Glucocorticoids Flashcards
Hay 2 types of corticosteroids. Describe these
Both synthesised and released from the adrenal cortex
Glucocorticoids (zona fasciculata): ‘Sugar’ hormone, carb & protein metabolism
Potent anti-inflammatory / immunosuppressant. eg= cortisol
Mineralocorticoids (zona glomerulosa): ‘Salt’ hormone, controls electrolyte & H2O in the kidney. eg=aldosterone
Describe control of cortisol release
The hypothalamus releases CRH and VP which acts on the anterior pituitary to release ACTH.
This acts on the adrenal cortex to release cortisol androgens
High levels of cortisol= Lower CRH and ACTH and vice versa
Give the effects of the glucocorticoids on metabolism
– Breaks down protein and fats (muscle wasting, etc.)
– Decreased glucose usage & increased gluconeogenesis
– The above + increased glycogen storage may increase hyperglycaemia tendency
Give the effects of the glucocorticoids on the CVS, CNS
CVS: decreases microvascular permeability & vasodilatation.
Na retention increases blood volume- can cause hypertension
CNS: mood changes, linked w changes in memory/stress
Explain the cellular mechanism of action of glucocorticoids
GC receptors=found intracellularly in almost all tissues.
Gccs enter cells via passive diffusion and form a complex w a receptor protein in the cytosol.
Irreversible activation: gcc binds to GCR + dissociates HSP
GCR complex translocates to nucleus and binds to DNA to alter gene expression
Eg it decreases expression of pro-inflammatory genes
How do GCs switch gene expression on and off?
Promoter regions contain Gcc Response Elements (GRE). When a steroid hormone binds to its receptor and occupies the GRE, it can turn on or off specific genes:
Steroid prevents gene activation by other transcription factors. Eg transcription factors AP-1 and NFκB can switch on pro-inflammatory COX-2, PLA2, IL-1, ICAM-1, IL-8, eotaxin, IκB-α genes
The steroid complex also induces IκB-α production (IkB alpha), which represses NF-κB–> less pro-inflammatory gene activation
How if NF-kB regulated?
IkB alpha (NF-kB inhibitor) keeps NF-kB in cytoplasm
If a cell receptor is occupied, eg by a hormone, it activates IKK (kinase).
This phosphorylates IkB alpha and degrades it by ubiquitin ligase
Once IkB alpha is degraded, NF-kB is free🤩 and can now translocate to the nucleus, control gene expression etc
Activation of NF-kB pathway= key in inflammatory response!
Induction of IkB alpha (inhibitor of NF-κB) causes NF-κB repression. What occurs as a result of this?
Leads to: increased expression of anti-inflammatory proteins:
Increased B2-adrenergic receptors, lipocortin which decreases AA/eicosanoids
Increased anti-inflammatory cytokines IL-10, IL-12
Decreased expression of pro-inflammatory proteins: TNF-alpha; IL-1B, endothelin-1
Give the therapeutic uses of GCs
Adrenal insufficiency or failure (Addison’s): congenital or drug-induced. Treatment=combined GC and MC
Inflammation: asthma, rhinitis, skin issues, sport injury, reduction of cerebral oedema in brain tumour patients
Immunosuppression: inhibit host reaction in tissue transplantation
Give examples of glucocorticoids
Hydrocortisone, prednisolone, dexamethasone, betamethasone, beclomethasone
Compare NSAIDs w GCs on Eicosanoid Biosynthesis using a diagram
Summarise the side effects of corticosteriods
A side-effect of corticosteroids is Cushing’s syndrome. Describe this
An example of an Endogenous mineralocorticoid is aldosterone. Describe its effects
Low Na+ plasma levels activate adrenal gland, stimulate RAAS to produce Ang II–>release aldosterone.
-Aldosterone increases Na+ retention in distal tubules of kidney
-Stimulates Na+/H+ exchanger
-Enters cells and up-regulates ENaC channels in cell membrane
-Causes H2O retention, and loss of K+ and H+
-Also up-regulates basolateral Na+/K+ ATPase pump which helps move sodium out of the cell and potassium into the cell.
Where are MCRs found?
Mineralocorticoid receptors found in only few tissues, kidney, colon, bladder
Give Therapeutic Uses of Mineralocorticoids
