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Unexpected effect

Corticoids activate inflammation mechanisms in some areas of the brain

NANA LAHOZThe one percent of the world population living with the terrible pain of rheumatoid arthritis, a chronic inflammation that causes articulations to degenerate, are well aware of the importance of corticoids to improve their quality of life. Not only them, but also the millions who suffer from respiratory allergies or skin diseases, along with brain tumor victims and patients with a variety of other conditions in which the body’s inflammation response is exaggerated, have benefitted over the last few decades from the powerful anti-inflammatory effect of these compounds. Generally, these are synthetic derivates of cortisone, the main corticoid secreted by the human adrenal glands.

Identified at the beginning of the last century by Edward Calvin Kendall and Philip Showalter Hench, the discovery brought them the Nobel Prize for Medicine in 1950. Corticoids, however, do not always work as expected – at least when one is talking about synthetic hormones. In some areas of the brain, the effect may be the exact opposite of the expected, increasing inflammation. This is suggested by the study of the researchers Carolina Demarchi Munhoz and Cristoforo Scavone, from the University of São Paulo (USP), and Robert Sapolsky, from Stanford University in the United States, published in the Journal of Neuroscience at the end of 2010.

By means of an intravenous injection of bacteria fragments, the group of researchers induced inflammatory responses in laboratory rats, to assess the power of corticoids to modulate biochemical reactions caused by brain inflammations, such as those that occur in the case of tumors or strokes. The body’s natural response to inflammation is known to be the secretion of corticoids – and the adrenal glands of rats produces corticosterone, a hormone similar to human cortisone.

Before provoking inflammation, Caroline removed the adrenal glands of the rats (adrenalectomy) and implanted under their skin slow-release corticosterone capsules. Thus, by controlling the dosages, she could investigate whether the anti-inflammatory action varied depending on the different levels of corticoids in the animals’ blood, separated into three groups – each with a different dose of the hormone. The first received a low level of corticosterone, equal to that normally produced by the rodents; the second, a medium dose, similar to what is found in the body in cases of light stress, such as the fright caused by the unexpected slamming of a door; and the last, a high dose, corresponding to moderate levels of stress, such as being worried about the inability to pay one’s bills at the end of the month. A fourth group, the adrenal glands of which had not been removed, was the control group.

The relation between the level of corticoids in the blood and the level of stress is important because this adaptive reaction of the body to new or threatening situations also causes the adrenal glands to release corticoids. Additionally, the group of researchers had already shown, years before, that chronic and unforeseeable stress may cause brain inflammation (see Pesquisa FAPESP issue 129). The question now was to discover whether corticoids mediate the effect and how this takes place.

Using immunology and molecular biology techniques, they evaluated what different levels of corticoids caused in two regions of rats’ brains: the hippocampus, involved with memory, learning and, in pathological situations, the development of epilepsy; and the frontal cortex, associated with the higher cognitive processes, such as decision-making. They observed a complex pattern of response of the analyzed genes.

Depending on the dose, some genes functioned with the same pattern in the two regions. For example, they were activated or deactivated in both. However, others worked differently, being active in one and inactive in the other. These changes resulted from the control of the activity of the nuclear factor kappaB (NF-kappaB), an intracellular communication molecule that is key for the biochemical process that regulates the inflammation response.

Until then, it had been generally thought that NF-kappaB was always blocked by corticoids, which would therefore have an anti-inflammatory effect. Indeed, in the higher dose, the corticoids reduced NF-kappaB activity and the inflammation of the hippocampus. However, at the lower and medium levels, they enhanced the effect of NF-kappaB and therefore the signal that triggers inflammation. In the frontal cortex, the relation was different: the high dose of corticosterone was anti-inflammatory, whereas the intermediary one made the inflammation more severe.

PATRICK LANDMANN / SCIENCE PHOTO LIBRARY / SPL DC / LATINSTOCKAffected cells in bipolar disorder: neurons in green and neuroglia in bluePATRICK LANDMANN / SCIENCE PHOTO LIBRARY / SPL DC / LATINSTOCK

Although these results are experimental, they may prove to be of clinical importance, in particular for neurology and psychiatry, both of which deal with brain inflammation and its consequences. According to Caroline, the doses used in the tests with the rats are close to those employed in human studies. She proposes, however, that the data be examined cautiously: “We showed that the effect of corticoids, even at appropriate doses, isn’t just anti-inflammatory; however,” she stresses, “the work was done with rats, using their natural corticoid.”

This can make a great difference. The corticoids produced by the body work differently from the synthetic ones, used as medication. One of the differences is that only 10% of the corticoids secreted by the adrenal glands is in free form in the blood, ready to act both on peripheral tissues and on the central nervous system. The synthetic ones, however, are totally available to act on peripheral tissues, but they are, to a significant extent, filtered when they enter the brain’s circulation – a special barrier (hematoencephalic) lines the brain’s blood vessels and controls the passage of various compounds.

Therefore, when they have to treat brain inflammation, doctors have to increase the dose of the drug, in the hope that a greater proportion may overcome the hematoencephalic barrier, which operates like a partially impermeable raincoat: when there is only drizzle, it keeps water from getting the person wet, but if it is pouring, a certain amount gets in through the pores of the fabric.

Because of this mechanism, the level of synthetic corticoids in peripheral blood may be substantially different from what reaches the brain. Thus, what doctors estimate as a high dose might actually be high on the periphery, but only medium in the brain tissue. As it was the medium doses that increased the inflammatory signaling in the hippocampus and in the frontal cortex, the results may be a warning regarding the medical use of these compounds when the target is the central nervous system. Still, further research must be conducted, which Carolina and Scavone plan to start soon, to determine whether the synthetic corticoids act on the brain in the same way as the natural ones do. ‘These data are a warning, indicating that there are variables at play that we still don’t understand regarding how corticoids work,” says Scavone.

Mood changes
Recently, Scavone started collaborating with the team of Beny Lafer, from the Psychiatry Department at the Medical School of USP, to identify the possible influence of inflammatory processes in the development of psychiatric problems. Lafer is particularly interested in finding out whether biochemical changes linked to inflammation might affect the balance of cells and induce them to die in people with bipolar disorder, which typically causes mood swings between depressive and manic (euphoria) episodes.

Described almost two thousand years ago by Aretaeous of Cappadocia, this mental condition, previously known as manic-depressive psychosis, affects about one percent of the population in its most severe form (type 1). It has been treated with relative efficiency in recent decades. However, its biological origin remains unclear. In the 1990s, international studies identified a considerable reduction in the number of cells (neurons and neuroglia) and a reduction in the cellular protection mechanisms in the brain of bipolar people. Associated with inflammation, this cell loss, which becomes stronger during mania and depression crises, affects the frontal cortex and possibly the hippocampus as well, two of the regions studied by Carolina and Scavone – the loss or malfunctioning of the frontal cortex neurons might help to explain patients’ difficulties controlling their impulses during the manic episodes.

In a review study published this year in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry, both he and Scavone propose a model that tries to explain how the inflammation mechanisms may change the pathway of intracellular signaling activated by Wnt, a protein that regulates the proliferation, migration and specialization of cells. All of these processes seem to be, to a greater or lesser extent, jeopardized during mood disorders, such as bipolar disorder and depression. A strong piece of evidence that something is amiss in the chain of chemical reactions triggered by this protein among victims of these psychiatric problems is the fact that two of the drugs most often used to treat bipolar disorder, lithium and valproate, act upon this way of intracellular communication, reestablishing this channel of information transmission and eventually avoiding neuron death. “The discoveries about the workings of mood stabilizers have changed the focus of the research on the receptors in the cell membranes and on the neurotransmitters that connect with these receptors in order for what happens in the intracellular world to materialize,” explains Beny Lafer.

This new way of looking at psychiatric problems brought together the teams of Scavone and Lafer and it might lead to new treatments. Among the molecules that in the future may become a good therapeutic target for bipolar disorder, Lafer highlights the brain-derived neurotrophic factor (BNDF). This molecule, among its many roles, regulates the survival and the ramification of the neurons, functions that involve Wnt signaling and that are somehow poorly regulated during depressive and manic episodes.

It really does seem that there is a molecular link between mood disorders, the action of the corticoids and the influence of stress, although it is yet to be determined. The researchers suspect that this link might be NF-kappaB, which is involved both in the brain response to corticoids and in Wnt signaling, which is altered in bipolar disorder.

In their quest for answers to these questions – and, if possible, for new forms of treatment – Lafer and his PhD student Li Wen Hu, in conjunction with Eliza Kawamoto, are investigating changes in the Wnt pathway. They want to compare the level of proteins in this biochemical chain in the blood of people with the disorder that have been medicated (with lithium) from the start of their research, with that of people with the same condition that haven´t used lithium, and that of healthy individuals. To date, they have obtained samples from 20 people in the first group, 17 in the second and 36 in the third. ‘We still don’t know whether the dysfunction of inflammation processes is the cause or the consequence of the episodes of the disease, which improve with mood stabilizers,” states Lafer.

The suspicion that corticoids worsen brain inflammation comes from clinical observation. Bipolar patients on corticoids to fight inflammation present a worsening of their psychiatric situation. Moreover, the use of medication with an action contrary to that of corticoids for treating depression is currently in its initial trial stage. Although lithium has a different action mechanism than corticoids, researchers do not disregard the possibility that they may act upon certain intracellular targets in common. Still, it is hard to know. “It’s a complex biochemical waterfall effect, finely regulated by the body in response to stress and to inflammation processes,” comments Scavone. “Interfering with this system might unleash consequences that we aren’t aware of yet.”

The projects
Stress and intracellular signaling in the inflammation unleashed by LPS in the central nervous system: participation of the glucocorticoids and of the glutamate-NO pathway in the modulation of the transcription factor NF-KB (nº 2002/02298-2); Type Regular Research Awards; Coordinator Cristoforo Scavone -ICB/USP; Investment R$ 191,086.25 (FAPESP).
2. Participation of map kinases, thermal shock proteins and apoptosis pathway in the adverse effects of glucocorticoids upon the central nervous system (nº 2004/11041-0); Type Regular Research Awards; Coordinator Cristoforo Scavone – ICB/USP; Investment R$ 229,197.46 (FAPESP).
3. Evaluation of the involvement of the Wnt signaling pathway in the physiopathology of affective bipolar disorder (nº 2008/08191-1); Type Regular Research Awards; Coordinator Beny Lafer – FM/USP; Investment R$ 57,564.57 (FAPESP).

Scientific Articles
Munhoz, C. D. et al. Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. Journal of Neuroscience. v. 30(41), p. 13.690-8. 13 Oct. 2010.
Hu, L. W. et al. The role of Wnt signaling and its interaction with diverse mechanisms of cellular apoptosis in the pathophysiology of bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry. v. 35(1), p. 11-17. 15 Jan. 2011.