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Heart failure (HF) and cardiovascular diseases present public health challenges. Although great progress was achieved in their treatment, there is continuous need for new therapies. Urocortins of the corticotropin neuropeptide family were reported to exert beneficial effects in animal models of HF and cardiovascular diseases. We aimed to assess the available clinical evidence on the potential role of urocortins in HF and other cardiovascular diseases. We explored MEDLINE, Embase, CENTRAL, and Scopus databases. Twenty-seven studies were included in the qualitative and 15 studies (2005 patients) in the quantitative syntheses. Available data allowed us to meta-analyze the blood pressure (BP) lowering and heart rate (HR) increasing effects of urocortin 2 in HF with reduced ejection fraction. We applied meta-regression to explore the association between left ventricular ejection fraction and serum urocortin 1 and urocortin 2 levels. Short-term urocortin 2 infusion decreased mean arterial pressure in chronic HF with reduced ejection fraction (mean difference = -9.161 mmHg, 95% confidence interval [CI] -12.661 to -5.660 mmHg, p < 0.001). Such infusions increased HR mildly (mean difference = 5.629 beats/min, 95% CI 1.612 to 9.646 beats/min, p = 0.006). Although some studies reported increased urocortin 1 and urocortin 2 levels in HF with growing severity, our meta-regressions failed to confirm associations between blood urocortin levels and left ventricular ejection fraction. Clinical evidence confirms short-term BP lowering effects of urocortin 2, whereas individual studies report additional beneficial effects. Further clinical investigations are necessary to confirm the latter and the long-term value of these peptides in cardiovascular diseases. Review protocol: CRD42020163203., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Urocortin-2 (Ucn-2) is a peptide of the corticotrophin releasing factor-related family with several effects within the cardiovascular system. A variety of molecular mechanisms has been proposed to underlie some of these effects, although others remain mostly hypothetical. Growing interest in the cardiovascular properties of this peptide promoted several pre-clinical studies in the settings of heart failure and ischemia, as well as some experiments in the fields of systemic and pulmonary arterial hypertension. Most of these studies report promising results, with Ucn-2 showing therapeutic potential in these settings, and few clinical trials to date are trying to translate this potential to human cardiovascular disease. Ucn-2 also appears to have potential as a biomarker of diagnostic/prognostic relevance in cardiovascular disease, this being a recent field in the study of this peptide needing further corroboration. Regarding the increasing amount of evidence in Ucn-2 investigation, this work aims to make an updated review on its cardiovascular effects and molecular mechanisms of action and therapeutic potential, and to identify some research barriers and gaps in the study of this cardioprotective peptide.

Several peptides play an important role in physiological and pathological conditions into the cardiovascular system. In addition to well-known vasoactive agents such as angiotensin II, endothelin, serotonin or natriuretic peptides, the vasoconstrictor Urotensin-II (Uro-II) and the vasodilators Urocortins (UCNs) and Adrenomedullin (AM) have been implicated in the control of vascular tone and blood pressure as well as in cardiovascular disease states including congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Therefore these peptides, together with their receptors, become important therapeutic targets in cardiovascular diseases (CVDs). Circulating levels of these agents in the blood are markedly modified in patients with specific CVDs compared with those in healthy patients, becoming also potential biomarkers for these pathologies. This review will provide an overview of current knowledge about the physiological roles of Uro-II, UCN and AM in the cardiovascular system and their implications in cardiovascular diseases. It will further focus on the structural modifications carried out on original peptide sequences in the search of analogues with improved physiochemical properties as well as in the delivery methods. Finally, we have overviewed the possible application of these peptides and/or their precursors as biomarkers of CVDs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Key Points: Impaired ventilatory capacity and diaphragm muscle weakness are prominent features of Duchenne muscular dystrophy, with strong evidence of attendant systemic and muscle inflammation. We performed a 2-week intervention in young wild-type and mdx mice, consisting of either injection of saline or co-administration of a neutralizing interleukin-6 receptor antibody (xIL-6R) and urocortin-2 (Ucn2), a corticotrophin releasing factor receptor 2 agonist. We examined breathing and diaphragm muscle form and function. Breathing and diaphragm muscle functional deficits are improved following xIL-6R and Ucn2 co-treatment in mdx mice. The functional improvements were associated with a preservation of mdx diaphragm muscle myosin heavy chain IIx fibre complement. The concentration of the pro-inflammatory cytokine interleukin-1β was reduced and the concentration of the anti-inflammatory cytokine interleukin-10 was increased in mdx diaphragm following drug co-treatment. Our novel findings may have implications for the development of pharmacotherapies for the dystrophinopathies with relevance for respiratory muscle performance and breathing., Abstract: The mdx mouse model of Duchenne muscular dystrophy shows evidence of hypoventilation and pronounced diaphragm dysfunction. Six-week-old male mdx (n = 32) and wild-type (WT; n = 32) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (xIL-6R; 0.2 mg kg -1 ) and corticotrophin-releasing factor receptor 2 agonist (urocortin-2; 30 μg kg -1 ) subcutaneously over 2 weeks. Breathing and diaphragm muscle contractile function (ex vivo) were examined. Diaphragm structure was assessed using histology and immunofluorescence. Muscle cytokine concentration was determined using a multiplex assay. Minute ventilation and diaphragm muscle peak force at 100 Hz were significantly depressed in mdx compared with WT. Drug treatment completely restored ventilation in mdx mice during normoxia and significantly increased mdx diaphragm force- and power-generating capacity. The number of centrally nucleated muscle fibres and the areal density of infiltrates and collagen content were significantly increased in mdx diaphragm; all indices were unaffected by drug co-treatment. The abundance of myosin heavy chain (MyHC) type IIx fibres was significantly decreased in mdx diaphragm; drug co-treatment preserved MyHC type IIx complement in mdx muscle. Drug co-treatment increased the cross-sectional area of MyHC type I and IIx fibres in mdx diaphragm. The cytokines IL-1β, IL-6, KC/GRO and TNF-α were significantly increased in mdx diaphragm compared with WT. Drug co-treatment significantly decreased IL-1β and increased IL-10 in mdx diaphragm. Drug co-treatment had no significant effect on WT diaphragm muscle structure, cytokine concentrations or function. Recovery of breathing and diaphragm force in mdx mice was impressive in our studies, with implication for human dystrophinopathies., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

The aim of the present study was to investigate the potential anxiolytic- and antidepressant-like actions of Urocortin 2 (Ucn2) and its two fragments, Ucn2 (1-21) and Ucn2 (22-38), in mice, in an attempt to identify the biologically active sequence of this 38 amino acid neuropeptide. In this purpose, male C57BL/6 mice were treated intracerebroventricularly (icv) with 0.125, 0.25, 0.5 and 1 µg/2 µl of Ucn2, Ucn2 (1-21) or Ucn2 (22-38). After 30 min, the mice were evaluated in an elevated plus-maze test and a forced swim test for anxiety- and depression-like behavior, respectively. Each test lasted 5 min. Ucn2 at dose of 0.25 µg/2 µl and Ucn2 (1-21) at dose of 0.125 µg/2 µl, but not Ucn2 (22-38), increased significantly the number of entries into and the time spent in the open-arms, without influencing the total number of entries. In parallel, the same doses of Ucn2 and Ucn2 (1-21), but not Ucn2 (22-38), increased significantly the climbing and the swimming activity, while decreasing significantly the time of immobility. In addition, Ucn2 at doses of 0.125 µg/2 µl and 0.5 µg/2 µl decreased significantly the time of immobility, but they did not change the other parameters. The present study demonstrates that Ucn2 exerts anxiolytic- and antidepressant-like effects in C57BL/6 mice, which are mediated by the N-terminal, but not the C-terminal fragment of the peptide. The establishment of the smallest active sequence by further fragmentation of Ucn2 (1-21) may allow the synthesis of new anxiolytic and antidepressant drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: There has been a constant pursuit for development of newer therapies which can contribute to the relatively nascent field of cardioprotection in the setting of myocardial ischemiareperfusion injury. One novel cardioprotective agent among others, that has shown promising results in the limited number of research studies undertaken till now, is Urocortin. Urocortins are peptides belonging to the Corticotropin-Releasing Hormone family., Results: Acting through a variety of downstream mechanisms, urocortin has been shown to alter cellular metabolism and modulate the mechanism of cell death occurring as a result of ischemia-reperfusion injury. New evidence continues to accumulate in support of urocortin's beneficial role in cytoprotection., Conclusion: We present here an updated review largely focused on the various mechanisms through which urocortin alters cellular metabolism, and discuss the clinical potential of urocortin's cardioprotective ability in myocardial ischemia-reperfusion injury., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aims: Hemodynamic instability occurs following cardiac arrest and is associated with high mortality during the post-cardiac period. Urocortin is a novel peptide and a member of the corticotrophin-releasing factor family. Urocortin has the potential to improve acute cardiac dysfunction, as well as to reduce the myocardial damage sustained after ischemia reperfusion injury. The effects of urocortin in post-cardiac arrest myocardial dysfunction remain unclear., Methods and Results: We developed a preclinical cardiac arrest model and investigated the effects of urocortin. After cardiac arrest induced by 6.5 min asphyxia, male Wistar rats were resuscitated and randomized to either the urocortin treatment group or the control group. Urocortin (10 μg/kg) was administrated intravenously upon onset of resuscitation in the experimental group. The rate of return of spontaneous circulation (ROSC) was similar between the urocortin group (76%) and the control group (72%) after resuscitation. The left ventricular systolic (dP/dt40) and diastolic (maximal negative dP/dt) functions, and cardiac output, were ameliorated within 4 h after ROSC in the urocortin-treated group compared to the control group (P<0.01). The neurological function of surviving animals was better at 6 h after ROSC in the urocortin-treated group (p = 0.023). The 72-h survival rate was greater in the urocortin-treated group compared to the control group (p = 0.044 by log-rank test). Cardiomyocyte apoptosis was lower in the urocortin-treated group (39.9±8.6 vs. 17.5±4.6% of TUNEL positive nuclei, P<0.05) with significantly increased Akt, ERK and STAT-3 activation and phosphorylation in the myocardium (P<0.05)., Conclusions: Urocortin treatment can improve acute hemodynamic instability as well as reducing myocardial damage in post-cardiac arrest myocardial dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Background: Renal dysfunction is a frequent complication and crucial determinant of outcome in acute decompensated heart failure (ADHF). The aim of the study was to assess urocortin 2 (Ucn2) as a short-term therapy in ADHF with a focus on its renal effects. Comparison was made with dobutamine to distinguish effects beyond pure inotropism., Methods: Sheep with ADHF received a 2-day infusion of a vehicle-control, Ucn2 or dobutamine (n=6/grp)., Results: Compared to controls, Ucn2 and dobutamine produced matched improvements in cardiac contractility and output and arterial pressure, whereas reductions in central venous and left atrial pressures were greater with Ucn2. Both agents comparably repressed ADHF-activated hormone systems with the exception of the natriuretic peptides, which fell significantly during dobutamine but not Ucn2. While Ucn2 and dobutamine increased creatinine clearance and urine volume similarly, only Ucn2 induced a significant natriuresis. Ucn2 also decreased collagen deposition in the heart and kidney and suppressed gene expression of collagen-1, transforming growth factor-β1, components of the angiotensin system (angiotensinogen, angiotensin-converting enzyme, type-1 receptor) and markers of hypertrophy (GATA binding protein-4, β-myosin heavy chain), apoptosis (caspase3) and inflammation/injury (interleukin-18, cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) in these tissues, while increasing cardiac natriuretic peptide mRNA. In contrast, dobutamine produced reduced or opposite effects on expression of these factors., Conclusions: Ucn2 administration in ADHF has favorable effects on hemodynamics, the natriuretic peptides and tissue mediators of inflammation, fibrosis, apoptosis and hypertrophy that stand in contrast to dobutamine. These data support Ucn2's potential as a renoprotective therapeutic in this setting., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Urocortin exerts neuroprotective effects in intracerebral hemorrhage (ICH) of rats. For pre-clinical trial, we intended to study the neuroprotective efficacy of human UCN (hUCN)-1, -2 and -3 in treating ICH rats. ICH was induced by infusing bacterial collagenase VII (0.23 U in sterile saline) to the striatum. The hUCN-1, -2, and -3 were administrated (2.5μg/kg, i.p.) at 1h after ICH insult, respectively. Neurological deficits were evaluated by modified Neurological Severity Scores. Brain edema and hematoma expansion was evaluated by coronal T2-WI and DWI magnetic resonance imaging on 1, 3, 6, 24, and 56h after ICH insult. Blood-brain barrier permeability was evaluated by Evans blue assay on day 3 after ICH. Brain lesion volume was evaluated by morphormetric measurement on day 7 after ICH. Our results demonstrated that the hUCN-1 significantly reduced hematoma, blood-brain barrier disruption and neurological deficits on day 3, and brain lesion volume on day 7 after ICH insult. The prediction of secondary structure of the hUCNs clarifies that the percentage of alpha-helix, random coil and extended strand between rat-UCN (rUCN)-1 and hUCN-1 are the same. The structure similarity between human- and rat-UCN-1 may be one of the reasons that both can exert similar therapeutic potential in ICH rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Urocortin (Ucn)-2 - corticotropin-releasing hormone receptor 2 signaling has favorable effects in the cardiovascular system, including coronary vasodilatation, with increased coronary blood flow and conductance and augmented cardiac contractility and output, as well as protection against ischemia/reperfusion injury. Indeed, several animal studies have confirmed the salutary therapeutic effects of Ucn-2 in chronic heart failure, with improvements in cardiac performance and animal survival. In addition, recent clinical trials have demonstrated the benefits of Ucn-2 in patients with stable chronic heart failure on optimal medical therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Urocortin (UCN) has exhibited antiinflammatory and neuroprotective effects on intracerebral hemorrhage (ICH). However, the underlying mechanisms are still not clear. Therefore, this study was aimed to investigate effects of UCN1 on ICH in vitro and in vivo and further explore the possible mechanism. ICH was induced by an infusion of autologous blood into the unilateral striatum of anesthetized male Sprague-Dawley rats. The rats were randomly divided into three groups (8 rats per group): sham ICH control group, ICH saline group and ICH UCN1 group. UCN1 was infused into the lateral ventricle after 1h post-ICH. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. The neurological cell metabolic activity of N2a and SH-SY5Y was detected by CCK-8. The level of VEGF, JNK and p38 were determined by enzyme-linked immunosorbent assay and western blot. Post-treatment with UCN1 could improve neurological deficits and reduce brain edema. Moreover, UCN1 could increase the metabolic activity of neuron cells dose-dependently and these effects could be abolished by corticotropin-releasing factor receptor 2 (CRFR2) antagonist anti-Svg-30. Furthermore, the level of VEGF, JNK and p38 were up-regulated by post-treatment with UCN1 via CRFR2. The protective effects of UCN1 against ICH are possibly mediated by activating the phosphorylation of JNK and p38 and further increasing the level of VEGF via CRFR2., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Urocortins (UCNs), peptides that belong to the corticotrophin-releasing hormone family, represent a novel group of inotropic agents that have a multifaceted effect on the body with significant effects on the cardiovascular, hemodynamic, neurohormonal, and renal systems. UCNs can potentially improve the overall picture of heart failure by targeting not only the cardiovascular and hemodynamic systems like many current inotropic agents but also other systemic tissues that contribute significantly to the mortality and morbidity of heart failure. The 3 types of UCNs (1, 2, and 3) have been shown in preclinical studies to be effective in improving cardiovascular, neurohormonal, and renal function. UCN 2 has been shown in clinical studies to induce significant cardiovascular benefit with limited systemic effects. UCNs, specifically UCNs 2 and 3, show great potential as additional treatment in the management of systolic heart failure.

Object: Intracerebral hemorrhage (ICH) accounts for about 15% of all deaths due to stroke. It frequently causes brain edema, leading to an expansion of brain volume that exerts a negative impact on ICH outcomes. The ICH-induced brain edema involves inflammatory mechanisms. The authors' in vitro study shows that urocortin (UCN) exhibits antiinflammatory and neuroprotective effects. Therefore, the neuroprotective effect of UCN on ICH in rats was investigated., Methods: Intracerebral hemorrhage was induced by an infusion of bacteria collagenase type VII-S or autologous blood into the unilateral striatum of anesthetized rats. At 1 hour after the induction of ICH, UCN (0.05, 0.5, and 5 μg) was infused into the lateral ventricle on the ipsilateral side. The authors examined the injury area, brain water content, blood-brain barrier permeability, and neurological function., Results: The UCN, administered in the ipsilateral lateral ventricle, was able to penetrate into the injured striatum. Posttreatment with UCN reduced the injury area, brain edema, and blood-brain barrier permeability and improved neurological deficits of rats with ICH., Conclusions: Posttreatment with UCN through improving neurological deficits of rats with ICH dose dependently provided a potential therapeutic agent for patients with ICH or other brain injuries.

A novel biodegradable brain drug delivery system, the lactoferrin (Lf) conjugated polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticle (Lf-NP) was constructed in this paper with its in vitro and in vivo delivery properties evaluated by a fluorescent probe coumarin-6. Lf was thiolated and conjugated to the distal maleimide function surrounding on the pegylated nanoparticle to form Lf-NP. TEM observation and ELISA analysis confirmed the existence of active Lf on the surface of Lf-NP. The results of qualitative and quantitative uptake studies of coumarin-6 incorporated Lf-NP showed a more pronounced accumulation of Lf-NP in bEnd.3 cells than that of unconjugated nanoparticle (NP). Further uptake inhibition study indicated that the increased uptake of Lf-NP was via an additional clathrin mediated endocytosis processes. Following intravenous administration, a near 3 fold of coumarin-6 was found in the mice brain carried by Lf-NP compared to that carried by NP. Intravenous injection of urocortin loaded Lf-NP effectively attenuated the striatum lesion caused by 6-hydroxydopamine in rats as indicated by the behavioral test, the immunohistochemistry test and striatal transmitter content detection results. The cell viability test and CD68 immunohistochemistry demonstrated the acceptable toxicity of the system. All these results demonstrated that Lf-NP was a promising brain drug delivery system with reasonable toxicity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Ischemia/reperfusion (I/R) damage in the heart occurs mainly during the first minutes of reperfusion. Urocortin (Ucn) is a member of the corticotrophin-releasing factor that has been identified as a potent endogenous cardioprotector peptide when used in pre- and postconditioning protocols. However, the underlying mechanisms are not completely elucidated. Here, we focused on intracellular calcium ([Ca(2+)](i)) handling by Ucn when applied in early reperfusion. We used Langendorff-perfused rat hearts to determine hemodynamic parameters, and confocal microscopy to study global [Ca(2+)](i) transients evoked by electrical stimulation in isolated cardiomyocytes loaded with fluorescence Ca(2+) dye fluo-3AM. We found that the acute application of Ucn at the onset of reperfusion, in isolated hearts submitted to ischemia, fully recovered the hearts contractility and relaxation. In isolated cardiac myocytes, following ischemia we observed that the diastolic [Ca(2+)](i) was increased, the systolic [Ca(2+)](i) transients amplitude were depressed and sarcoplasmic reticulum (SR) Ca(2+) load was reduced. These effects were correlated to a decrease in the Na(+)/Ca(2+) exchanger (NCX) activity. Importantly, Ucn applied at reperfusion produced a complete recovery in diastolic [Ca(2+)](i) and global [Ca(2+)](i) transient amplitude, which were due to NCX activity improvement. In conclusion, we demonstrated that [Ca(2+)](i) handling play an essential role in postconditioning action of Ucn., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Urocortin 3 (Ucn 3) and various Ucn 3 fragments were tested with regard to antidepressive action in a modified forced swimming test following icv administration to mice. The fragment Ucn 3 (34-36) proved ineffective, whereas Ucn 3 (18-38), Ucn 3 (19-27), Ucn 3 (28-38), Ucn 3 (34-38), and Ucn 3 (36-38) demonstrated antidepressive-like action by shortening the immobility time and increasing the climbing and swimming times. The shortest molecule which elicited most of the antidepressive effects was the tripeptide Ucn 3 (36-38), H-Ala-Gln-Ile-NH(2). The results indicate that the total sequence of Ucn 3 is not necessary for the antidepressive action of Ucn 3. Furthermore, the antidepressant actions of Unc3 (19-27) and Ucn 3 (36-38) can be blocked by the CRF2 receptor antagonist Astressin 2β. Establishment of the smallest active sequence of the molecule may allow the synthesis of analogs or mimetics for antidepressive drugs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The influence of intracerebroventricullary-administered urocortin-2, a selective corticotropin-releasing factor receptor 2 (CRF(2)) agonist, on rat anxiety-like behaviour, the expression of c-Fos and CRF, and plasma corticosterone levels was examined in the present study. When applied to animals exposed to the conditioned fear-induced context, urocortin-2 enhanced a conditioned freezing fear response. Urocortin-2 also significantly decreased rat exploratory activity in the open field test. Exogenous urocortin-2 increased the conditioned fear-induced expression of c-Fos in the central amygdala (CeA), and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), and revealed the effect of conditioned fear in the medial amygdala (MeA). In the fear-conditioned animals, immunocytochemistry showed an increase in the density of CRF-related immunoreactive complexes in the lateral septum (LS), 35min after urocortin-2 administration and 10min after the conditioned fear test, compared with saline-pretreated fear-conditioned animals. These data suggest a role of urocortin-2 in the behavioural and immunocytochemical responses to stress, in which it strengthens the measures of anxiety-like responses., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Aims: To test acute effects of the corticotropin-releasing factor-related peptide urocortin 2 (Ucn2) on left ventricular (LV) function and the propensity for ventricular arrhythmias in the isolated heart of an animal model of hypertension-induced heart failure., Methods and Results: Hearts from Dahl salt-sensitive rats with severe LV dysfunction were perfused according to Langendorff. Left ventricular developed pressure and the positive and negative derivatives of LV pressure were analysed before and after perfusion with Ucn2 (n = 15) or normal perfusion solution (control, n = 9). Intracellular calcium cycling parameters were assessed by surface fluorometry. Furthermore, monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were determined, the latter by a train-of-pulses method at increasing voltage to scan the vulnerable period of repolarization. Urocortin 2 significantly affected intracellular calcium cycling and improved LV contractile function and relaxation. Compared with baseline values, Ucn2 significantly decreased MAPD at 30, 50, and 90% repolarization and significantly increased VFT compared with baseline values. No changes were observed in control experiments., Conclusion: Administration of Ucn2 rapidly improves LV function and increases VF threshold in failing, isolated rat hearts with increased propensity for ventricular arrhythmias. These observations suggest a potential use of Ucn2 as a safe and novel agent for the treatment of acute heart failure.

Despite considerable therapeutic advances over recent years, chronic heart failure remains associated with significant morbidity and mortality. Further improvements in the treatment of this syndrome are therefore needed and this will require advances in the understanding of its underlying pathophysiology. This article reviews the literature regarding recently identified neurohormonal pathways that are declaring themselves as potential therapeutic targets in chronic heart failure.

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, alpha-helical CRF(9-41) (0, 1, 5, 10 microg/1 microl). The contribution of central CRF type 2 receptor (CRF(2)R) signaling was assessed with i.c.v. infusion of the selective CRF(2)R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 microg/1 microl). The role of the hypothalamic-pituitary-adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 mg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 mg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF(1)R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 microg dose of alpha-helical CRF(9-41) significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF(1)R and CRF(2)R signaling, such that blockade of CRF(1)R or activation of CRF(2)R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior.

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K(+) channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.

Background and Purpose: Renal function can be assessed by measuring albuminuria and glomerular filtration rate, and the latter is often estimated by creatinine clearance rate (Ccr). Transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are two important factors involved in the progressive loss of renal function in diabetic nephropathy (DN), especially in terms of albuminuria. We investigated the effect of urocortin 1 on renal function of rats with DN and the mechanisms involved., Experimental Approach: A modified rat model of DN (multiple injections of low-dose streptozotocin and complete Freund's adjuvant) and a rat mesangial cell line were used. Albuminuria and Ccr were measured or calculated. Expression and secretion of TGF-beta1 and VEGF were measured by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) or enzyme-linked immunosorbent assay (R&D System, Inc., Minneapolis, MA, USA). Urocortin 1 and astressin [a non-selective antagonist of corticotrophin-releasing factor (CRF) receptors] were given as daily injections for 8 weeks., Key Results: Treatment of DN rats with urocortin 1 decreased albuminuria, renal weight and overexpression of TGF-beta1 and VEGF but enhanced Ccr. Furthermore, VEGF mRNA was increased in kidneys of DN rats, and this increase was reduced by treatment with urocortin 1. The secretion of VEGF induced by TGF-beta1 in mesangial cells was inhibited by urocortin 1 pretreatment. Astressin given with urocortin 1 prevented most of the effects of urocortin 1, in our models, in vivo or in vitro., Conclusion and Implications: Our results strongly suggest that urocortin 1 improved renal function in rats with DN by inhibiting the overproduction of TGF-beta1 and VEGF.

Urocortin 2 (Ucn 2) is corticotropin-releasing factor (CRF) paralog that preferentially activates CRF(2) receptors. Ucns exert CRF(2)-mediated cytoprotective effects against ischemia-reperfusion injury in cardiomyocytes. However, little is known regarding potential retinoprotective effects of Ucns despite the known presence of CRF family peptides and their receptors (predominantly CRF(2 alpha)) in retina. Therefore, the present study investigated the effects of post-ischemic intravitreal Ucn 2 (2 nmol) administration on ischemia-induced retinal degeneration. Two-month-old rats were subjected to permanent bilateral common carotid artery occlusion, and their retinas were processed histologically after two weeks survival to determine the density of viable cells in the ganglion cell layer and the thickness of all retinal layers. In vehicle-treated subjects, carotid occlusion reduced retina thickness by approximately 60% as compared to sham-operated animals. In contrast, intraocular Ucn 2 treatment led to a marked amelioration of the retinal layers, and the thickness of all layers was significantly increased by 40% compared to ischemic vehicle-treated subjects. Ucn 2 treatment also increased the number of cells by 55% in the ganglion cell layer as compared to those from carotid-occluded retinas of vehicle-treated subjects. These findings suggest that intraocular Ucn 2 treatment may protect against ischemia-induced retinal degeneration, results with potential therapeutic implications for ophthalmic diseases.

The urocortins are members of the corticotropin releasing hormone (CRH) family of peptide hormones. The archetypal member of this family, CRH, plays an important role in regulating thermogenesis and homeostasis by acting centrally and systemically in target organs via its two receptors CRH-R1 and CRH-R2. However, by virtue of their much greater relative affinity for CRH-R2, the physiological effects of the urocortin peptides are largely restricted to peripheral organs such as the heart. A powerful cytoprotective effect of urocortin peptide administration against ischemia and reperfusion injury has been demonstrated in isolated cardiomyocyte models, as well as in the intact heart both in vitro and in vivo. Extremely promising data has shown the beneficial effect of treating pacing-induced heart failure in sheep with urocortin molecules. Though the efficacy and specificity of these molecules in humans is not yet established, molecular dissection of the cytoprotective pathways activated by urocortin peptides suggests that the beneficial effects may be separable from potentially deleterious effects.

We have recently observed that the corticotropin releasing factor related peptide urocortin (UCN) reverses key features of nigrostriatal neurodegeneration following intracerebral injection of either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS). To determine the potential therapeutic utility of UCN here we have studied whether these effects are sustained for several weeks following peptide injection. In addition we have studied whether UCN still shows efficacy in rats with more pronounced nigrostriatal lesions. Rats were lesioned using 6-OHDA or LPS and injected with UCN either 7 or 14 days later. At different time points animals were tested for rotational behaviour (apomorphine, 0.5 mg/kg) and subsequently implanted with bilateral dialysis probes into the striata. The following day rats were dialysed to estimate extracellular striatal dopamine (DA) and then sacrificed for estimation of striatal tissue DA and subsequent immunohistochemistry of TH(+) cells in the substantia nigra (SN). Toxin treated rats given UCN 7 days later showed clear evidence of reduced nigrostriatal damage both 28 and 84 days following UCN compared with saline injection. In rats given UCN 14 days after toxin injection, by which time deficits were maximal, a restoration of nigrostriatal damage was observed. This suggests that UCN is able to elicit a sustained restoration of functional nigrostriatal integrity and has the ability to produce a recovery in severely lesioned rats. These findings suggest that stimulation of CRF (probably CRF(1)) receptors could have therapeutic utility in PD.

Urocortin (UCN) functions via corticotrophin-releasing factor receptors (CRFRs), CRFR1 & 2. CRFR2 is reported to be a tonic suppressor of vascularization, implying its role in tumor angiogenesis. Here, it was found that UCN inhibited the growth of hepatocellular carcinoma (HCC) and reduced tumor microvessel density in nude mice. Hepatoma cells didn't express CRFRs whereas vessels expressed CRFRs, mainly CRFR2. In vitro three-dimensional culture assay showed UCN inhibited angiogenesis, this effect was abolished by CRFR2 antagonist, anti-sauvagine-30, demonstrating involvement of CRFR2. Furthermore, UCN inhibited the proliferation and promoted the apoptosis of endothelial cells and down-regulated VEGF expression in vivo via CRFR2.

Originally described as a nuclear protein that bends DNA, the high mobility group box 1 protein (HMGB1) has recently emerged as a necessary and sufficient late mediator of severe sepsis. HMGB1 is therefore a molecular target that provides a wide window for clinical intervention in sepsis. Vasoactive intestinal peptide (VIP) and urocortin are two well known anti-inflammatory neuropeptides that protect against several immune disorders by regulating a wide panel of inflammatory mediators. In this study, we demonstrate the therapeutic effect of VIP and urocortin in various models of established sepsis: both agents reduced lethality induced by cecal ligation and puncture or by injection of live Escherichia coli. The therapeutic effect of VIP and urocortin was accompanied by a decrease in systemic levels of HMGB1. In addition, administration of recombinant HMGB1 completely reversed the protective effect of VIP and urocortin in experimental sepsis. In vitro and ex vivo studies show that both VIP and urocortin down-regulate translocation of HMGB1 from the nucleus to the cytoplasm and its subsequent secretion by activated macrophages, suggesting that macrophages are major targets in the inhibitory activity of these neuropeptides. To our knowledge, VIP and urocortin are the first endogenous inhibitors of HMGB1 secretion shown to improve sepsis survival in a clinically relevant time frame.

Ucn2 (urocortin 2) is a recently discovered peptide with therapeutic potential in heart failure. As any new treatment is likely to be used in conjunction with standard ACEI (angiotensin-converting enzyme inhibitor) therapy, it is important that the combined effects of these agents are assessed. In the present study, we investigated the effects of Ucn2 and an ACEI (captopril) administered for 3 h, both separately and together, in eight sheep with pacing-induced heart failure. Ucn2 and captopril alone both increased CO (cardiac output; Ucn2>captopril) and decreased arterial pressure (captopril>Ucn2), left atrial pressure (Ucn2>captopril) and peripheral resistance (Ucn2=captopril) relative to controls. Compared with either treatment alone, combined treatment further improved CO and reduced peripheral resistance and cardiac preload, without inducing further falls in blood pressure. In contrast with the marked increase in plasma renin activity observed with captopril alone, Ucn2 administration reduced renin activity, whereas the combined agents resulted in intermediate renin levels. All active treatments decreased circulating levels of aldosterone (Ucn2+captopril>Ucn2=captopril), endothelin-1 and the natriuretic peptides (Ucn2+captopril=Ucn2>captopril), whereas adrenaline (epinephrine) fell only with Ucn2 (Ucn2+captopril=Ucn2), and vasopressin increased during captopril alone. Ucn2, both separately and in conjunction with captopril, increased urine output, sodium and creatinine excretion and creatinine clearance. Conversely, captopril administered alone adversely affected these renal indices. In conclusion, co-treatment with Ucn2 and an ACEI in heart failure produced significantly greater improvements in haemodynamics, hormonal profile and renal function than achieved by captopril alone. These results indicate that dual treatment with these two agents is beneficial.

Most of the evidence suggests that corticotropin-releasing hormone (CRH) is involved in mood disorders. The CRF receptors type 1 (CRF(1) receptors) elicit a stress response, and their natural and synthetic antagonists have been studied as possible drugs against depression, whereas CRF receptors type 2 (CRF(2) receptors) appear to alleviate the stress response and mediate anxiolytic action. Other CRF family peptides are urocortin 1 (Ucn 1), urocortin 2 (Ucn 2) and urocortin 3 (Ucn 3). Little is known about the action of Ucn 1, Ucn 2 and Ucn 3 on depressive disorders. Antidepressant-like effects of Ucn 1, Ucn 2 and Ucn 3 (0.13, 0.25 and 0.5 microg/2 microl, i.c.v.) were assayed in mice in a modified forced swimming test (FST). This modified FST predicts the clinical efficacy of an antidepressant drug through the scoring of immobility, climbing and swimming behavior. The study demonstrated that Ucn 1 had no action on any of parameters studied in the modified FST. Ucn 2 elicited antidepressive-like action by shortening the immobility time. Additionally Ucn 2 significantly increased the climbing and swimming times. Ucn 3 likewise displayed an antidepressive-like effect by shortening the immobility time, and increasing the climbing and swimming times. The results suggest that CRF(2) receptor stimulation by Ucn 2 or Ucn 3 leads to antidepressant-like action, but dual stimulation of the CRF(1) and CRF(2) receptors by Ucn 1 does not trigger antidepressant-like action in the modified mouse FST.

The corticotropin-releasing factor (CRF) system mediates stress responses. Extrahypothalamic CRF1 receptor activation has anxiogenic-like properties, but anxiety-related functions of CRF2 receptors remain unclear. The present study determined the effects of intracerebroventricular administration of a CRF2 agonist, urocortin 3, on behavior of male Wistar rats in the shock-probe, social interaction, and defensive withdrawal tests of anxiety-like behavior. Equimolar doses of stressin1-A, a novel CRF1 agonist, were administered to separate rats. The effects of pyrazolo[1,5-a]-1,3,5-triazin-4-amine,8-[4-(bromo)-2-chlorophenyl]-N, N-bis(2-methoxyethyl)-2,7-dimethyl-(9Cl) (MJL-1-109-2), a CRF1 antagonist, on behavior in the shock-probe test also were studied. Stressin1-A increased anxiety-like behavior in the social interaction and shock-probe tests. Stressin1-A elicited behavioral activation and defensive burying at lower doses (0.04 nmol), but it increased freezing, grooming, and mounting at 25-fold higher (1-nmol) doses. Conversely, systemic administration of MJL-1-109-2 (10 mg/kg) had anxiolytic-like effects in the shock-probe test. Unlike stressin1-A or MJL-1-109-2, i.c.v. urocortin 3 infusion did not alter anxiety-like behavior in the shock-probe test across a range of doses that reduced locomotion and rearing and increased grooming. Urocortin 3 also did not decrease social interaction, but it decreased anxiety-like behavior in the defensive withdrawal test at a 2-nmol dose. Thus, i.c.v. administration of CRF1 and CRF2 agonists produced differential, but not opposite, effects on anxiety-like behavior. Urocortin 3 (i.c.v.) did not consistently decrease or increase anxiety-like behavior, the latter unlike effects seen previously after local microinjection of CRF2 agonists into the septum or raphe. With increasing CRF1 activation, however, the behavioral expression of anxiety qualitatively changes from "coping" to "noncoping" and offensive, agonistic behaviors.