Choline on the Brain? A Guide to Choline in Chronic Fatigue Syndrome
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What do we know about CT38/Urocortin II?

Discussion in 'Other Health News and Research' started by nanonug, Mar 19, 2018.

  1. nanonug

    nanonug Senior Member

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    Based on some detective work by people here on PR, the overhyped Cortene peptide CT38 appears to be Urocortin II, a selective agonist of the CRF2 receptor. I'm starting this thread as a way to force myself to learn about this peptide. I'll be posting any studies I find relevant here, together with some observations, and I invite others to do the same, if they so desire.
     
  2. Navid

    Navid Senior Member

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    Os this something that is available to patients for purchase?
     
  3. nanonug

    nanonug Senior Member

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    Urocortins: Actions in health and heart failure.
    https://www.ncbi.nlm.nih.gov/pubmed/28887029

    Abstract
    The urocortins (Ucns), endogenous peptides belonging to the corticotropin-releasing factor (CRF) family, are increasingly recognized as having diverse and important multi-system functions, especially within the cardiovascular system. The biological actions of the three Ucns (Ucn1, Ucn2, Ucn3) are mediated via G-protein-coupled CRF receptors, with both peptides and receptors widely distributed throughout tissues and organs contributing to pressure/volume homeostasis including the heart, vasculature, kidneys and adrenals. The Ucns activate a variety of signaling cascades in cardiomyocytes, vascular smooth muscle cells and endothelial cells including, but not limited to, adenyl cyclase/cAMP and several kinase pathways, with downstream effects comprising vasodilation, augmented cardiac contractility, and protection against hypoxic injury. Increasing evidence suggests the Ucns may be clinically significant molecules in the pathogenesis, treatment and/or management of several conditions, with some of the most compelling data demonstrating a therapeutic potential for the peptides in the setting of heart failure. Circulating levels of the Ucns are elevated in this setting, and antagonism of the endogenous peptides exacerbates manifestations of the syndrome in animal models. All three Ucns exert salutary hemodynamic, neurohormonal and renal effects in experimental heart failure and recent clinical trials have demonstrated hemodynamic benefits of Ucn2 administration.
     
  4. nanonug

    nanonug Senior Member

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    I don't think so.
     
  5. nanonug

    nanonug Senior Member

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    Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502432/

    Abstract
    Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein–coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3′-5′-cyclic adenosine monophosphate (cAMP)–dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.
     
  6. Ema

    Ema Senior Member

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    As far as I know, @Cort is the only one who has reported on Cortene at all and the company themself has been very cautious to keep expectations guarded but optimistic while they do a proper trial.

    I’m not sure at all how that reads as “overhyped”. What would you have them say instead?
     
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  7. nanonug

    nanonug Senior Member

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    Combined XIL-6R and urocortin-2 treatment restores MDX diaphragm muscle force
    https://www.ncbi.nlm.nih.gov/pubmed/28294390

    Abstract
    INTRODUCTION:
    Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration leading to immobility, respiratory failure, and premature death. As chronic inflammation and stress are implicated in DMD pathology, the efficacy of an anti-inflammatory and anti-stress intervention strategy in ameliorating diaphragm dysfunction was investigated.
    METHODS:
    Diaphragm muscle contractile function was compared in wild-type and dystrophin-deficient mdx mice treated with saline, anti-interleukin-6 receptor antibodies (xIL-6R), the corticotrophin-releasing factor receptor 2 (CRFR2) agonist, urocortin 2, or both xIL-6R and urocortin 2.
    RESULTS:
    Combined treatment with xIL-6R and urocortin 2 rescued impaired force in mdx diaphragms. Mechanical work production and muscle shortening was also improved by combined drug treatment.
    DISCUSSION:
    Treatment which neutralizes peripheral IL-6 signaling and stimulates CRFR2 recovers force-generating capacity and the ability to perform mechanical work in mdx diaphragm muscle. These findings may be important in the search for therapeutic targets in DMD. Muscle Nerve 56: E134-E140, 2017.
     
  8. nanonug

    nanonug Senior Member

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    The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response
    http://www.eurekaselect.com/150590/article

    Abstract:
    Background: Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and consequently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2.
    Objective: Here we review the past and current state of the CRF/CRFR field, ranging from pharmacological studies to genetic mouse models and virus-mediated manipulations.
    Results: Although it is well established that CRF/CRFR1 signaling mediates aversive responses, including anxiety and depression-like behaviors, a number of recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRF/CRFR1 circuits. In contrast, the UCN/CRFR2 system is less well understood and may possibly also exert divergent functions on physiology and behavior depending on the brain region, underlying circuit, and/or experienced stress conditions.
    Conclusion: A plethora of available genetic tools, including conventional and conditional mouse mutants targeting CRF system components, has greatly advanced our understanding about the endogenous mechanisms underlying HPA system regulation and CRF/UCN-related neuronal circuits involved in stress-related behaviors. Yet, the detailed pathways and molecular mechanisms by which the CRF/UCN-system translates negative or positive stimuli into the final, integrated biological response are not completely understood. The utilization of future complementary methodologies, such as cell-type specific Cre-driver lines, viral and optogenetic tools will help to further dissect the function of genetically defined CRF/UCN neurocircuits in the context of adaptive and maladaptive stress responses.
     
  9. nanonug

    nanonug Senior Member

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    The relationship of urocortin-2 with insulin resistance patients having PCOS
    https://www.tandfonline.com/doi/abs/10.1080/09513590.2016.1240772?journalCode=igye20

    Abstract
    In this study, we aimed to compare the serum urocortin-2 (UCN2) levels in women with polycystic ovary syndrome (PCOS) and healthy women. Thirty-eight patients with PCOS and 41 healthy women were included in the study whose age and BMI matched. The fasting serum glucose, insulin, free testosterone, hs-CRP and UCN2 levels of the all participants were examined. HOMA-IR formula was used in order to calculate the insulin resistance. Circulating UCN2 levels were significantly elevated in women with PCOS compared with controls (142.93 ± 59.48 versus 98.56 ± 65.01 pg/ml, p = 0.002). FBG, serum insulin, hs-CRP and HOMA-IR levels were found to be increased in women with PCOS. There was a positive correlation between UCN2 and free-testosterone in only PCOS group (r = 0.235, p = 0.027). Multivariate logistic regression analyses revealed that the odds ratio for PCOS was 2.31 for patients in the highest quartile of UCN2 compared with those in the lowest quartile (OR = 2.31, 95% CI = 1.88–2.83, p=0.021). Multiple linear regression analysis revealed that HOMA-IR, hs-CRP and free-testosterone independently predicted UCN2 levels (p < 0.05). UCN2 levels were significantly higher in PCOS cases when compared to control group. UCN2 is thought to be effective on pathophysiology of PCOS by paracrine and autocrine pathways.
     
  10. nanonug

    nanonug Senior Member

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    Selective CRF2 receptor agonists ameliorate the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice
    https://www.ncbi.nlm.nih.gov/pubmed/27693397

    Abstract
    The aim of the present study was to investigate the effects of the selective agonists of the corticotropin-releasing factor (CRF) 2 receptor, urocortin 2 (UCN 2) and urocortin 3 (UCN 3), on the anxiety- and depression-like signs induced by acute nicotine withdrawal in mice. In order to do so, male CFLP mice were exposed for 7 days to repeated intraperitoneal (IP) injection with nicotine or saline solution and 1day of acute withdrawal and then a single intracerebroventricular (ICV) injection with UCN 2, UCN 3 or saline solution. After 30min the mice were observed in an elevated plus-maze test or a forced swim test, for anxiety- and depression-like behavior. After 5min of testing, the plasma corticosterone concentration reflecting the activity of the hypothalamic-pituitary-adrenal (HPA) axis was also determined by a chemo-fluorescent method. Half of the animals were treated ICV and evaluated on the 8th day, the other half on the 9th day. On the 8th day, nicotine-treated mice presented signs of anxiolysis and depression, but no significant elevation of the plasma corticosterone concentration. On the 9th day, nicotine-treated mice exhibited signs of anxiety and depression and a significant increase of the plasma corticosterone levels. Central administration of UCN 2 or UCN 3 ameliorated the anxiety- and depression-like state including the hyperactivity of the HPA axis, developed during acute withdrawal following chronic nicotine treatment. The present study suggests that selective CRF2 receptor agonists could be used as a therapy in nicotine addiction.
     
  11. nanonug

    nanonug Senior Member

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    Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430862/

    Abstract
    Background
    The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.
    Methods
    Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.
    Results
    Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.
    Conclusions
    Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders.
     
  12. Hip

    Hip Senior Member

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    The Cortene Peptide CT38 inhibits the expression of the corticotropin-releasing hormone receptor 2 (CRF2) — ref: here. So that will result in less CRF2 receptor messaging.

    Whereas urocortin II activates CRF2, so that will have the opposite effect, increasing receptor messaging.

    Thus CT38 does not look to be the same as urocortin II.
     
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  13. nanonug

    nanonug Senior Member

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    That link gets me to an error page...
     
  14. Hip

    Hip Senior Member

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    OK, I fixed it: click here, and then select "Science" from the menu.
     
  15. nanonug

    nanonug Senior Member

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    Got it!

    In general (there are important exceptions) hitting a receptor hard with an agonist leads to downregulation of said receptor. This is not therefore inconsistent with CT38 being Urocortin II. I would expect an antagonist to upregulate CRF2.
     
  16. nanonug

    nanonug Senior Member

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    Going from 1) a mathematical model of the HPA-axis to, 2) a belief that certain states of this mathematical model accurately describe SEID to, 3) a belief that this experimental drug might "fix it" almost immediately, comes across to me as overhyping.
     
  17. Ema

    Ema Senior Member

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    A long shot? Sure. Overhyping? Nah.

    IF they were proceeding straight to sales at this point, by all means, cry snake oil. But when you have an idea that is at least somewhat plausible, why not test it? At the worst, maybe we will learn something new or unexpected. At the best, some people may get their lives back.

    Why not celebrate new researchers getting involved with MECFS at all? We can use all the interest we can get, even if this is a big nothing.
     
  18. Hip

    Hip Senior Member

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    There's been almost no publicity about CT38, apart from the very small website of Cortene, so I would not say there was any hype at all. One could say they are being optimistic, but I am glad someone is looking into this angle.


    Makes sense.

    I think CT38 is Procter and Gamble's drug PG873637, which is in fact a CRF2 receptor agonist (Cort's first blog mentions CT38 was first developed by Procter and Gamble, and Cortene then bought the licence).

    There are a few studies on PG873637 if you Google search.
     
    Last edited: Mar 19, 2018
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  19. nanonug

    nanonug Senior Member

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    Nice catch! I've see other studies mentioning P&G cloning urocortin II. Would PG873637 therefore be a urocortin II analog?

    EDIT: Just found this: https://www.ncbi.nlm.nih.gov/pubmed/16476507
     
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  20. Hip

    Hip Senior Member

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    So that study, which was done by Procter & Gamble, suggests CT38 / PG873637 might be a slightly modified urocortin II protein — modified to make CT38 more potent and effective than urocortin II.

    This paper describes PG873637 as "a CRF2R-selective CRF analogue" (the corticotropin-releasing factor family includes urocortin II).
     

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