Nov. 7, 2007 A drug used to treat high blood pressure and enlargement of the prostate may protect the brain from damage caused by post-traumatic stress disorder, Alzheimer's disease, depression and schizophrenia.
Prazosin, also prescribed as an antipsychotic medication, appears to block the increase of steroid hormones known as glucocorticoids, Oregon Health & Science University and Portland Veterans Affairs Medical Center researchers have found. Elevated levels of glucocorticoids are associated with atrophy in nerve branches where impulses are transmitted, and even nerve cell death, in the hippocampus.
The hippocampus is the elongated ridge located in the cerebral cortex of the brain where emotions and memory are processed.
"It's known, from human studies, that corticosteroids are not good for you cognitively," said study co-author S. Paul Berger, M.D., assistant professor of psychiatry and behavioral neuroscience, OHSU School of Medicine and the PVAMC. "We think prazosin protects the brain from being damaged by excessive levels of corticosteroid stress hormones."
The study, titled "Prazosin attenuates dexamethasone-induced HSP70 expression in the cortex," is being presented during a poster session today at Neuroscience 2007, the annual Society for Neuroscience conference in San Diego.
Scientists believe stress activates a neurochemical response in the brain that triggers the release of glucocorticoids in the brain, and that high levels of glucocorticoids in blood serum are associated with such psychiatric conditions as schizophrenia, depression, PTSD and Alzheimer's disease. This mechanism has been linked to decreases in cognitive performance in older people who are not suffering from clinical dementia.
"Our hypothesis is that just being afraid of being blown up all the time means you have high levels of steroids all the time," Berger said, referring to PTSD among military personnel.
Low levels of glucocorticoids have anti-inflammatory effects in the brain, but high levels can trigger inflammatory mechanisms that damage nerve cells by activating an enzyme that causes oxidative stress. Even a single exposure to a high dose of glucocorticoids can be sufficient to damage nerve cells: A previous study showed synthetic glucocorticoid therapy to treat autoimmune disorders such as rheumatoid arthritis can induce mood disorders, including psychosis, and cognitive impairment known as "steroid dementia" in severe forms.
To determine the effects of prazosin, OHSU and PVAMC researchers, led by Altaf Darvesh, Ph.D., formerly of the OHSU Department of Psychiatry, administered a glucocorticoid called dexamethasone to rats, then measured the expression of a protein known as heat shock protein 70, or HSP70, that serves as a marker for neurotoxicity. Pretreatment with prazosin, an alpha-1 receptor antagonist, resulted in "significant" slowing of dexamethasone-induced expression in the cerebral cortex.
"The one thing we don't know for sure is, would you have to get it before you're traumatized," Berger said. "Lots of people have high levels of corticosteroids when they're under stress, so could we give them prazosin ahead of time to protect them from brain damage?"
Berger said future research will continue to look at where and how steroids cause brain damage, and just when prazosin would have to be administered to most effectively protect the brain against damage.
"We just looked at brain damage," he said. "Steroids are known to cause cognitive impairment in both rats and people, so the next step is to see if we can correlate brain damage with cognitive effects and determine if we can protect against brain damage to protect cognition."
The study was funded by the U.S. Department of Veterans Affairs.
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