Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease

Behan, Dominic P.; Heinrichs, Stephen C.; Troncoso, Juan C.; Liu, Xin Jun; Kawas, Claudia H.; Ling, Nicholas; Souza, Errol B. De

doi:10.1038/378284a0

Cited by 217 publications

(168 citation statements)

References 22 publications

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“…CRH signaling through CRH receptors is further complicated because CRH is bound to CRHbinding protein (CRH-BP) which has an affinity for CRH that is equal to or greater than the respective CRH receptors (Potter et al 1991). This 37-kDA protein binds 40-90% of total CRH and is present in most human brain regions at tenfold higher concentrations than total CRH, which points to a major role of CRH-BP as regulator of CRH, "buffering" its actions under conditions of excessive release (Behan et al 1995).…”

Section: Knock-out or Transgenic Manipulation Of Crh And Corticosteromentioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,978

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Knock-out or Transgenic Manipulation Of Crh And Corticosteromentioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,978

1,228

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“…1). The resulting acidic Ast analog [Glu 11,16 ]Ast (c max ϭ 290 M) showed a 40 times higher maximum solubility in aCSF compared with Ast (Table 4). However, [Glu 11 ]Ast, which was much more soluble at physiological pH than Ast, appeared to be less charged than Ast based on IEF measurements.…”

Section: Pharmacological Relevance Of Residue 22 Of H͞rcrfmentioning

confidence: 99%

“…Consistent with the results of experiments on CRFBPdeficient mice (9), the physiological role of endogenous CRFBP in the central nervous system may be at least in part to limit the availability of free ligand for CRFR-mediated actions in brain regions where CRFBP, CRFR, and CRF are colocalized. In addition, central injection of CRF antagonists such as ␣-helical CRF 9-41 (␣-hel-CRF 9-41 ) (10), which are bound by CRFBP with high affinity, may release endogenous CRF by displacement from CRFBP (11). Therefore, strategies to synthesize CRF analogs binding selectively to CRFBP or CRFR are of great importance for the investigation of CRF receptor-mediated brain functions.…”

mentioning

confidence: 99%

A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: Implications for the design of agonists and antagonists

Eckart

Jahn

Radulovic

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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In view of the observation that corticotropin-releasing factor (CRF) affects several brain functions through at least two subtypes of G protein-dependent receptors and a binding protein (CRFBP), we have developed synthetic strategies to provide enhanced binding specificity. Human͞rat CRF (h͞rCRF) and the CRF-like peptide sauvagine (Svg), differing in their affinities to CRFBP by two orders of magnitude, were used to identify the residues determining binding to CRFBP. By amino acid exchanges, it was found that Ala 22 of h͞rCRF was responsible for this peptide's high affinity to CRFBP, whereas Glu 21 located in the equivalent position of Svg prevented high affinity binding to CRFBP. Accordingly, [Glu 22 ]h͞rCRF was not bound with high affinity to CRFBP in contrast to [Ala 21 ]Svg, which exhibited such high affinity. Furthermore, the affinity of both peptides to either CRF receptor (CRFR) subtype was not reduced by these replacements, and their subtype preference was not changed. Thus, exchange of Ala and Glu and vice versa in positions 22 and 21 of h͞rCRF and Svg, respectively, serves as a switch discriminating between CRFBP and CRFR. On the basis of this switch function, development of new specific CRF agonists and antagonists is expected to be facilitated. One application was the modification of the CRF antagonist astressin (Ast), whose employment in animal experiments is limited by its low solubility in cerebrospinal fluid. Introduction of Glu residues into Ast generated with [Glu 11,16 ]Ast an acidic astressin, which efficiently antagonized in vivo the CRFR1-dependent reduction of locomotion induced by ovine CRF without detectable binding to CRFBP.

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“…2,13,15 In addition, physiological effects of CRH on hippocampal neurons have been found, including facilitation of memory retention and increased protein phosphorylation. 10,33 Conversely, abnormalities of CRH-mediated limbic neurotransmission may contribute to neurological disorders such as depression 43 or Alzheimer's disease. 10,33 The source of endogenous CRH that may act on hippocampal CRH receptors has been a focus of investigation.…”

mentioning

confidence: 99%

“…10,33 Conversely, abnormalities of CRH-mediated limbic neurotransmission may contribute to neurological disorders such as depression 43 or Alzheimer's disease. 10,33 The source of endogenous CRH that may act on hippocampal CRH receptors has been a focus of investigation. Scattered CRH-immunoreactive neurons had been described in the hippocampal formation, 41,48,53 and recent double-labeling and ultrastructural studies have demonstrated a robust population of CRH-expressing GABAergic interneurons in the hippocampal formation of non-stressed developing rats.…”

mentioning

confidence: 99%

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

et al. 2000

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Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide's expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration.Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges. Keywordshippocampus; corticotropin-releasing factor; c-fos; rat; hypothalamus; stress Corticotropin-releasing hormone (CRH) is a peptide with both neuroendocrine and neurotransmitter properties. 57 The neuroendocrine effects of CRH, the key mediator of the stress response, originate from clusters of peptidergic cells in the hypothalamic paraventricular nucleus (PVN). 24,34 CRH also functions as a neuromodulator in a number of NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 July 5. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript limbic and autonomic brain circuits. 21,22,24,43 CRH-producing neurons are widely but specifically distributed in the brain, 49 including a substantial CRH-expressing neuronal population located in the central nucleus of the amygdala (ACe), 22,53 a region considered as a major source for extra-endocrine CRH-mediated neurotransmission. 24 Abundant target neurons for CRH, expressing cognate receptors, have been demonstrated in the hippocampus. 2,13,15 In addition, physiological effects of CRH on hippocampal neuron...

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Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease

Cited by 217 publications

References 22 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: Implications for the design of agonists and antagonists

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

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