Search NEL Online

Evaluation Studies 2009; 30(1): 11-16 PubMed PMID: 19300389 Citation  Keywords:  Antidepressive Agents:pharmacology, Humans, Hypothalamo-Hypophyseal System:drug effects, Mood Disorders:drug therapy, Pituitary-Adrenal System:drug effects, Receptors, Glucocorticoid:physiology, Transcription, Genetic:physiology,.   

: Changes in the hypothalamic-pituitary-adrenal (HPA) axis are characteristic of major depression. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GR's in depressed patients. Review scientific evidences have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of corticotropin-releasing hormone (CRH) in various brain regions postulated to be involved in the causality of major depression. Hyperactivity of HPA axis is the main biochemical change, besides disturbed monoaminergic neurotransmission, observed in the patients suffering from a major depression. High incidence of depression in Cushing's syndrome as well as antidepressant effects of adrenocortical enzyme inhibitors in major depression support hypothesis that hyperactivity of HPA axis may be involved in pathogenesis of depression. Major alterations of the HPA axis that can be reversed by successful antidepressant therapy are often seen in depressed patients. A possible explanation for this is that the antidepressant-induced increase in GR's renders the HPA axis more sensitive to glucocorticoid feedback. This new insight into antidepressant drug action suggests a novel approach to the development of antidepressant drugs....

Read abstract  Full text PDF

Journal Article 2006; 27(1-2): 60-62 PubMed PMID: 16648774 Citation  Keywords:  Adrenocorticotropic Hormone:blood, Animals, Corticosterone:blood, Growth Hormone:blood, Injections, Intraventricular, Male, Nerve Tissue Proteins:pharmacology, Pituitary-Adrenal System:drug effects, Prolactin:blood, Rats, Rats, Inbred WKY,.   

OBJECTIVE: It has been reported that the cocaine and amphetamine regulated transcript (CART) is widely expressed in the hypothalamic nuclei involved in the mechanism of hormonal secretion.

RESEARCH METHODS: In order to evaluate the effect of CART on the activation of the pituitary-adrenal axis in the rat, CART (55-102) in a dose of 0.5 microg in 5 microl CSF was infused into the third ventricle (icv) with an automatic pump. At 10, 30, 60, 120 min after the infusion of CART or vehicle, the animals were decapitated and the trunk blood was collected. Serum ACTH and corticosterone concentrations were measured with RIA kits provided by Phoenix Pharmaceuticals and ICN Biomedicals USA, respectively.

RESULTS: The stimulating effect of CART on ACTH concentration was observed only 30 min after icv injection. However, CART stimulated corticosterone release at 10, 30, 60 min after icv injection.

CONCLUSIONS: CART (55-102) administered intracerebroventricularly (icv) stimulated ACTH and corticosterone release. The stimulating effect of CART on ACTH was short-lived....

Read abstract

Comment 2005; 26(6): 757-758 PubMed PMID: 16380670 Citation  Keywords:  Circadian Rhythm:drug effects, Diabetes Mellitus, Type 2:blood, Double-Blind Method, Humans, Hydrocortisone:blood, Hypoglycemic Agents:pharmacology, Hypothalamo-Hypophyseal System:drug effects, PPAR gamma:agonists, Pituitary-Adrenal System:drug effects, T.   

OBJECTIVES: PPAR-gamma agonists are able to inhibit pituitary tumour development and tumoral hormonal secretion in rodents both in vitro and in vivo. Their use for treatment of Cushing Disease (CD) has been suggested but the clinical experience with the two PPAR-gamma agonists commercially available (rosiglitazone and pioglitazone) was not impressive. Short-time treatment has been proposed to be the cause of unsuccessful results on CD in humans. We report here the effect on early-morning plasma cortisol levels of a long-time treatment with rosiglitazone at the highest approved dose.

METHODS: Because PPAR-gamma receptors are located in normal corticotroph cells we tested in a placebo-controlled study the influence of rosiglitazone on cortisol secretion. The study enrolled 30 newly diagnosed type 2 patients which were assigned to receive either rosiglitazone (8 mg/day) or placebo. Plasma morning cortisol (8.00 a.m.) was measured at the baseline and at the end of the study.

RESULTS: Rosiglitazone vs placebo did not modify the early morning plasma levels of cortisol (13 microg/dl [3-21] vs 11 microg/dl [7-23] [median and range]) after 26 weeks of treatment.

CONCLUSION: The discrepancy between in vitro and animal data on one side and clinical data on the other side warrant further investigations into the mechanisms of action of PPAR-gamma agonists on ACTH secretion before other clinical studies will be conducted....

Read abstract  Full text PDF