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Don't stress about CRF: assessing the translational failures of CRF1antagonists.

ABSTRACT: Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts.We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology.Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, (5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF2 receptor or CRF-binding protein molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation.The therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF's role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

SUBMITTER: Spierling SR

PROVIDER: S-EPMC5420464 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Don't stress about CRF: assessing the translational failures of CRF<sub>1</sub>antagonists.

Spierling Samantha R SR Zorrilla Eric P EP

Psychopharmacology 20170307 9-10

<h4>Background</h4>Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts.<h4>Methods</h4>We explore potential causes for the failure of CRF<sub>1</sub> antagonists and review recent findings concerning CRF-CRF<sub>1</sub> systems in psychopathology.<h4> ...[more]

PMID: 28265716

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Project description:BackgroundChronic stress is a major contributor in the development of metabolic syndrome and associated diseases, such as diabetes. High-fat diet (HFD) and sex are known modifiers of metabolic parameters. Peptide hormones corticotropin-releasing factor (CRF) and urocortins (UCN) mediate stress responses via activation and feedback to the hypothalamic-pituitary-adrenal (HPA) axis. UCN3 is a marker of pancreatic β-cell differentiation, and UCN2 is known to ameliorate glucose levels in mice rendered diabetic with HFD. CRF receptor 2 (CRF2) is the only known cognate receptor for UCN2/3. Here, we ascertained the role of CRF2 in glucose clearance, insulin sensitivity, and other parameters associated with metabolic syndrome in a mouse model of nutritional stress.MethodsWild-type (WT) and Crhr2-/- (null) mice of both sexes were fed either normal chow diet or HFD. After 8 weeks, blood glucose levels in response to glucose and insulin challenge were determined. Change in body and fat mass, plasma insulin, and lipid profile were assessed. Histological evaluation of liver sections was performed.ResultsHere, we show that genotype (Crhr2), sex, and diet were all independent variables in the regulation of blood glucose levels, body and fat mass gain/redistribution, and insulin resistance. Surprisingly, CRF2-deficient mice (Crhr2-/-) male mice showed similarly impaired glucose clearance on HFD and chow. HFD-fed female Crhr2-/- mice redistributed their fat depots that were distinct from wild-type females and male mice on either diet. Blood cholesterol and low-density lipoprotein (LDL) levels were elevated significantly in male Crhr2-/- mice; female Crhr2-/- mice were protected. Male, but not female Crhr2-/- mice developed peripheral insulin resistance. HFD, but not chow-fed wild-type male mice developed hepatic macrovesicular steatosis. In contrast, livers of Crhr2-/- male mice showed microvesicular steatosis on either diet, whereas livers of female mice on this 8-week HFD regimen did not develop steatosis.ConclusionsCRF2 receptor dysregulation is a sexually dimorphic risk factor in development of pre-diabetic and metabolic symptoms.

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Don't stress about CRF: assessing the translational failures of CRF1antagonists.

Publications

Don't stress about CRF: assessing the translational failures of CRF<sub>1</sub>antagonists.

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