Abstract
Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11β-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3β and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.
Highlights
Glucocorticoids, cortisol in humans and corticosterone in rodents (CORT), are endogenous steroid hormones secreted by the adrenal glands under the regulation of the hypothalamicpituitary-adrenal (HPA) axis
It has been suggested that the cognitive impairment associated with type 2 diabetes may involve CORT [13, 14], and CORT hypersecretion has been reported in Alzheimer’s disease [15, 16] with the speed of cognitive decline being linked to increases in both blood and central nervous system CORT levels at the predementia clinical stage [17, 18]
Total-CORT levels in the hippocampus did not change as a consequence of Corticosteroid-binding globulin (CBG) deficiency (20.34 ± 2.62 vs. 22.31 ± 2.28 ng CORT/g protein in cbg+/+ and cbg-/- mice respectively, P = 0.512), but the free-CORT levels were slightly elevated in cbg-/- mice compared to those in cbg+/+ mice (20.90 ± 3.11 vs. 12.61 ± 3.45 ng CORT/g protein respectively, P = 0.047) (Fig 1B)
Summary
Glucocorticoids, cortisol in humans and corticosterone in rodents (CORT), are endogenous steroid hormones secreted by the adrenal glands under the regulation of the hypothalamicpituitary-adrenal (HPA) axis. They have pleiotropic functions involved in the stress response [1, 2], energy metabolism [3], reproductive function [4], and inflammatory and immune responses [5]. It has been suggested that the cognitive impairment associated with type 2 diabetes may involve CORT [13, 14], and CORT hypersecretion has been reported in Alzheimer’s disease [15, 16] with the speed of cognitive decline being linked to increases in both blood and central nervous system CORT levels at the predementia clinical stage [17, 18]
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