Effects of imidazoline agents in a rat conditioned place preference model of addiction.

Agmatine (AG), idazoxan (IDZ), and efaroxan (EFR) are imidazoline receptor ligands with beneficial effects in central nervous system disorders. The present study aimed to evaluate the interaction between AG, IDZ, and EFR with an opiate, tramadol (TR), in a conditioned place preference (CPP) paradigm. In the experiment, we used five groups with 8 adult male Wistar rats each. During the condition session, on days 2, 4, 6, and 8, the rats received the drugs (saline, or TR, or IDZ and TR, or EFR and TR, or AG and TR) and were placed in their least preferred compartment. On days 1, 3, 5, and 7, the rats received saline in the preferred compartment. In the preconditioning, the preferred compartment was determined. In the postconditioning, the preference for one of the compartments was reevaluated. TR increased the time spent in the non-preferred compartment. AG decreased time spent in the TR-paired compartment. EFR, more than IDZ, reduced the time spent in the TR-paired compartment, but without statistical significance. AG reversed the TR-induced CPP, while EFR and IDZ only decreased the time spent in the TR-paired compartment, without statistical significance.

Involvement of agmatine in antidepressant-like effect of HMG-CoA reductase inhibitors in mice.

3-Hydroxy-3-methyl-glutaryl-co-enzyme-A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 µg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 µg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 µg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.

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

BACKGROUND: 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]). METHODS: LSL 60101 was administered in adult male Sprague-Dawley rats daily during 16 days (doses of 10 and 20 mg/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. RESULTS: 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. CONCLUSION: 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.

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

OBJECTIVES: 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. DESIGN: Clinical/laboratory investigations. SETTING: Medical centers/University-based research laboratory. SUBJECTS: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Inhibitory influence of agmatine in ethanol withdrawal-induced depression in rats: Behavioral and neurochemical evidence.

Although ethanol withdrawal depression is one of the prominent reasons for ethanol consumption reinstatement and ethanol dependence, its neurochemical basis is not clearly understood. The present study investigated the role of the agmatinergic system in ethanol withdrawal-induced depression using the forced swim test (FST) in rats. Chronic exposure of animals to ethanol for 21 days and its abrupt withdrawal produced depression-like behavior, as evidenced by increased immobility time in the FST, compared to the pair-fed control animals. The ethanol withdrawal-induced depression was significantly attenuated by agmatine (20-40 µg/rat, i.c.v. [intracerebroventricularly]), moxonidine (50 µg/rat, i.c.v.), 2-BFI (20 µg/rat, i.c.v.), L-arginine (80 µg/rat, i.c.v.), amino-guanidine (25 µg/rat, i.c.v.), and arcaine (50 µg/rat, i.c.v.) by their once-daily administration during the withdrawal phase (Days 21, 22, and 23). The antidepressant effect of agmatine in ethanol-withdrawn rats was potentiated by the imidazoline receptor I1 agonist moxonidine (25 µg/rat, i.c.v.) and the imidazoline receptor I2 agonist, 2-BFI (10 µg/rat, i.c.v.) at their sub-effective doses. On the other hand, it was completely blocked by the imidazoline receptor I1 antagonist, efaroxan (10 µg/rat, i.c.v.) and the imidazoline receptor I2 antagonist, idazoxan (4 µg/rat, i.c.v.). In addition, agmatine levels were significantly reduced in brain samples of ethanol-withdrawn rats as compared to the pair-fed control animals. In conclusion, the present study suggests the importance of the endogenous agmatinergic system and the imidazoline receptors system in ethanol withdrawal-induced depression. The data project agmatine as a potential therapeutic target for the alcohol withdrawal-induced depression.

Agmatine reverses ethanol consumption in rats: Evidences for an interaction with imidazoline receptors.

Alcohol is one of the most widely abused recreational drugs, largely linked with serious health and social concerns. However, the treatment options for alcohol-use disorders have limited efficacy and exhibit a range of adverse drug reactions. Large numbers of preclinical studies have projected a biogenic amine, agmatine as a promising potential treatment option for drug addiction, including alcoholism. In the present study, administration of agmatine (20-40 mg/kg, i.p.) resulted in significant inhibition of ethanol self-administration in the right p-VTA in operant conditioning paradigm. Further, acute intracranial administration of agmatine (20 and 40 µg/rat) significantly reduced the ethanol consumption in the two bottle choice paradigm. Agmatine is degraded to putrescine and guanido-butanoic acid by the enzyme agmatinase and diamine oxidase respectively and inhibition of these enzymes results in augmentation of endogenous agmatine. In the present study, diamine oxidase inhibitor, aminoguanidine and agmatinase inhibitor, arcaine were used to block the agmatine metabolic pathways to increase brain agmatine levels. Drugs that augment endogenous agmatine levels like L-arginine (80 µg/rat, i.c.v.) or arcaine (50 µg/rat, i.c.v.) and aminoguanidine (25 µg/rat, i.c.v.) also reduced the ethanol consumption following their central administration. The pharmacological effect of agmatine on ethanol consumption was potentiated by imidazoline receptor agonists, I1 agonist moxonidine (25 µg/rat, i.c.v.), and imidazoline I2 agonist, 2-BFI (10 µg/rat, i.c.v.) and was blocked by imidazoline I1 antagonist, efaroxan (10 µg/rat, i.c.v.), and I2 antagonist, idazoxan (4 µg/rat, i.c.v.) at their ineffective doses per se. Thus, our result suggests the involvement of imidazoline I1 and I2 receptors in agmatine induced inhibition of ethanol consumption in rats.

Dysregulation of IRAS/nischarin and other potential I1-imidazoline receptors in major depression postmortem brain: Downregulation of basal contents by antidepressant drug treatments.

BACKGROUND: Major depressive disorder (MDD) has been associated with altered brain densities of imidazoline receptors (I1-IR and I2-IR types). METHODS: The contents of potential I1-IR IRAS/nischarin (167kDa) and, for comparison, those of I1- (85kDa) and I2- (45kDa and 30kDa) IR proteins were quantified by western blotting in postmortem prefrontal cortex (PFC/BA9) of antidepressant-free ([MDD(-)], n=9) and antidepressant-treated ([MDD(+)], n=12) subjects and matched controls (n=19). RESULTS: In MDD, regardless of antidepressant treatment (n=21), IRAS/nischarin was not altered in PFC/BA9. However, the content of IRAS/nischarin was found modestly and not significantly increased (+19%, p=0.075) in MDD(-) and significantly decreased (-24%, p=0.001) in MDD(+), revealing that basal I1-IR content was downregulated by antidepressants. Putative 85kDa I1-IR was upregulated (+35%, p=0.035) in MDD(-) but it was not reduced (-14%, p=0.37) in MDD(+). There was a positive correlation (r=0.33, p=0.037, n=40) between the contents of IRAS/nischarin and 85kDa IR proteins in PFC/BA9 (control and MDD subjects). In MDD and regardless of antidepressants, the content of cortical 45kDa I2-IR was increased (+31%, p=0.006) and that of 30kDa I2-IR decreased (-14%, p=0.002), indicating basal dysregulations of these potential IRs. LIMITATIONS: MDD(+) subjects had been treated with a variety of antidepressant drugs. The results must be understood in the context of suicide victims with MDD. CONCLUSIONS: The dysregulation of IRAS/nischarin in depressed brains is a major novel finding that supports a role of this potential I1-IR in the neurobiology of MDD and in the molecular mechanisms of antidepressant drugs.

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice.

This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

Circulatory effect of TCS-80, a new imidazoline compound, in rats.

BACKGROUND: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. METHODS: Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. RESULTS: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. CONCLUSION: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.

Constructing the ecstasy of MDMA from its component mental organs: Proposing the primer/probe method.

The drug MDMA, commonly known as ecstasy, produces a specific and distinct open hearted mental state, which led to the creation of a new pharmacological class, "entactogens". Extensive literature on its mechanisms of action has come to characterize MDMA as a "messy" drug with multiple mechanisms, but the consensus is that the distinctive entactogenic effects arise from the release of neurotransmitters, primarily serotonin. I propose an alternative hypothesis: The entactogenic mental state is due to the simultaneous direct activation of imidazoline-1 (I1) and serotonin-2 (5-HT2) receptors by MDMA. This hypothesis emerges from "mental organ" theory, which embodies many hypotheses, the most relevant of which are: "Mental organs" are populations of neurons that all express their defining metabotropic receptor, and each mental organ plays a distinct role in the mind, a role shaped by evolution as mental organs evolve by duplication and divergence. Mental organs are the mechanism by which evolution sculpts the mind. Mental organs can be in or out of consciousness. In order for a mental organ to enter consciousness, three things must happen: The mental organ must be activated directly at its defining receptor. 5-HT2 must be simultaneously activated. One of the functions of activated 5-HT2 is to load other simultaneously activated mental organs fully into consciousness. In some cases THC must be introduced to remove long-term blocks mediated by the cannabinoid system. I propose the "primer/probe" method to test these hypotheses. A "primer" is a drug that selectively activates 5-HT2 (e.g. DOB or MEM) or serotonin-1 (5-HT1) and 5-HT2 (e.g. DOET or 2C-B-fly). A "probe" is a drug that activates a receptor whose corresponding mental organ we wish to load into consciousness in order to understand its role in the mind. The mental organ is loaded into consciousness when the primer and probe are taken together, but not when taken separately. For example, the blood pressure medications rilmenidine and moxonidine are selective for imidazoline-1 and can be used to test the hypothesis that the entactogenic mental effects of MDMA are due to loading the imidazoline-1 mental organ into consciousness. The primer/probe method is not limited to testing the specific hypothesis about MDMA and imidazoline, but is a general method for studying the role of mental organs in the mind. For example, the role of dopamine mental organs can be studied by using Parkinson's drugs such as ropinirole or pramipexole as probes.

Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding.

RATIONALE: Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies. OBJECTIVE: This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. METHODS: Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. RESULTS: 2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. CONCLUSIONS: Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.

Vagotomy reveals the importance of the imidazoline receptors in the cardiovascular effects of marsanidine and 7-ME-marsanidine in rats.

BACKGROUND: The recently synthesized novel benzazole derivates - marsanidine (1-[(imidazolidin-2-yl)imino]indazole) and 7-Me-marsanidine (1-[(imidazolidin-2-yl)imino]-7-methylindazole) display promising effects on the circulatory system. We previously indicated that i.v. administration of both compounds decreased the mean arterial blood pressure (MAP) and heart rate (HR) in rats. The cardiovascular effect of the tested compounds may consist not only in inhibiting the sympathetic, but also in activating the parasympathetic pathways related to vagal nerves. Present experiments were performed to determine how vagotomy, with or without an α2 adrenoreceptor blockade, may affect hypotensive and HR limiting actions of marsanidine and 7-Me-marsanidine. METHODS: Both compounds were infused i.v. (10 µg/kg b.w.) to anesthetized rats, half of which underwent vagotomy. Half the intact, and half the vagotomised rats received RX821002, an α2 adrenorereceptor inhibitor. MAP and HR were monitored directly throughout the experiment. RESULTS: Vagotomy enhanced hypotension observed after marsanidine administration. The α2 adrenergic blockade abolished the action of marsanidine in both the intact and vagotomised rats. Vagotomy did not affect the 7-Me-marsanidine-induced decrease of MAP or HR. However, it abolished the reducing effect of the α2 adrenergic receptor blockade on the hypotension triggered by 7-Me-marsanidine. CONCLUSION: The results show that although cardiovascular effects of marsanidine and 7-Me-marsanidine are not mediated by the vagal nerves, vagotomy enhanced sensitivity of the sympathetic pathways for the tested compounds. While the action of marsanidine in vagotomised and intact rats may be explained by activation of the α2 adrenoreceptors, the effects of 7-Me-marsanidine seem to be α2 adrenoreceptor-independent. It seems likely that activation of I1 imidazoline receptors could mediate the observed effects.

Imidazoline binding sites mediates anticompulsive-like effect of agmatine in marble-burying behavior in mice.

Agmatine is a cationic amine formed by decarboxylation of l-arginine by the mitochondrial enzyme arginine decarboxylase and widely distributed in mammalian brain. Although the precise function of endogenous agmatine has been largely remained unclear, its exogenous administration demonstrated beneficial effects in several neurological and psychiatric disorders. This study was planned to examine the role of imidazoline binding sites in the anticompulsive-like effect of agmatine on marble-burying behavior. Agmatine (20 and 40mg/kg, ip), mixed imidazoline I1/α2 agonists clonidine (60µg/kg, ip) and moxonidine (0.25mg/kg, ip), and imidazoline I2 agonist 2- BFI (10mg/kg, ip) showed significant inhibition of marble burying behavior in mice. In combination studies, the anticompulsive-like effect of agmatine (10mg/kg, ip) was significantly potentiated by prior administration of moxonidine (0.25mg/kg, ip) or clonidine (30µg/kg,) or 2-BFI (5mg/kg, ip). Conversely, efaroxan (1mg/kg, ip), an I1 antagonist and idazoxan (0.25mg/kg, ip), an I2 antagonist completely blocked the anticompulsive-like effect of agmatine (10mg/kg, ip). These drugs at doses used here did not influence the basal locomotor activity in experimental animals. These results clearly indicated the involvement of imidazoline binding sites in anti-compulsive-like effect of agmatine. Thus, imidazoline binding sites can be explored further as novel therapeutic target for treatment of anxiety and obsessive compulsive disorders.

A new pyrroline compound selective for I1-imidazoline receptors improves metabolic syndrome in rats.

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.

Mydriasis model in rats as a simple system to evaluate α2-adrenergic activity of the imidazol(in)e compounds.

Imidazol(in)e compounds show the diversity of pharmacological effects including mydriasis, hypotension, sedation, bradycardia and hypothermia. At first it was postulated that these effects are mediated via α2-adrenoceptors exclusively. Clonidine is well known as a model agent to produce pupillary dilation in rats. However, it became obvious later that clonidine-like imidazol(in)e adrenoceptor agonists which produced mydriasis in rats, exhibit also a high affinity for imidazoline I1-receptors. That short report attempts to review the present status of studies to confirm that the mydriasis model in rats can be a selective system to evaluate the α2-adrenergic activity of potential pharmacologically active compounds of imidazol(in)e structure.

Adenosinergic modulation of the imidazoline I1-receptor-dependent hypotensive effect of ethanol in acute renal failure.

We reported that inhibition of central sympathetic pools of imidazoline I(1) receptors abolishes the hypotensive effect of ethanol in rats with glycerol-induced acute renal failure (ARF). This study investigated whether adenosine receptors modulate the ethanol-I(1)-receptor interaction. The effect of selective blockade of adenosine A(1), A(2A), or A(2B) receptors on hemodynamic responses to ethanol in the absence and presence of the I(1)-receptor agonist moxonidine was determined in ARF rats. Ethanol (1g/kg i.v.) decreased and increased blood pressure (BP) and heart rate (HR), respectively. Pretreatment with moxonidine abolished the hypotensive but not the tachycardic effect of ethanol. The hypotensive effect of ethanol remained unaltered after selective blockade of A(1), A(2A), or A(2B) receptors with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-(3-chlorostyryl) caffeine (CSC) and alloxazine, respectively. Neither was ethanol hypotension affected after inhibition of adenosine uptake by dipyridamole (DPY). Alternatively, the ability of moxonidine to abolish ethanol hypotension was still evident in presence of alloxazine whereas it disappeared or weakened in rats pretreated with CSC and DPCPX, respectively. These findings implicate adenosine A(2A) receptors in the moxonidine-evoked inhibition of the hypotensive action of ethanol. A modulatory role for adenosine A(1) site in the ethanol-I(1)-receptor interaction is also possible through as yet unidentified mechanism.

Agmatine inhibits morphine-induced memory impairment in the mouse step-down inhibitory avoidance task.

The effect of agmatine on memory formation in morphine-treated mice on the step-down inhibitory avoidance test was examined. Pre-training and pre-test administration of agmatine (5, 10 and 20mg/kg, s.c.) facilitated memory formation and retrieval while post-training administration of agmatine (5, 10 and 20mg/kg, s.c.) had no effect on memory consolidation. Idazoxan (5mg/kg, i.p.) inhibited the effect of agmatine on memory formation and retrieval. Pre-training administration of morphine (1.25, 2.5 and 5mg/kg, s.c.) impaired memory formation while post-training and pre-test administration of morphine (1.25, 2.5 and 5mg/kg, s.c.) had no effect on memory consolidation and retrieval. Pre-training agmatine treatment reversed the impairment of morphine on memory formation. Moreover, pre-test administration of agmatine inhibited morphine-induced amnesia. Pre-training and pre-test idazoxan (5mg/kg, i.p.) treatment inhibited the effect of agmatine on morphine induced memory impairment. In conclusion, agmatine inhibited morphine-induced memory impairment on the mice step-down inhibitory avoidance test. The mechanism was exerted, at least in part, through activation of imidazoline receptors.

Characterization of the postconditioning effect of dexmedetomidine in mouse organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation.

BACKGROUND: There is an increasing interest in the use of dexmedetomidine for anesthesia and sedation. Here, we used the mouse organotypic hippocampal slice culture to investigate whether dexmedetomidine exhibits postconditioning properties against oxygen and glucose deprivation (OGD). The role of the focal adhesion and extracellular-regulated kinases pathways in these effects were examined in both postconditioning and preconditioning. MATERIALS AND METHODS: Slices were obtained from P5 mouse. In postconditioning experiments, Dexmedetomidine (1 microm) was incubated 60 min after the end of OGD. In preconditioning experiments, dexmedetomidine was applied 3 h before OGD. Pharmacologic modulation of the studied pathways was achieved by using selective inhibitors of these cascades. Cell death was assessed 72 h after OGD using propidium iodide labeling and protein expression of activated caspase 3. RESULTS: Maximum cell death increased with the duration of OGD. Dexmedetomidine induced a postconditioning effect in the CA1 (but not dentate gyrus) subfield area, which was significantly reduced by modulators of the focal adhesion and the extracellular-regulated kinases pathways. The combination of the inhibitors of the two pathways completely abolished the postconditioning effect of dexmedetomidine. The preconditioning effect of dexmedetomidine against ischemia-induced injury was observed in all hippocampal subfield areas. Results obtained with the pharmacologic modulation used for postconditioning also applied to dexmedetomidine-induced preconditioning. DISCUSSION: Dexmedetomidine exhibits significant, but moderate, postconditioning properties against oxygen and glucose deprivation-induced injury. Activation of focal adhesion and the imidazoline 1 receptors-extracellular-regulated kinases pathways is involved in dexmedetomidine-induced postconditioning and preconditioning as well.

Synthesis and biological activity of some 2-imidazolinylhydrazone derivatives.

A series of N-(imidazolidin-2-ylidene)hydrazones and N-(4,5-dihydro-1H-imidazol-2-yl)-N-methylhydrazones were prepared and examined for alpha 1-, alpha 2-adrenergic and imidazoline I1, I2 receptors binding affinities as well as cytotoxic activity against human tumor cell lines. Among the compounds tested, 2-naphthaldehyde N-(imidazolidin-2-ylidene)hydrazone (3e) exhibited a significant affinity for both alpha 2-adrenergic and imidazoline I1 receptors (Ki = 94.3 nM and IC50 = 51.7 nM, respectively). Moreover, pyridine-2-carboxaldehyde N-(imidazolidin-2-ylidene)hydrazone (3l) showed the highest binding affinity to alpha 1-adrenoceptors (Ki = 24.6 nM), while quinoline-2-carboxaldehyde N-(imidazolidin-2-ylidene)hydrazone (3m) displayed the highest I2 affinity with a Ki value of 26.7 nM and a high selectivity with respect to alpha 2-adrenergic and imidazoline I1 receptors (Ki = 22470.0 nM and IC50 = 6145.0 nM, respectively). None of the tested N-(4,5-dihydro-1H-imidazol-2-yl)-N-methylhydrazones 4p-u displayed cytotoxic activity.

Facilitation of central imidazoline I(1)-site/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase signalling mediates the hypotensive effect of ethanol in rats with acute renal failure.

BACKGROUND AND PURPOSE: This study investigated the role of central sympathetic activity and related mitogen-activated protein kinase (MAPK) signalling in the cardiovascular effects of ethanol in a model of acute renal failure (ARF). EXPERIMENTAL APPROACH: The effects of pharmacological interventions that inhibit peripheral or central sympathetic activity or MAPK on the cardiovascular actions of ethanol in rats with ARF induced by glycerol were evaluated. KEY RESULTS: Glycerol (50%, 10 mL.kg(-1), i.m.) caused progressive increases and decreases in blood pressure (BP) and heart rate (HR) respectively. Subsequent i.v. ethanol (0.25 or 1 g.kg(-1)) elicited dose-related changes in BP (decreases) and HR (increases). These effects were replicated after intracisternal (i.c.) administration of ethanol. Blockade of nicotinic cholinoceptors (nAChR, hexamethonium, 20 mg.kg(-1)) or alpha(1)-adrenoceptors (prazosin, 1 mg.kg(-1)) attenuated cardiovascular effects of ethanol. Ethanol hypotension was also attenuated after the centrally acting sympatholytic drug moxonidine (selective I(1)-site agonist, 100 microg.kg(-1) i.v.), but not guanabenz (selective alpha(2)-receptor agonist, 30 microg.kg(-1), i.v.), suggesting involvement of central circuits of I(1) sites in ethanol-evoked hypotension. Selective blockade I(1) sites (efaroxan) but not alpha(2) (yohimbine) adrenoceptors abolished the hypotensive response to ethanol. Intracisternal administration of PD98059 or SB203580, inhibitors of extracellular signal-regulated kinase (ERK 1/2) and p38 MAPK, respectively, reduced the hypotensive action of moxonidine or ethanol. When used simultaneously, the two MAPK inhibitors produced additive attenuation of ethanol hypotension. CONCLUSIONS AND IMPLICATIONS: Sympathoinhibitory pathways of central I(1)-sites and downstream ERK/p38 MAPK signalling were involved in the hypotensive action of ethanol in ARF.