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Living is very dangerous

Prolonged stress intensifies inflammation of the brain linked to neuron death

ANDRÉS SANDOVAL and MARIANA ZANETTIThe long hours wasted in the traffic in the big cities and the generalized insecurity that makes people lock themselves in houses surrounded by railings or hide themselves behind the dark windows of their cars generate more than passing simple irritation and fear. Added to the excess of work that is common nowadays, these day to day situations in Brazilian metropolises take tension to the limit of the bearable, with harmful effects on health.

In the last few years, studies carried out in the United States and in Brazil have shown that stress for prolonged periods favors the emergence of diabetes, cardiovascular diseases, anxiety, depression, impotence, infertility, and even some forms of cancer. Now, a survey conducted by teams from two São Paulo universities – the University of São Paulo (USP) and the Federal University of São Paulo (Unifesp) – reveals another possible devastating effect of stress. This natural reaction of the organism that facilitates adaptation to new or threatening situations also boosts inflammatory processes that can culminate in the death of nerve cells (neurons) in two specific regions of the brain: the hippocampus, associated with the formation of the memory, and the frontal cortex, responsible for complex thinking.

“Stress, in itself, is a natural adaptation mechanism, not a disease”, says neuropharmacologist Cristoforo Scavone, from USP’s Biomedical Sciences Institute, the coordinator of the São Paulo team. “The problem arises when you lose control over the level of stress.”

The results of this work, published in April this year in the Journal of  Neuroscience, bring down an ancient belief amongst neurologists: that the nervous system was a set of privileged organs, unsusceptible to inflammation. “A membrane that covers the central nervous system, the so-called hematoencephalic barrier, prevents the arrival at this organ of various substances and aggressive agents, for which reason it used to be believed that the encephalon was free from inflammations”, Scavone says. Unfortunately, it is not quite like that.

Scavone and pharmacologist Carolina Demarchi Munhoz, who embarked at the end of October for a second period of research at the laboratory of neuroscientist Robert Sapolsky, at Stanford University, United States, found a double function of cortisol, a hormone released in situations of stress by glands located above the kidneys. The fright caused both by a real threat, such as a dog that leaps to the gate of a house barking to those passing by on the sidewalk, and by an imaginary one, like the fear of being held up when stopping the car at the next red traffic light, leads to the production of this hormone of stress.

It has been known for a long time that, in relatively low doses, cortisol is a potent compound capable of containing inflammation – the chain of reactions of the organism’s defense system intended to combat invading microorganisms, like viruses, funguses and bacteria. In the article in the Journal of  Neuroscience, Carolina and Scavone also proved that cortisol, in high quantities and for long periods, can cause the opposite effect, in particular in the brain. This is also what is observed when the doctors prescribe the use of compounds derived from cortisol to control the immune system that turns on its own body and causes the so-called autoimmune ailments, like the inflammation of the joints (arthritis) or serious cases of redness and intense scaling of the skin (psoriasis).

“This work has a probable clinical relevance for suggesting that the use of synthetic versions of the hormone associated with stress, cortisol, can aggravate inflammation in the brain”, Sapolsky tells Pesquisa FAPESP. However, this does not mean that people should rebel against the doctors and interrupt the treatment, since, Carolina reminds us, “the relationship between the costs and the benefits of a medicine is generally evaluated before prescribing it”.  But, in Scavone’s opinion, it is time to pay attention to these effects and to start a search for alternatives that do not produce these undesirable effects.

Scavone and Carolina observed the harmful action of cortisol on the brain in an extensive work at USP’s Molecular Neuropharmacology Laboratory in which they submitted a group of healthy rats to different situations that cause stress similar to the stress that people experience in the day-to-day.

Marathon in the laboratory
Over two weeks, they selected rodents at random to leave the comfort of their boxes and to undergo some activity that took them out of the routine, obliging the organism to adapt itself to the new conditions. On one day, for example, Carolina would put them in a tank to swim without resting for fifteen minutes. On next, the rats would remain an hour and a half in an environment a few degrees colder than usual. The also had to remain immobile for one hour, or spend half a day without food and water. The animals also experimented the discomfort of a night with the lights switched on, or a daytime period in the dark – a total inversion of habits, since rats are nocturnal animals and go out looking for food at night and rest during the day.

All this disarrangement, called by the biologists chronic unpredictable stress, is not very different from what is experienced in perturbed periods in which one has to give up a few hours of sleep to handle some extra work, and even to replace a balanced diet with snacks or savories with the objective of having a bit of time left over to settle the bill that can only be paid in the bank or at last to make that visit to the dentist, put off for months.

The first consequence of so many changes was detected in the blood. One day after the battery of tests, the levels of corticosterone -the equivalent in rats to the human cortisol – remained high, in a concentration that varied from 25 to 30 micrograms per deciliter of blood. “These values are five or six times higher than normal, similar to those that one observes in the organism of people under treatment to suppress the activity of the defense system and to prevent the rejection of a transplant”, Carolina explains.

The effects of stress, though, are even more comprehensive and involve a complicated network of interactions between the central nervous system and the rest of the body. As soon as a threatening situation arises, or one that alters the routine, the hypothalamus activates the production of the adrenocorticotropin hormone (ACTH) in the pituitary gland, at the base of the brain. In instants, the level of ACTH in the blood increases and activates the glands located above the kidneys (the suprarenal glands), which start to make cortisol.

In the blood, this hormone blocks the characteristic chemical reactions of inflammation and reduces the activity of the defense system, for which reason it used to be imagined that it worked mainly as an anti-inflammatory when used for weeks or, at the most, for a few months – although its use for a longer time causes a series of undesirable effects, like an increase in the blood pressure, depression, diabetes and cardiac insufficiency, besides facilitating the emergence of infections, since it leaves the defense system disarmed against bacteria and funguses.

ANDRÉS SANDOVAL and MARIANA ZANETTIIn partnership with pharmacologist Maria Christina Werneck Avellar, from Unifesp, Scavone and Carolina found that this hormone, by ways not yet entirely understood, activates in the inside of the neurons a protein called kappa B transcription factor, which is manufactured in inflammatory processes. This transcription factor, in turn, activates at least three genes responsible for the production of proteins associated with inflammation and cell toxicity – interleukin 1-B, tumor necrosis factor-alpha, and nitric oxide-induced synthesis. In low concentrations, these molecules generate a benefic effect and help to combat invading microorganisms. In excess, though, they appear to destroy the cells that they ought to protect.

Sapolsky himself, one of the most respected scholars of the effects of stress on the central nervous system, was surprised with the partial results of  this work about two years ago, during Carolina’s first spell with his laboratory in Stanford. The discovery of the inflammatory action of stress on the central nervous system helped to complete the jigsaw puzzle that Sapolsky had begun to put together ten years before. Although he had dedicated himself for a long period to analyzing the effects of chronic stress generated by social disputes amongst baboons from Kenya, animals that live in a society with rather complex relationships of power, it was in rats Sapolsky demonstrated that prolonged stress intoxicated the neurons by increasing the levels of glutamate in the hypothalamus.

Carolina proved cortisol’s double effect when comparing the level of inflammation of the brain in rats submitted to lasting stress with that observed in healthy rodents. After inducing a generalized inflammation in the animals’ organisms by means of an injection into the blood of particles of  bacteria, she analyzed the action of the three inflammatory genes on the central nervous system. The rats free from stress showed a slight inflammation in the whole of the encephalon, as had been observed three years before by another neuropharmacologist from the team from USP, Isaías Glezer, currently in a period of specialization at Laval University, in Canada. This inflammation, though, was more intense in the hippocampus and in the frontal cortex of the chronically stressed rodents. Preliminary results of another test still under way suggest that this inflammation is in fact responsible for the death of the neurons in the animals debilitated by stress. “It is possible that the brain of a person that lives under stress may be more susceptible to this damage”, Carolina comments.

Although they were done with rats, these experiments provide a good clue to what must also occur in human beings, highly inclined to suffer from a form of stress associated with the Western lifestyle: psychological stress caused by anticipation. Different from a real threat to life, anticipation is a sort of imaginary stress. Simply thinking of a situation that may or may not occur, such as the fear of suffering a kidnapping every time one goes to an ATM, is already sufficient to activate the biochemical mechanisms relating to stress, which, it is estimated, affects between 10% and 20% of the population in the developed countries.

More levity
It is not only the body that pays the price of this adaptation, since diseases caused by stress eat up a part of the budget of the public health system. Last year, researchers Sophie Béjean and Hélène Sultan-Taïeb, from the University of  Burgundy, in France, presented in the European Journal of  Health Economics a clear example of the social cost of stress: they calculated the expenditure with the treatment of three diseases (cardiovascular, muscular and mental) arising, at least in part, from the stress associated with the conditions of work. Of the 24.5 million people of a productive age in France in 2000, from 300 thousand to 400 thousand had health problems relating to stress because of work – and between 2,300 and 3,600 of them died. The expenditure with treatment and with the loss of working days cost from 1.2 billion to 2 billion, amounts that correspond to 14% to  24%  of what the French public health system spends on occupational diseases.

Until a cure for stress is discovered-  if one day there will be one, since properly speaking it is not a disease -, one way out is to prevent it, leading life in a lighter way and performing physical activities, counsels Sapolsky, a confessed stress sufferer. “We have to be more superficial”, challenged the neuroscientist from Stanford in an interview published in April by the Folha de S.Paulo [S.Paulo Newssheet]. “By more superficial, I mean less cerebral. We manage this, paradoxically, by being more cerebral. I’ll explain. If you manage to think scientifically and constantly, you will manage to discern whether what is stressing you is, shall we say, a physical reality, or just a psychosocial one. If  it’s physical, you can get stressed.  If  it’s psychosocial, forget it.”

The Project
Participation of the MAP kinases, heat shock proteins and from the apoptosis route in the adverse effects of glucocorticoids on the central nervous system (04/11041-0); Modality: Regular Line of Research Grants; Coordinator: Cristoforo Scavone – USP; Investment: R$ 251,175.22 (FAPESP)