically the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the effects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline receptor agonists.

Evaluating the effects of 2-BFI and tracizoline, two potent I2-imidazoline receptor agonists, on cognitive performance and affect in middle-aged rats.

Cognitive performance and affective-like responses are particularly susceptible to decline during the aging process. Since imidazoline receptors I2 are altered in neurodegenerative and psychiatric disorders, the pharmacological modulation of I2 receptors could be of potential interest to improve these age-related behavioral deficits. In this context, the present study explored the potential pro-cognitive as well as antidepressant-like effects of two potent I2 agonists, 2-BFI (2-(2-benzofuranyl)-2-imidazoline), and tracizoline (2-styryl-4,5-dihydro-lH-imidazole, also known as LSL 61122 or valldemossine) in middle-aged male rats. Following a preliminary study performed to select a dose regimen capable of inducing neuroplastic events (i.e., regulation of hippocampal FADD cell fate adaptor), 2-BFI or tracizoline (10 mg/kg, i.p.) was administered to 9-10-month-old Sprague-Dawley rats. Cognitive performance was evaluated in the 8-arm radial maze and antidepressant-like responses under the stress of the forced-swim test. At the dose selected, 2-BFI and tracizoline did not alter body weight or cognitive performance. Interestingly, 2-BFI (but not tracizoline) induced hypothermia over the course of treatment and an antidepressant-like response in the forced-swim test. These compounds did not improve cognitive performance in middle-aged rats; however, 2-BFI exerted an antidepressant-like response. These results are in line with prior reports suggesting a beneficial impact induced by certain I2 ligands on affective-like behavior, while adding that the beneficial effects were mediated by increasing climbing behavior and with the novelty and importance of demonstrating this effect for middle-aged rats.

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.

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 (0.1-10 mg kg-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 (1 mg kg-1) for 14 days, 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 24 h 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.

Agmatine reverses memory deficits induced by Aß1-42 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 Aß1-42 peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aß1-42 peptide (3 µg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aß1-42, 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 Aß1-42 peptide administration, there was a significant increase in Aß1-42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20 mg/kg); imidazoline I1 receptor agonist, moxonidine and imidazoline I2 receptor agonist, 2-BFI starting from day 8 to 27 post-Aß1-42 injection, significantly prevented the cognitive deficits and normalized the Aß1-42 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 Aß1-42 induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.

Effect of imidazoline-1 receptor agonists on renal dysfunction in rats associated with chronic, sequential fructose and ethanol administration.

Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12 weeks and then with ethanol (20%, v/v) for another 8 weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.

Combining opioids and non-opioids for pain management: Current status.

Pain remains a global health challenge. For decades, clinicians have been primarily relying on µ-opioid receptor (MOR) agonists and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management. MOR agonists remain the most efficacious analgesics available; however, adverse effects related to MOR agonists use are severe which often lead to forced drug discontinuation and inadequate pain relief. The recent opioid overdose epidemic urges the development of safer analgesics. Combination therapy is a well-established clinical pharmacotherapeutic strategy for the treatment of various clinical disorders. The combination of MOR agonists with non-MOR agonists may increase the analgesic potency of MOR agonists, reduce the development of tolerance and dependence, reduce the diversion and abuse, overdose, and reduce other clinically significant side effects associated with prolonged opioid use such as constipation. Overall, the combination therapy approach could substantially improve the therapeutic profile of MOR agonists. This review summarizes some recent developments in this field. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors.

BACKGROUND: 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. METHODS: Mice received daily single intraperitoneal injection of EtOH (2.5 g/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 40 µg/mouse), endogenous agmatine enhancers (l-arginine [80 µg/mouse], arcaine [50 µg/mouse], aminoguanidine [25 µg/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. RESULTS: Agmatine (20 to 40 µg/mouse) administration for 7 days (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 (80 µg/mouse) or arcaine (50 µg/mouse) and aminoguanidine (25 µg/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. CONCLUSIONS: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.

I1-imidazoline receptor-mediated cardiovascular and metabolic effects in high-fat diet-induced metabolic syndrome in rats.

OBJECTIVES: The objective of this study was to investigate the effects of a new I1-imidazoline receptor-selective pyrroline compound on the hemodynamic, metabolic and microvascular alterations in a high-fat diet (HFD)-induced model of metabolic syndrome in rats. METHODS: In total, twenty adult male Wistar rats were fed a high-fat diet (HFD, n = 20) for 20 weeks. Thereafter, the rats received a new pyrroline compound selective for I1-imidazoline receptors (LNP599; 10 mg/kg/day) or vehicle (n = 10/group) orally by gavage for 4 weeks. Functional microcirculation was assessed using intravital video microscopy, and structural microcirculation was evaluated using histochemical analysis. RESULTS: LNP599 induced concomitant reductions in the SBP, HR and plasma catecholamine levels. The animals treated with this new antihypertensive compound also presented an improvement in body weight and the metabolic parameters related to metabolic syndrome, such as the glucose and lipid profiles. These effects were accompanied by a reversal of the functional and structural capillary rarefaction in the skeletal muscle. CONCLUSIONS: The modulation of the sympathetic nervous system by a selective agonist for I1-imidazoline receptors improves the hemodynamic and metabolic parameters in an experimental model of metabolic syndrome. LNP599 can also contribute to the restoration of microcirculatory parameters.

Synergism of myocardial ß-adrenoceptor blockade and I1-imidazoline receptor-driven signaling: Kinase-phosphatase switching.

Recently identified imidazoline receptors of the first type (I1Rs) on the cardiomyocyte's sarcolemma open a new field in calcium signaling research. In particular, it is interesting to investigate their functional interaction with other well-known systems, such as ß-adrenergic receptors. Here we investigated the effects of I1Rs activation on L-type voltage-gated Ca2+-currents under catecholaminergic stress induced by the application of ß-agonist, isoproterenol. Pharmacological agonist of I1Rs (I1-agonist), rilmenidine, and the putative endogenous I1-ligand, agmatine, have been shown to effectively reduce Ca2+-currents potentiated by isoproterenol. Inhibitory analysis shows that the ability to suppress voltage-gated Ca2+-currents by rilmenidine and agmatine is fully preserved in the presence of the protein kinase A blocker (PKA), which indicates a PKA-independent mechanism of their action. The blockade of NO synthase isoforms with 7NI does not affect the intrinsic effects of agmatine and rilmenidine, which suggests NO-independent signaling pathways triggered by I1Rs. A nonspecific serine/threonine protein phosphatase (STPP) inhibitor, calyculin A, abrogates effects of rilmenidine or agmatine on the isoproterenol-induced Ca2+-currents. Direct measurements of phosphatase activity in the myocardial tissues showed that activation of the I1Rs leads to stimulation of STPP, which could be responsible for the I1-agonist influences. Obtained data clarify peripheral effects that occur during activation of the I1Rs under endogenous catecholaminergic stress, and can be used in clinical practice for more precise control of heart contractility in some cardiovascular pathologies.

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.

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice.

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aß degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.

Agmatine modulates spontaneous activity in neurons of the rat medial habenular complex-a relevant mechanism in the pathophysiology and treatment of depression?

The dorsal diencephalic conduction system connects limbic forebrain structures to monaminergic mesencephalic nuclei via a distinct relay station, the habenular complexes. Both habenular nuclei, the lateral as well as the medial nucleus, are considered to play a prominent role in mental disorders like major depression. Herein, we investigate the effect of the polyamine agmatine on the electrical activity of neurons within the medial habenula in rat. We present evidence that agmatine strongly decreases spontaneous action potential firing of medial habenular neurons by activating I1-type imidazoline receptors. Additionally, we compare the expression patterns of agmatinase, an enzyme capable of inactivating agmatine, in rat and human habenula. In the medial habenula of both species, agmatinase is similarly distributed and observed in neurons and, in particular, in distinct neuropil areas. The putative relevance of these findings in the context of depression is discussed. It is concluded that increased activity of the agmatinergic system in the medial habenula may strengthen midbrain dopaminergic activity. Consequently, the habenular-interpeduncular axis may be dysregulated in patients with major depression.

Imidazoline Receptor Agonists for Managing Hypertension May Hold Promise for Treatment of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), which accounts for 10% of all strokes, leads to higher morbidity and mortality compared with other stroke subtypes. Hypertension has been recognized as a major risk factor for ICH. Current antihypertensive options have not been fully effective for either prevention of ICH or ameliorating its complications. Therefore, attempts should be made to use novel antihypertensive medications for more effective management of blood pressure (BP) in the acute phase of ICH. Imidazoline receptor (IR) agonists can potentially be effective agents for BP control with the adjunctive ability to attenuate post-ICH brain injury. IR agonists render neuroprotective effects including inhibition of inflammatory reactions, apoptotic cell death, excitotoxicity, and brain edema. Given these properties, the present review aims to focus on the application of IR agonists for managing BP in ICH patients.