Corticotrophin releasing factor

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Among a number of peptides studied it is only the reduction of somatostatin in the temporal, parietal and frontal cortices that correlates with the severity of dementia in AzD, although corticotrophin-releasing factor is lower. Reductions in somatostatin do not generally parallel those of ChAT, its concentration being almost normal in the hippocampus and nucleus basalis, where ChAT levels are lowest and there is no evidence that it is localised in cholinergic neurons. 

Swerdlow N. R., Koob G. F. (1985). Separate neural substrates of the locomotoractivating properties of amphetamine, heroin, caffeine and corticotrophin releasing factor (CRF) in the rat. Pharmacol. Biochem. Behav. 23, 303-7. 

Substance P Cholecystokinin Corticotrophin-releasing factor Melatonin... 

Neuropeptides are often grouped by their structural similarity or tissue source. Among these are the hypothalamic releasing factors (e.g., corticotrophin-releasing factor [CRF], thyrotropin-releasing hormone), anteior pituitary hormones (e.g., adrenocorticotrophic hormone [ACTFI], follicle-stimulating hormone [FSFI]), and posterior pituitary hormones... 

Several neurotransmitter and receptor changes are observed in Alzheimer s disease (Nordberg 1992). Losses occur in nicotinic receptors, but muscarinic receptors are relatively preserved. Reductions are also seen in serotonin 5-HTl and 5-HT2 receptors. Glutamate NMDA receptors decrease, while kainate receptors increase. j8-adrenergic and dopamine receptors are preserved. Decreases occur in receptors for somatostatin and neuropeptide Y, but corticotrophin-releasing factor receptors increase. Across all receptor subtypes for which there is a loss, the number of receptors decrease but the affinity constant remains unchanged. 

Recent in vitro hybridization studies in the rat have demonstrated that t)rpical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the s)mthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid s)mthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRT) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB (1997) Corticotrophin-releasing factor receptors from molecular biology to drug design. Trends Pharmacol Sci 17 166-172... 

Lightman SL, Young WS 3rd (1988) Corticotrophin-releasing factor, vasopressin and proopiomelanocortin mRNA responses to stress and opiates in the rat. J Physiol 403 511-523 Lolait SJ, O Carroll AM, Mahan LC, Felder CC, Button D, Yoimg III WS, et al (1995) Extra-pituitary expression of the rat Vlb vasopressin receptor gene. Proc Natl Acad Sci USA 92 6783-6787... 

Nemeroff, C.B., Bissette, G., Akil, H., and Fink, M. (1991) Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin. Br J Psychiatry 158 59-63. 

Anonymous. Corticorelin ACTH RF, corticoliberin, corticotrophin-releasing hormone, corticotropin-releasing factor, human corticotropin-releasing hormone, ovine corticotrophin-releasing factor, Xerecept. Drugs R D 2004 5(4) 218-9. 

Dunn AJ, Berridge CW. Physiological and behavioral responses to corticotrophin-releasing factor administration is CRF a mediator of. anxiety or stress responses Brain Res Rev 1990 15 71-100. 

Fawcett et al. proposed four hypothetical pathways leading to suicide in clinical depression an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor levels, trait baseline and reactivity hopelessness, severe anhedonia, and trait impulsiveness associated with low brain serotonin turnover, with low total cholesterol as a... 

Corticotrophin releasing factor ligands - alpha helical CRF has been shown to block the anxiogenic effects of alcohol withdrawal in rats. It is possible that CRF interacts with neuropeptide Y receptors NPY 1 receptor agonists to have anticonflict effects in animal studies. 

Reduction in somatostatin and corticotrophin releasing factor immunoreactivity in cortex. No convincing evidence of change in die concentration of substance P, enkephalins, cholecystokinin, neuropeptide Y, glutamate, aspartate or GABA... 

Figure 18.2. Endocrine-immune inter-relationship in normal subject. The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are corticotrophin releasing factor (CRF), arginine vasopressin (AVP) and adrenocorticotrophic hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (e.g. hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

The effect of stress on the endocrine and immune systems depends upon its duration and severity. Following acute stress, the rise in ACTH in response to the release of corticotrophin releasing factor (CRF) from the hypothalamus results in a rise in the synthesis and release of cortisol from the adrenals. The increase in the plasma cortisol concentration results in a temporary suppression of many aspects of cellular immunity. Due to the operation of an inhibitory feedback mechanism, stimulation of the central glucocorticoid receptors in the hypothalamus and pituitary causes a decrease in the further release of CRF, thereby decreasing the further... 

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

Flores M, Carvallo P, Aguilera G (1990) Physicochemical characterization of corticotrophin releasing factor receptor in rat pituitary and brain. Life Sci 47(22) 2035—40... 

Q4 Glucocorticoid secretion is controlled by the hypothalamus and anterior pituitary gland. Corticotrophin releasing factor (CRF) is produced in the hypothalamus and travels in the hypophyseal portal blood vessels to the anterior pituitary to release ACTH (adrenocorticotrophic hormone). There is a daily (circadian) rhythm in CRF and ACTH secretion, with a peak in the morning between 7 and 9 a.m. and a low point during the night. 

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