CHICAGO --- Stress -- or, rather, the body's response to it -- is not just a condition of the "nerves," but an intricate combination of biological and behavioral compensatory mechanisms that are regulated by hormones and other substances in the body and in the brain.
Chronic, severe exposure to stress or an innate vulnerability to stress causes destructive biochemical reactions in the body that may lead to a variety of illnesses, including depression.
Now, researchers from Northwestern University Medical School and San Diego State University have published the first study to show that a peptide found in the brain and in the body can reduce both hormonal and behavioral manifestations of stress. The study was published in a recent issue of the Journal of Neuroscience.
Eva Redei, an associate professor of psychiatry and behavioral sciences and of molecular pharmacology and biological chemistry at Northwestern, and an author of the study, believes that in some forms of depression, there is an abnormal amount of this peptide. Finding the peptide and subsequently demonstrating its modulatory effects on hormonal and behavioral responses to stress may have dramatic implications on the diagnosis and treatment of depression and other stress-related illnesses, she said.
Redei, who is also the Dunbar Scholar of the Asher Center for the Study and Treatment of Depressive Disorders at the Medical School, identified and isolated the peptide, known as prepro-TRH178-199, in 1995. In laboratory studies, she and her co-researchers showed that the peptide reduced secretion of corticotropin, or ACTH -- a hormone that plays a major role in controlling the body's response to stress -- by nearly 50 percent.
In the current study, they found that administering the peptide in an animal model prior to exposure to stress significantly reduced levels of ACTH and prolactin, another pituitary hormone that is also elevated in response to stress. Central nervous system effects were tested in behavioral models, and the results showed that the peptide decreased fear and anxiety-related behaviors while simultaneously promoting arousal. This combination of behavioral responses is unique for anxiety-reducing agents.
Thus, the peptide may have a dual role in inhibiting neuroendocrine response to stress as well as central modulatory influences over stress-related behaviors.
Stress causes an immediate and marked increase in secretion of ACTH by the anterior pituitary gland. Release of ACTH is regulated by corticotropin-releasing factor, which is widely distributed in the brain and also plays a role in a number of stress-related behavioral effects in the nervous system and the facilitation of the "fight-or-flight" response. ACTH secretion is followed within minutes by greatly increased adrenocortical secretion of the hormone cortisol. Cortisol in turn initiates a series of metabolic effects directed toward relieving the damaging nature of the stressful state. However, if cortisol secretion persists, it can precipitate or worsen illnesses such as depression, infectious diseases or cardiovascular illnesses.
Hypercortisolemia, or overproduction of cortisol, is one of the most consistent neuroendocrine findings in serious depression, as well as in certain anxiety disorders and anorexia nervosa, Redei noted. Recent data indicate that reducing hypercortisolemia could represent a new approach to treating serious depression. The novel peptide identified by Redei and co-researchers may open new treatment opportunities.
Redei believes that the peptide is an endogenous inhibiting factor of the body's stress response and is an important component of the body's stress regulatory system. In addition, the fact that this peptide is part of a larger molecule (precursor) that also gives rise to thyrotropin-releasing hormone, or TRH, is extremely important, she said.
"Cortisol and thyroid hormones are frequently elevated or decreased in parallel in different illnesses, but until this finding, there was no real understanding why. Now, with the characterization of the effects of this peptide, the simultaneous regulation of the secretion of these two hormones can be explained and exploited for therapeutic purposes," she said.
Collaborating with Redei on this study were Robert F. McGivern, San Diego State University, San Diego, Calif.; Peter Rittenhouse, University of Pennsylvania, Philadelphia; Fraser Aird, Northwestern University Medical School; and Louis D. Van de Kar, Loyola University, Maywood, Ill.
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