Download Pathophysiological roles

The physiological and
pathophysiological roles of the
Urocortins
Krisztina Kárpáti and Hélène Rivière
JPEMS 2015
2015-10-8
Content
• Introduction
• Physiological roles of the urocortins:
 Regulation of stress response
 Energy balance and expenditure
 Gastrointestinal motility and function
 Immune function
 Cardiovascular function
• Pathophysiological roles:
 Anxiety
 Depression
• Therapy
CRF and CRF-related peptides
• CRF (1981)  CRFR1  in stress response
- PVN of hypothalamus
• Ucn 1 (1995):
- structure similar to CRF
- 100-fold higher affinity to CRFR2
- Edinger-Westphal nucleus
• Ucn 2 and 3 (2001): CRFR2 selective ligands
• CRF binding protein
• These petides have different localisations and
differents affinity for the receptors
different physiological and
pathophysiological functions
Physiological roles
Regulation of the neuroendocrine
response to stress
• Dualism of CRF/Ucn2 and 3
• CFR/CRFR1 control the initiation of
stress, by the activation of the HPA
axis: production of glucocorticoids
Increase the blood sugar
availability
• Ucn 2,3/CRFR2 control the recovery
from stress, by the inhibition of the
HPA axis
essential to maintain body and
mental health under environmental
threating conditions
Role on energy balance and expenditure
• Ucns stimulate the energy expenditure and decrease the food
intake.
• Mediated by brain CRFR2 and mainly by Ucn1
• To enhance the energy expenditure Ucn 1 elevate the arterial
pressure, body temperature, stimulate the fat utilization and block
the effect of orexigen peptides
• Leptin is an anorexigen peptide which:
- contributes to the catabolic functions of the Ucns
- provide assistance for the peripheral Ucn 1 to get into the central
compartment
- stimulate the expression of brain CRFR2
Roles on the immune system: the dualistic
action of Urocortin 1
• Exogenous administration: reduce inflammation
- Inhibit cytokines and TNF release
- Have palliative effects in experimental models of autoimmune diseases
•
-
Endogenous Ucn1: pro-inflammatory effect
Ucn1 stimulates IL-1beta and IL-6 secretion by immune cells.
Mediated by CRFR1
Rheumatoid arthritis, endometriosis, asthma, gastritis, psoriasis, etc
• CRFR2: protective against CRFR1 deleterious effects ?
-the stomach is richer in CRFR2 than in CRFR1, and Ucn1 injection within the
stomach seems to repair gastric mucosa from injury.
Role on gastrointestinal motility and function
• Ucns inhibit gastric motility
- the gastric emptying is reduced
- responsible for the anorectic effects of Ucns?
- Mediated by brain CRFR2 (vagal efferents which inhibit gastric contractions) and gut
CRFR2
• Ucns stimulate colonic motor function
-
colonic motility ,
colonic transit time
- watery diarrhea
- Mediated by CRFR1
• Ucns participate in the “irritable bowel syndrome”
- painful gastrointestinal stimuli
- Nociception is increased by CRFR1 and reduced by CRFR2.
Protective and undesired effects on
cardiovascular function
• Inotropic effects:
cardiac contractility, heart rate and aortic blood flow
• Vasodilatory effects via CRFR2.
• Cardioprotective effect:
 in hypoxic stress
 in heart failure:
- Ucn 1 stimulate the synthesize of Atrial Natriuretic Peptide (ANP)
- ANP causes hemodynamic adaptations to heart failure, mediated by CRFR2.
• Undesired hypertrophic effects: Ucn1 expression is elevated in hypertrophic
cardiomyopathy and dilated cardiomyopathy
Pathophysiological roles
Anxiety
• CRF  HPA-axis  stress, anxiety
• CRF deficiency  aberrant stress response
• In mice: CRFR1 antagonist antalarmin  anxiolisis
• Ucn 1:
- exogenous administration: increased anxiety
- endogenous Ucn1: minor importance
• Ucn 2 and 3:
• CRFR2: anxiogenesis or no change
• homeostasis
Depression
• disturbances in HPA axis and
aberrant stress coping
• increased level of CRF in CSF in suicide victims
• decreased level CRFR1 in suicide victims
• Ucn 2 and 3:
• antidepressant-like
• Ucn 2 or CRFR2 deficiency  depression (altered recovery)
• Ucn 2 – serotonin level:
• Administration of Ucn 2  depressive-like behavior
• Localization-dependant effect
Therapeutical possibilities
• further researches
• anxiety and depression-like disorders  CRFR1 antagonists
• obesity: Ucn 1  CRFR2  increased energy expenditure
• cardioprotective effects: through CRFR2  reduce heart failure
• GI tract: CRFR2 antagonists  gastric motility increase
• inflammatory disorders
• cancer:
• CRF receprors expression are increased
• agonists may inhibit proliferaton
Acknowledegment
Department of Pathophysiology, University of Szeged
• Zsolt Bagosi M.D., Ph.D.
• Professor Dr. habil Gyula Szabó, M.D., Ph.D., D.Sc