Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
29
2010

Glucocorticoids

Drug Summary: Glucocorticoids are powerful anti-inflammatory compounds that have the ability to inhibit all stages of the inflammatory response. Common glucocorticoids include prednisone, dexamethasone, and hydrocortisone. While glucocorticoids are widely used as drugs to treat various inflammatory conditions, prolonged glucocorticoid use may have adverse side effects such as immunosuppression, fluid shifts, brain changes, and psychological changes. Physicians are therefore very cautious about prescribing these medications, especially for long periods of time.

What are glucocorticoids?^

Natural glucocorticoids are steroid hormones with powerful anti-inflammatory effects produced by the human body. Glucocorticoid drugs are usually synthetic compounds that have anti-inflammatory effects similar to those of natural glucocorticoids.

Natural glucocorticoids are produced by the cortex of the adrenal gland. The adrenal glands are organs located immediately above our kidneys (ad = top of, renal = kidney). They are divided into two distinct regions:

Drugs with glucocorticoid activity are compounds that have similar effects to the natural steroid hormones produced by the adrenal cortex. While glucocorticoid drugs are steroids, they are unlike the anabolic steroids that some athletes take to build up and increase their muscle mass. Glucocorticoids are catabolic steroids, which means that they are designed to break down the body’s stored resources through their various metabolic effects. As stated above, glucocorticoids have two principal effects in the body: metabolic and anti-inflammatory. It therefore follows that glucocorticoid drugs affect both metabolism and inflammation.

Metabolic Effects^

The name “glucocorticoid” derives from early observations that these hormones were involved in glucose (sugar) metabolism. During times when no food is being taken into the body, glucocorticoids stimulate several processes that serve to increase and maintain normal glucose concentrations in the blood. These processes include:

  • Stimulation of glucose production in cells, particularly in the liver.
  • Stimulation of fat breakdown in adipose (fat) tissues.
  • Inhibition of glucose and fat storage in cells.

Anti-Inflammatory Effects^

Glucocorticoids (both naturally produced and synthetic) are powerful anti-inflammatory compounds due to their ability to inhibit all stages of the inflammatory response, from redness to wound healing to cell proliferation. (For more on the relationship between inflammation and HD, click here). They affect all types of inflammatory responses, regardless of the mode of injury or type of disease-causing substance.

Glucocorticoids are steroid hormones, which can cross the cell membrane. Most of their effects involve interactions with intracellular receptors (receptors inside the cell). They bind to these receptors, and the hormone-receptor complex then enters the nucleus and acts as a transcription factor.

Transcription is the set of processes in the nucleus by which the base sequence “code” of DNA is converted to a sequence of complementary bases in mRNA. (For more on DNA, complementary and nitrogenous bases, click here.) Once mRNA is formed from transcription, it is transported into the cytoplasm where it is used as to help in the construction of a protein molecule. The process by which the protein molecule is formed from the mRNA blueprint is called translation.

Glucocorticoids bind to glucocorticoid receptors (GR) inside the cell and form a glucocorticoid-GR complex. This complex enters the nucleus and causes changes that alter the synthesis of mRNA from the DNA molecule, thereby altering the production of different proteins. Glucocorticoids can cause an increase in the production of certain proteins and a decrease in the production of other proteins by binding to key sites in the gene and enhancing or suppressing their transcription into mRNA. Glucocorticoids have also been found to cause changes in the mRNA molecule itself. Modifications to the mRNA can further alter the production of proteins in the cell.

Studies have shown that glucocorticoids can suppress the production of proteins involved in inflammation (resulting in their role as anti-inflammatory compounds). Aside from interfering with the transcription of enzymes involved in inflammation, glucocorticoids further suppress inflammation by activating a group of enzymes known as lipocortins. Lipocortins have been found to inhibit or slow the action of phospholipase A2 (PLA2), a key enzyme involved in the release of arachidonic acid (AA) from the cell membrane.

Arachidonic acids are a type of omega-6 fatty acid. The omega-6 fatty acids in our body often come from the vegetable oils and animal meats in our food. Once arachidonic acid is in our body, it is usually incorporated into our cell membranes. When a cell is damaged or under attack by foreign substances, arachidonic acid is released from the cell membrane and is converted into substances such as prostaglandins which mediate inflammation. Free arachidonic acid is converted into inflammatory prostaglandins by enzymes known as COX-2. (For more information on COX-2 enzymes, click here.)

Release of arachidonic acids require the activation of the enzyme PLA2. As stated previously, lipocortins inhibit PLA2 activity. By activating lipocortins, glucocorticoids cause the inhibition of PLA2, thereby inhibiting release of AA and consequent prostaglandin synthesis in the cell. Because lower amounts of inflammatory prostaglandins are synthesized, inflammation is suppressed and damage caused by chronic inflammation is decreased.

Glucocorticoids can also directly inhibit COX-2 enzymes directly. More details on these studies can be found at the section Research on Glucocorticoids.

Problems with glucocorticoid drugs^

We have discussed how glucocorticoids can have both metabolic and anti-inflammatory effects. So far, it has been impossible to give glucocorticoid treatments that have only anti-inflammatory effects. Glucocorticoids have been found to increase blood glucose levels as well as suppress calcium absorption through their various metabolic affects. As such, long-term anti-inflammatory therapy with glucocorticoids can often lead to swelling, skin changes, decreased immunity, and psychological changes. More severe side effects such as diabetes or osteoporosis can also occur (even short-term glucocorticoid therapy tends to cause the patient to become temporarily diabetic.) Moreover, patients on long-term glucocorticoid therapy must be gradually tapered off their medications when discontinuing them in order to avoid rebound effects produced by the body.

In addition to the difficulty of separating the metabolic and anti-inflammatory effects of glucocorticoids, most synthetic drugs often referred to as glucocorticoids are actually synthetic corticosteroids. These synthetic drugs have both mineralcorticoid and glucocorticoid activity. However, in a particular compound, one type of activity will predominate over the other. Synthesis of pure glucocorticoid drugs has so far been elusive.

Commonly prescribed steroid drugs:^

  • Prednisone and Prednisolone – Most commonly used glucocorticoid because of its high glucocorticoid activity. Prednisone is transformed by the liver into prednisolone. Prednisolone may be administered in tablet form or produced by the body from prednisone. These medications are often considered to be interchangeable.
  • Dexamethasone – Has a particularly high glucocorticoid activity and low mineralcorticoid activity and can therefore be used in high doses. Often used to reduce nerve swelling following neurotrauma and neurosurgery.
  • Hydrocortisone – Has much more mineralcorticoid activity than Prednisone and is therefore not suitable for long-term use internally. Externally, it is used extensively as a cream or lotion for skin conditions such as rashes or itches.

Recent Research^

Newton, et al. (1998) conducted an experiment to try to explain the mechanism by which the glucocorticoid dexamethasone suppresses the production of mediators involved in inflammation. Previous studies indicate that synthetic drugs such as dexamethasone act by mimicking the natural glucocorticoid cortisol in binding to the glucocorticoid receptor (GR). The glucocorticoid-GR complex then moves to the nucleus, where it can activate transcription of anti-inflammatory genes.

This study investigated how glucocorticoids cause suppression of inflammatory mediators such as COX-2 and inflammatory prostaglandins, and proposed possible mechanisms to explain the suppressive effect of glucocorticoids and their inhibitory effects on various transcription factors.

Glucocorticoids have been found to interact with two transcription factors that help in the transcription of inflammatory genes. These factors, NF-kappa B and AP-1 are believed to interact with the GR complex. Scientists believe that the both the NF-kappa B/GR and AP-1/GR interactions result in the decreased transcription of COX-2 mRNAs.

The researchers in this study also discovered that aside from its interactions with various transcription factors, dexamethasone is capable of suppressing COX-2 production by another mechanism as well. The researchers exposed cells to molecules that induce the production of COX-2 proteins and the release of inflammatory prostaglandins. To the surprise of the researchers, they discovered that dexamethasone not only lowers the rate of COX-2 mRNA transcription by about 44%, but it also causes structural changes in the COX-2 mRNA, further lowering the amount of COX-2 enzymes produced.

Previous experiments have shown that the COX-2 mRNA is extremely stable; its slow rate of degradation enables increased production of COX-2 proteins. Dexamethasone administration causes a decrease in the amount of COX-2 mRNA by suppressing its transcription and modifying the mRNA molecule. Modification of the COX-2 mRNA destabilized it, causing it to degrade at a faster rate, which in turn, decreases the production of COX-2 proteins.

The researchers are still uncertain as to what specific changes are induced by dexamethasone to cause the modification found in the COX-2 mRNA. The results of this study indicate that glucocorticoids such as dexamethasone exert their anti-inflammatory effects through a variety of mechanisms: by interacting with transcription factors that slow COX-2 mRNA transcription and by modifying the COX-2 mRNA, destabilizing it, and increasing its rate of degradation.

The researchers proposed that the inflammation mechanisms of glucocorticoids need further study to determine how to control the production and activation of the various inflammatory mediators.

Aisen, et al. (2000) hypothesized that glucocorticoid administration may have beneficial effects for people with Alzheimer’s Disease (AD). Their hypothesis was based on observations that the brains of people with AD showed increased inflammation. The researchers conducted a clinical trial to determine the usefulness of the glucocorticoid prednisone in slowing the rate of cognitive decline in people with AD.

The study enlisted 138 people with AD ages 50 or older. Half the participants were given a placebo and the other half were given prednisone. The treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks, lowered to a maintenance dose of 10 mg daily for one year, followed by a gradual tapering off of the drug for another 4 months.

Cognitive and behavioral assessments were done at specific intervals over the trial period to determine the efficacy of prednisone treatment. The researchers looked for changes over a one-year period as determined by the cognitive component of the Alzheimer’s Disease Assessment Scale (ADAS) and other tests. Safety tests were also performed to monitor how the participants tolerated the drug.

Overall, the testing showed that low-dose prednisone did not slow the rate of cognitive decline when the prednisone-treated group was compared to those taking the placebo. Participants treated with prednisone also showed greater behavioral decline than those in the placebo group.

The researchers suggested some reasons why prednisone may not have been successful in treating AD. It is possible that the dosage given may not have been sufficient to suppress the destructive brain inflammatory activity. Much higher doses are used to treat inflammatory diseases of the brain such as cerebral lupus, a chronic autoimmune disease that causes inflammation in the brain. However, higher doses may not be safe for long-term treatment, particularly in the elderly. In this study, the incidence of hyperglycemia (greater than normal levels of blood glucose) and significant decline in bone density suggest that higher doses may cause substantial side effects.

Despite the negative results, the researchers believe that the study does not refute the potential benefit of anti-inflammatory compounds as treatment for neurological diseases such as AD. Rather, the study suggests that testing of other anti-inflammatory compounds such as NSAIDs (examples include aspirin and ibuprofen) or selective COX-2 inhibitors (examples include rofecoxib and celecoxib) is critical in the search for the right combination of therapies for AD. (For more on NSAIDs and COX-2 inhibitors, click here) Both NSAIDs and COX-2 inhibitors have more limited anti-inflammatory effects in comparison to glucocorticoids and may be appropriate candidates for future trials. The study on prednisone serves as an important step in directing scientists toward what may or may not work at certain stages of AD, HD, and other neurological diseases that involve chronic inflammation.

Diamond, et al. (2000) investigated the role of glucocorticoid receptors (GR) in the aggregation of expanded polyglutamine proteins. Previous studies have shown that binding of the glucocorticoid dexamethasone to the GR receptor forms a glucocorticoid- GR complex that causes changes in the transcription of certain genes. The researchers in this study speculated that glucocorticoid may affect the transcription of certain proteins that could inhibit the aggregation of expanded polyglutamine proteins.

Studies indicate that several polyglutamine diseases, including HD, are caused by multiple C-A-G repeats within a unique gene. Other examples include spinobulbar muscular atrophy (SBMA), Huntington’s Disease (HD), dentatorubro-pallidoluysian atrophy, and several spinocerebellar ataxias (SCAs) (For more on the polyglutamine diseases, click here.)

The altered genes result in the production of altered proteins that cause selective nerve cell death within the nervous system. For example, polyglutamine expansion within the androgen receptor (AR) protein results in SBMA, a disease associated with selective death of motor nerve cells. In the case of Huntington’s disease, the altered huntington gene results in the production of an altered huntingtin protein that causes selective death of nerve cells found in the basal ganglia.

Studies indicate that the nerve cell death associated with these polyglutamine diseases may be linked to the formation of neuronal aggregates of the altered proteins. These altered proteins have been found to form aggregates called neuronal inclusions (NIs) in the nucleus of the nerve cell. (For more on NIs, click here.) Some studies have shown that reducing aggregate formation could improve conditions in animal models of the polyglutamine diseases.

The researchers in the current study attempted to discover ways on how these aggregations can be reduced. Based on the role of GRs as regulators of transcription, the researchers wondered whether they may have any role in the aggregation of polyglutamine proteins. The researchers found that the addition of dexamethasone to human kidney cells and mouse nerve cells expressing HD reduced the aggregation of the altered huntingtin protein. Similarly, dexamethasone administration to cells expressing SBMA showed decreased androgen receptor (AR) aggregation.

The results of the study indicate that aggregation of expanded polyglutamine proteins are regulated within the cell. The aggregation process can be manipulated through glucocorticoid-controlled gene expression. The researchers believe that the glucocorticoid-GR complex acts as a transcriptional regulator: in the nucleus, the complex binds to sites that can control and modulate the expression of nearby genes. It is possible that the transcriptional changes induced by the complex may result in the production of proteins that could inhibit polyglutamine aggregation. What proteins are produced is still currently unknown.

More studies need to be done to identify the genes and proteins involved in the pathways that determine polyglutamine aggregations and nerve cell dysfunction. However, the results of this study raise the possibility that glucocorticoids could reduce polyglutamine aggregations. By reducing these aggregations, glucocorticoids could play essential roles in delaying or inhibiting the progression of diseases such as HD, SBMA, and possibly other polyglutamine diseases as well.

For further reading^

  1. Newton, et al. “Repression of Cyclooxygenase-2 and Prostaglandin E2 Release by Dexamethasone Occurs by Transcriptional and Post-transcriptional Mechanisms Inolving Loss of Polyadenylated mRNA.” Journal of Biological Chemistry. 1998; 273(48): 32312-32321.
    This study reports that the glucocorticoid dexamethasone acts to modify COX-2 mRNAs as well as regulate the transcription of some genes involved in inflammation.
  2. Diamond, et al. “Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor.” Proceedings of the National Academy of Sciences of the United States of America. 2000; 97(2): 657-661.
    This study reports that glucocorticoids may reduce the aggregations found in polyglutamine diseases such as SBMA and HD.
  3. Aisen, et al. “A randomized controlled trial of prednisone in Alzheimer’s Disease.” Neurology. 2000; 54:588.
    This study reports that prednisone was not effective in slowing the cognitive decline of people with AD.
  4. Information on immunomodulation available online at: http://www.users.dircon.co.uk/~rosebud/drugs/Immune.html
    This page contains some information on the various pathways involved in the inflammatory response.

-E. Tan, 6/15/02; Revised by P. Chang, 5/7/03