The Role of Corticotropin-Releasing Factor (CRF) in Preclinical Models of Depression

신경호 대한정신약물학회 2010 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.8 No.2

Corticotropin-releasing factor (CRF) has been implicated in the pathophysiology of depression and anxiety, as it plays a critical role in the neuroendocrine, autonomic, and behavioral responses to stress. Moreover, CRF in the extrahypothalamic area has been closely linked to depression and anxiety. As recent studies have strengthened the view that CRF in the dorsal raphe nucleus and locus ceruleus is involved in preclinical animal models of depression, the recent progress concerning CRF is worthy of review. First, we describe the distribution and function of CRF in brain. Then, we present the role of CRF in preclinical animal models of depression. Further research on CRF and its receptors should help to clarify the pathophysiology of depression and improve the treatment of this debilitating disease.

사전 경험에 따라 편도체에서 부신피질 자극호르몬 방출인자를 분비하는 뉴런들이 행동에 미치는 영향

조용상 한국인지및생물심리학회 2020 한국심리학회지 인지 및 생물 Vol.32 No.4

The central nucleus of the amygdala (CeA) contains a group of cells that produce a neuropeptide, corticotropin releasing factor (CRF). The literature suggests that CRF in the CeA has a negative effect on behavior, such as increased anxiety and fear. However recent studies reported a conflicting result showing a rewarding effect of CRF. To understand how CRF lead to different behavioral effects, CRF neurons in the CeA were genetically manipulated to express a light-activated cation channel, channelrhodopsin-2, using CRF-cre mice. When the animals were initially tested to press a lever for light delivery in an operant conditioning (OP) and to visit one of two compartment for light presentation in a real-time place preference task (RTPP), CRF activation did not alter animals’ behavior at all. Stimulation of CRF neurons also failed to change animals’ anxiety levels compared to their control group in an elevated plus maze (EPM). After experiencing a lever press for food rewards for 5 days, however, CRF activation in the same mice induced rewarding effects in both OP and RTPP. Using a different set of mice, it was also examined whether CRF activation after forming fear memory resulted in negative effects on behavior. Indeed, CRF activation did not produce any effects before fear conditioning, but the same manipulation significantly elevated anxiety levels in EPM and induced aversive effects in RTPP after fear conditioning. These results demonstrate that CRF neurons can exert either positive or negative impacts on behavior depending on prior experiences. 편도체내에는 부신피질 자극호르몬 방출인자(corticotropin releasing factor, 이하 CRF)를 분비하는 뉴런들이 존재한다. 기존에는 CRF이 방출되면 불안 및 공포와 같은 부정적 행동결과를 초래한다고 알려져 있었으나, 최근 보상효과를 일으킨다는 상반된 주장이 제기되고 있다. 본 연구에서는 사전 경험에 따라서 CRF뉴런들의 활성화 효과가 달라질 수 있다는 가설을 검증하기 위해서 동물실험을 진행하였다. 유전자변형 동물들을 이용하여 광유전학적으로 편도체내의 CRF뉴런들을 선택적으로 활성화할 수 있도록 조작하였다. 사전에 특별한 경험이 없는 상태에서 CRF뉴런들을 활성화하였을 경우 통제집단과 비교해서 행동반응에 유의미한 차이가 관찰되지 않았다. 그러나 먹이 보상물을 이용한 도구적 조건화 훈련을 마친 뒤에 CRF뉴런들을 활성화하였을 때에는 이전 행동을 지속하게 만드는 보상효과를 유발하였다. 새로운 집단의 동물들을 대상으로 공포조건화 전후로 CRF활성화가 행동에 미치는 영향도 실험하였다. 공포를 경험하기 전에는 나타나지 않았으나, 공포기억을 형성한 후에 CRF뉴런들을 활성화하면 불안 및 기피행동을 관찰 할 수 있었다. 이러한 실험결과들은 사전 경험에 따라서 행동에 미치는 CRF의 영향이 달라지는 것을 보여준다. 따라서 편도체의 CRF뉴런들은 정서가치를 표상하는 것이 아니라, 최근에 형성한 경험 및 기억이 더 발현되도록 유도하는 기능을 하는 것으로 판단된다.

Special Review : Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

( Bruno K Rodino Janeiro ),( Carmen Alonso Cotoner ),( Marc Pigrau ),( Beatriz Lobo ),( Maria Vicario ),( Javier Santos ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2015 Journal of Neurogastroenterology and Motility (JNM Vol.21 No.1

The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal microflora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and supersystems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions.

Special Review : Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

( Yvette Tache ),( Mulugeta Million ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2015 Journal of Neurogastroenterology and Motility (JNM Vol.21 No.1

The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.

Special Review : Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis

( Eunok Im ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2015 Journal of Neurogastroenterology and Motility (JNM Vol.21 No.1

The family of corticotropin-releasing factor (CRF) composed of 4 ligands including CRF, urocortin (Ucn) 1, Ucn2, and Ucn3 is expressed both in the central nervous system and the periphery including the gastrointestinal tract. Two different forms of G protein coupled receptors, CRF1 and CRF2, differentially recognize CRF family members, mediating various biological functions. A large body of evidence suggests that the CRF family plays an important role in regulating inflammation and angiogenesis. Of particular interest is a contrasting role of the CRF family during inflammatory processes. The CRF family can exert both proand anti-inflammatory functions depending on the type of receptors, the tissues, and the disease phases. In addition, there has been a growing interest in a possible role of the CRF family in angiogenesis. Regulation of angiogenesis by the CRF family has been shown to modulate endogenous blood vessel formation, inflammatory neovascularization and cardiovascular function. This review outlines the effect of the CRF family and its receptors on 2 major biological events: inflammation and angiogenesis, and provides a possibility of their application for the treatment of inflammatory vascular diseases.

목단피(牧丹皮)가 강제수영부하시험에서 Corticotropin-Releasing Factor, c-Fos 와 Tyrosine Hydroxylase에 미치는 영향

성영석,이태희,Sung, Young-Suk,Lee, Tae-Hee 대한한의학방제학회 2009 大韓韓醫學方劑學會誌 Vol.17 No.1

Objectives : The goal of this study was to investigate the effect of Moutan Cortex as antidepressant in forced swimming test(FST) model. Methods : The expressions of corticotropin-releasing Factor(CRF), c-Fos and tyrosine hydroxylase(TH) were measured with immunohistochemical method at paraventricular nucleus (PVN), locus coeruleus(LC) and ventral tegmental area(VTA). Results : The duration of immobility in the forced swimming test was significantly decreased in the Moutan Cortex 100 mg/kg treated group in comparison with the control group(p<0.01). CRF and c-Fos expressions at PVN were decreased in the Moutan Cortex 100mg/kg treated group in comparison with the control group. But only the expression of c-Fos was shown the significance(p<0.05). TH expressions at LC and VTA were significantly decreased in the Moutan Cortex 100mg/kg and 400mg/kg treated group in comparison with the control group(p<0.001). Conclusion : According to the results, Moutan Cortex has the antidepressant effect by showing the reduced immobility through the reduction of c-Fos expression at PVN and the reduction of TH expression at LC and VTA.

The Effect of Trimebutine on the Overlap Syndrome Model of Guinea Pigs

( Zahid Hussain ),( Da Hyun Jung ),( Young Ju Lee ),( Hyojin Park ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2018 Journal of Neurogastroenterology and Motility (JNM Vol.24 No.4

Background/Aims Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common gastrointestinal (GI) disorders and these patients frequently overlap. Trimebutine has been known to be effective in controlling FD co-existing diarrhea-dominant IBS, however its effect on overlap syndrome (OS) patients has not been reported. Therefore, we investigated the effect of trimebutine on the model of OS in guinea pigs. Methods Male guinea pigs were used to evaluate the effects of trimebutine in corticotropin-releasing factor (CRF) induced OS model. Different doses (3, 10, and 30 mg/kg) of trimebutine were administered orally and incubated for 1 hour. The next treatment of 10 μg/kg of CRF was intraperitoneally injected and stabilized for 30 minutes. Subsequently, intragastric 3 mL charcoal mix was administered, incubated for 10 minutes and the upper GI transit analyzed. Colonic transits were assessed after the same order and concentrations of trimebutine and CRF treatment by fecal pellet output assay. Results Different concentrations (1, 3, and 10 μg/kg) of rat/human CRF peptides was tested to establish the OS model in guinea pigs. CRF 10 μg/kg was the most effective dose in the experimental OS model of guinea pigs. Trimebutine (3, 10, and 30 mg/kg) treatment significantly reversed the upper and lower GI transit of CRF induced OS model. Trimebutine significantly increased upper GI transit while it reduced fecal pellet output in the CRF induced OS model. Conclusions Trimebutine has been demonstrated to be effective on both upper and lower GI motor function in peripheral CRF induced OS model. Therefore, trimebutine might be an effective drug for the treatment of OS between FD and IBS patients. (J Neurogastroenterol Motil 2018;24:669-675)

Stress-induced Alterations in Mast Cell Numbers and Proteinase-activated Receptor-2 Expression of the Colon: Role of Corticotrophin-releasing Factor

Kim, Dong Hoon,Cho, Young Ju,Kim, Jang Hee,Kim, Young Bae,Lee, Kwang Jae The Korean Academy of Medical Sciences 2010 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.25 No.9

<P>This study was performed in order to assess whether acute stress can increase mast cell and enterochromaffin (EC) cell numbers, and proteinase-activated receptor-2 (PAR2) expression in the rat colon. In addition, we aimed to investigate the involvement of corticotrophin-releasing factor in these stress-related alterations. Eighteen adult rats were divided into 3 experimental groups: 1) a saline-pretreated non-stressed group, 2) a saline-pretreated stressed group, and 3) an astressin-pretreated stressed group. The numbers of mast cells, EC cells, and PAR2-positive cells were counted in 6 high power fields. In proximal colonic segments, mast cell numbers of stressed rats tended to be higher than those of non-stressed rats, and their PAR2-positive cell numbers were significantly higher than those of non-stressed rats. In distal colonic segments, mast cell numbers and PAR2-positive cell numbers of stressed rats were significantly higher than those of non-stressed rats. Mast cell and PAR2-positive cell numbers of astressin-pretreated stressed rats were significantly lower than those of saline-pretreated stressed rats. EC cell numbers did not differ among the three experimental groups. Acute stress in rats increases mast cell numbers and mucosal PAR2 expression in the colon. These stress-related alterations seem to be mediated by release of corticotrophin-releasing factor.</P>

Corticotropin-releasing factor decreases IL-18 in the monocyte-derived dendritic cell

Lee, Hee Jung,Kwon, Yeon Sook,Park, Chang Ook,Oh, Sang Ho,Lee, Ju Hee,Wu, Wen Hao,Chang, Nam Soo,Lee, Min-Geol,Lee, Kwang Hoon Blackwell Publishing Ltd 2009 Experimental dermatology Vol.18 No.3

<P>Abstract: </P><P>Recent evidence suggests that crosstalk between mast cells, nerves and keratinocytes might be involved in the exacerbation of inflammatory conditions by stress, but the mechanism by which this occurs remains unclear. Corticotropin-releasing factor (CRF), which activates the hypothalamo-pituitary-adrenal (HPA) axis under stress, also has pro-inflammatory peripheral effects. However, there have been no reports about CRF receptor expression and the functional role of CRF in the dendritic cell (DC), which is considered to be the link between allergen uptake and the clinical manifestations of allergic diseases, such as atopic dermatitis. The purpose of this study was to investigate the expression of CRF receptors and the functional role of CRF in the monocyte-derived DC (MoDC) of atopic dermatitis patients and non-atopic healthy controls. In this study, mRNAs for CRF-R1&agr; and 1&bgr;, as well as the CRF-R1 protein, were detected in MoDCs. CRF-R2&agr; (but not R2&bgr; or R2&ggr;) mRNA and the CRF-R2 protein were present in MoDCs. Exposure of DCs to CRF resulted in a decrease of IL-18 in both atopic dermatitis patients and non-atopic healthy controls. However, CRF did not alter the expression of IL-6, CCL17, CCL18, and CCL22. Therefore, our results demonstrate that CRF could modulate immune responses by acting directly upon DCs.</P>

CRF1 길항제 스크리닝을 위한 에쿼린 기반 세포실험 개발연구

노효진(Noh, Hyojin),이승호(Lee, Sung-Hou) 한국산학기술학회 2015 한국산학기술학회논문지 Vol.16 No.11

corticotropin releasing factor(CRF)는 스트레스에 의해 유도되는 신경펩타이드 물질들 중 하나로서 모발의 손실 및 재성장에 영향을 미친다고 광범위하게 제기되어 왔다. 이에 CRF1 수용체 길항제 개발을 위하여 세포 내 칼슘 신호전달 기전 을 이용한 스크리닝 시스템을 개발하고 최적화 연구를 수행하고자 하였다. 이를 위하여 에쿼린 모체세포에 CRF1 수용체와 만능 G 단백질인 Gα16 유전자를 동시에 발현시켜 안정화 세포주를 구축하였다(HEK293a16/hCRF1). 표준 효현제인 sauvagine 의 반응이 임시 발현세포와 비교하여 안정화 세포주에서 농도 의존적 반응 범위가 12배 이상 증가하였으며(EC50:15.21±1.83 nM), 이에 따라 길항제 스크리닝에 필수적인 안정적인 신호와 높은 용매 허용도를 확보할 수 있었다. CRF1 수용체에 대한 표준 길항제인 antalarmin과 CP154526에 대한 IC50 수치는 각각 414.1±5.5와 290.7±1.9 nM로 확인되었는데 냉동보관세포의 경우에도 유사한 결과를 얻었다. 에쿼린 기반 세포 기능실험의 최적화 연구를 통해 구축된 CRF 수용체 안정화 세포주는 모발 의 재형성과 관련된 신규의 기능성 화장품 및 조절물질 개발 연구에 적극적으로 활용 가능 할 것으로 판단된다. Corticotropin-releasing factor(CRF), one of the stress driven neuropeptides, was widely proposed to influence hair loss and re-growth. For the development of receptor antagonists, the screening system based on intracellular calcium signal process was developed and optimized. The aequorin parental cells were transfected with CRF1 receptor and alpha 16 promiscuous G protein cDNA to establish HEK293a16/hCRF1, a stable cell line for the human CRF1 receptor. In HEK293a16/hCRF1 cells, the range of sauvagine dose response was 12-fold higher(EC50:15.21±1.83 nM) than in the transiently expressed cells, hence essential conditions for the antagonist screening experiments such as the robust signals and high solvent tolerance were secured. The standard antagonists for the CRF1 receptor, antalarmin and CP154526, resulted IC50 values of 414.1±5.5 and 290.7±1.9 nM, respectively. Similar results were presented with frozen HEK293a16/hCRF1 cells. Finally, our HEK293a16/hCRF1 cells with the aequorin based cellular functional assay can be a model system for the development of functional cosmetics and modulators that can have a clinical efficacy on hair re-growth.