Long periods of estrogen deprivation jeopardizes brain receptors, stroke protection

ScienceDaily (Aug. 2, 2011) — Prolonged estrogen deprivation in aging rats dramatically reduces the number of brain receptors for the hormone as well as its ability to prevent strokes, researchers report.

However the damage is forestalled if estrogen replacement begins shortly after hormone levels drop, according to a study published in the journal Proceedings of the National Academy of Sciences.

"This is further evidence of a critical window for estrogen therapy, either right before or right after menopause," said Dr. Darrell W. Brann, Chief of GHSU's Developmental Neurobiology Program and the study's corresponding author.

The surprising results of the much-publicized Women's Health Initiative -- a 12-year study of 161,808 women ages 50-79 -- found hormone therapy generally increased rather than decreased stroke risk as well as other health problems. Critics said one problem with the study was that many of the women, like Brann's aged rats, had gone years without hormone replacement, bolstering the case that timing is everything.

Brann's earlier work in the hippocampus, a center for cognition, learning and memory, also showed a reduction in hormone receptors in younger rodents that were models of surgical menopause but left questions about why the loss occurred and whether it occurred naturally with aging. The new study documents that loss as unused receptors become targets for elimination in rats mimicking 60-65 year olds, about a decade past menopause. Interestingly, the receptor loss did not occur in the uterus, which remained sensitive to estrogen.

After long periods without estrogen, researchers found that an enzyme called CHIP -- carboxyl terminus of Hsc70 interacting protein -- increased binding with estrogen receptor alpha, a major brain receptor for neuroprotection. While CHIP levels remain unchanged, the increased binding results in about half the receptors getting hauled to the cell's proteosome to be chopped up and degraded. "We think this is the mechanism for how the receptor gets degraded," Brann said.

When researchers later treated the aged rats with estrogen, they found what the Women's Health Initiative showed: increased mortality. "So it did not seem to do anything good and maybe it did some harm in older rats and that is similar to what the WHI found," Brann said. The brain protection afforded by estrogen when given earlier to the rats, suggested the "critical window." Additionally when CHIP activity was blocked, so was the receptor destruction.

Next steps include estrogen-treating those rats where CHIP-related destruction is blocked to see if salvaged receptors will respond and looking at the process in other areas of the brain.

"We think the estrogen receptor decrease is why the sensitivity decreases," said Brann, who also is Associate Director of GHSU's Institute of Molecular Medicine and Genetics. "If the hormone is gone long enough it is logical there would be decreased sensitivity as normal feedback between the receptor and hormone is reduced."

Collaborators include scientists at Hebei United University in China and the University of Texas Health Sciences Center at San Antonio. Dr. Quan-guang Zhang, Research Scientist in Brann's lab, is the study's first author. Aged rats were obtained from the National Institute on Aging and studies were funded by the National Institutes of Health and American Heart Association.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Georgia Health Sciences University.

Journal Reference:

Q.-g. Zhang, D. Han, R.-m. Wang, Y. Dong, F. Yang, R. K. Vadlamudi, D. W. Brann. PNAS Plus: C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-  and the critical period hypothesis of estrogen neuroprotection. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1104391108

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here sciencedaily.com

Traumatic brain injury linked with tenfold increase in stroke risk

ScienceDaily (July 29, 2011) — If you suffer traumatic brain injury, your risk of having a stroke within three months may increase tenfold, according to a new study reported in Stroke: Journal of the American Heart Association.

"It's reasonable to assume that cerebrovascular damage in the head caused by a traumatic brain injury can trigger either a hemorrhagic stroke [when a blood vessel bursts inside the brain] or an ischemic stroke [when an artery in the brain is blocked]," said Herng-Ching Lin, Ph.D., senior study author and professor at the School of Health Care Administration, College of Medicine, Taipei Medical University in Taiwan. "However, until now, no research had been done showing a correlation between traumatic brain injury and stroke."

It is the first study that pinpoints traumatic brain injury as a potential risk factor for subsequent stroke.

Traumatic brain injury occurs when an external force such as a bump, blow or jolt to the head disrupts the normal function of the brain. Causes include falls, vehicle accidents, and violence.

In the United States alone, approximately 1 in 53 individuals sustain a traumatic brain injury each year, according to 2004 statistics from the Centers for Disease Control and Prevention.

Worldwide, traumatic brain injuries are a major cause of physical impairment, social disruption and death.

Using records from a nationwide Taiwanese database, researchers investigated the risk of stroke in traumatic brain injury patients during a five-year period. The records included 23,199 adult traumatic brain injury patients who received ambulatory or hospital care between 2001 and 2003. The comparison group comprised 69,597 non-traumatic brain injury patients. The average age of all patients was 42 and 54 percent were male.

During the three months after injury, 2.91 percent of traumatic brain injury patients suffered a stroke compared with only 0.30 percent of those with non-traumatic brain injury -- a tenfold difference.

Stroke risk in patients with traumatic brain injury decreased gradually over time, researchers said:

After one year, the risk was about 4.6 times greater for patients who suffered a traumatic brain injury than for those who had not.After five years, the risk was 2.3 times greater for traumatic brain injury patients.

Stroke risk among traumatic brain injury patients with skull bone fractures was more pronounced than in traumatic brain injury patients without fractures, researchers said.

During the first three months, those with skull bone fractures were 20 times more likely to have a stroke than patients without skull bone fractures. The risk decreased over time.

Furthermore, the risk of subarachnoid hemorrhage (bleeding in the area between the brain and the thin tissues that cover the brain) and intracerebral hemorrhage (bleeding in the brain caused by the rupture of a blood vessel) increased significantly in patients with traumatic brain injury versus non-traumatic brain injury patients.

After considering age and gender, patients with traumatic brain injury were more likely to have hypertension, diabetes, coronary heart disease, atrial fibrillation and heart failure than non-traumatic brain injury patients.

Early neuroimaging examinations -- such as MRI -- and intensive medical monitoring, support and intervention should be required following a traumatic brain injury, especially during the first few months and years, Lin said. Moreover, better health education initiatives could increase public awareness about the factors that cause strokes and the signs and symptoms of stroke in patients with traumatic brain injuries.

"Stroke is the most serious and disabling neurological disorder worldwide," said Lin. "Our study leads the way in identifying stroke as an additional neurological problem that may arise following traumatic brain injury."

Co-authors are: Yi-Hua-Chen, Ph.D, lead author and Jiunn-Horng Kang, M.D.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Heart Association, via EurekAlert!, a service of AAAS.

Journal Reference:

Y.-H. Chen, J.-H. Kang, H.-C. Lin. Patients With Traumatic Brain Injury: Population-Based Study Suggests Increased Risk of Stroke. Stroke, 2011; DOI: 10.1161/STROKEAHA.111.620112

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Scientists discover potential stroke treatment that may extend time to prevent brain damage

ScienceDaily (July 25, 2011) — A naturally occurring substance shrank the size of stroke-induced lesions in the brains of experimental mice -- even when administered as much as 12 hours after the event, Stanford University School of Medicine researchers have shown. The substance, alpha-B-crystallin, acts as a brake on the immune system, lowering levels of inflammatory molecules whose actions are responsible for substantial brain damage above and beyond that caused by the initial oxygen deprivation of a stroke.

The finding, which will be published online July 25 in Proceedings of the National Academy of Sciences, is of great potential significance. Every year brings nearly 800,000 new stroke patients in North America. "That's one every 40 seconds," said Gary Steinberg, MD, PhD, director of Stanford's Institute for Neuro-Innovation and Translational Neurosciences and one of the study's two senior authors. Steinberg is also the Bernard and Ronni Lacroute-William Randolph Hearst Professor of Neurosurgery and the Neurosciences, and chair of neurosurgery at the medical school.

The largest single cause of severe neurological disability and the third-leading cause of death in the United States, stroke accounts for an estimated $74 billion annually in related costs, including treatment and additional assistance for the three of every four stroke patients whose ability to perform the activities of daily life is impaired. Strokes are caused by a sudden drop in the flow of blood to the brain resulting from a clot or, less often, bleeding. One of every three stroke patients is under the age of 65. In all, there are 5.4 million stroke survivors in the United States and 15 million worldwide.

The only currently approved drug for stroke -- tissue plasminogen activator, or tPA -- dissolves clots that keep oxygenated blood from reaching brain tissue. To be effective, tPA must be administered within about 4.5 hours after the stroke. But patients' brains must first be scanned to rule out the possibility that the stroke was caused by bleeding, which tPA would exacerbate, rather than by blockage.

Moreover, tPA does nothing to counter the stroke's insidious inflammatory aftershock: a flood of noxious chemicals secreted by angry immune cells that rush in to the affected area, causing significant further damage.

Alpha-B-crystallin appears to act as a sponge, sopping up those bad actors and stopping inflammation from making a bad situation worse.

Alpha-B-crystallin is a major structural protein in the eye's lens. It is also constantly made in the heart. In other tissues, including the brain, its production can be triggered by stressful events, such as oxygen deprivation or excessive heat or cold. Growing evidence suggests that alpha-B-crystallin can help curb inflammatory activity in the brain.

"The brain doesn't roll over and play dead when it's under attack," said Lawrence Steinman, MD, the other senior author of the new study, who is the George A. Zimmermann Professor of Neurology and Neurological Sciences and Pediatrics as well as chair of Stanford's interdepartmental program in immunology.

In an earlier study, published in Nature in 2007, Steinman and his colleagues found that the presence of alpha-B-crystallin could help reduce the severity of brain damage caused by multiple sclerosis, a chronic, debilitating autoimmune disease of the brain. Other studies published this year by his group have shown that alpha-B-crystallin limits the damage caused by blood-supply cutoffs to heart tissue and the retina.

It seemed logical to see if this protein could mitigate the effects of a stroke. "We made a jump from its relevance in inflammatory diseases such as multiple sclerosis," Steinberg said. "To my knowledge, nobody had looked at concentrations of alpha-B-crystallin after a stroke, either in people or in an experimental animal model before."

So, along with first authors Ahmet Arac, MD, a postdoctoral scholar in Steinberg's lab, and Steinman's former graduate student Sarah Brownell, PhD, Steinberg and Steinman turned to a standard animal model: the laboratory mouse. They found that, in mice bioengineered to lack alpha-B-crystallin, experimentally induced stroke lesions were more massive than those induced in otherwise genetically similar mice whose cells were capable of making the protein. The alpha-B-crystallin-deficient mice had worse neurological function after the stroke than did the normal mice.

The researchers also found that supplying synthetic alpha-B-crystallin to the deficient mice reduced brain-lesion sizes after a stroke, even when the substance was administered 12 hours after the stroke was induced. And they saw elevated alpha-B-crystallin levels in blood plasma from both human patients and mice after a stroke. (The human samples were obtained from study co-author Gregory Albers, MD, the Coy Foundation Professor of Neurology and Neurological Sciences and the director of the Stanford Stroke Center).

"In younger patients, the larger the stroke, the higher the concentration of alpha-B-crystallin," said Steinberg. Interestingly, increased alpha-B-crystallin levels were not detected in plasma from patients over the age of 80, whose strokes typically have worse consequences than those affecting younger patients.

Finally, the investigators demonstrated that alpha-B-crystallin-treated mice produce fewer inflammatory immune-signaling molecules and more anti-inflammatory ones than untreated mice.

At the doses given to the mice in this study, alpha-B-crystallin appeared to be nontoxic. "This is a naturally occurring molecule the body is already producing, although maybe just not enough of it," said Steinberg. "We're just supplementing it." If further studies by other labs and in other models confirm and extend the findings, alpha-B-crystallin may be an excellent candidate for clinical trials in stroke, Steinman and Steinberg both said.

"This is the first demonstration of an efficacious brain-protecting agent that targets the inflammatory aspect of stroke in a novel way, and it can be given at quite a delay," said Thomas Carmichael, MD, PhD, professor and vice chair of neurology at the David Geffen School of Medicine at UCLA. Carmichael, a stroke expert, did not participate in the study but is familiar with its methodology and results. "Tissue plasminogen activator has a fairly narrow risk-to-benefit ratio. The longer you wait, the more likely it is to stimulate a hemorrhage."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Stanford University Medical Center. The original article was written by Bruce Goldman.

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Optimism associated with lower risk of having stroke

ScienceDaily (July 22, 2011) — A positive outlook on life might lower your risk of having a stroke, according to new research reported in Stroke: Journal of the American Heart Association.

In an observational study, a nationally representative group of 6,044 adults over age 50 rated their optimism levels on a 16-point scale. Each point increase in optimism corresponded to a 9 percent decrease in acute stroke risk over a two-year follow-up period.

"Our work suggests that people who expect the best things in life actively take steps to promote health," said Eric Kim, study lead author and a clinical psychology doctoral student at the University of Michigan.

Optimism is the expectation that more good things, rather than bad, will happen.

Previous research has shown that an optimistic attitude is associated with better heart health outcomes and enhanced immune-system functioning, among other positive effects.

The study is the first to discover a correlation between optimism and stroke. Previous research has shown that low pessimism and temporary positive emotions are linked to lower stroke risk. Researchers analyzed self-reported stroke and psychological data from the ongoing Health and Retirement Study, collected between 2006 and 2008. Participants were stroke-free at the beginning of the study.

Researchers measured optimism levels with the modified Life Orientation Test-Revised, a widely used assessment tool in which participants rank their responses on a numeric scale.

The team used logistic regression analysis to establish the association between optimism and stroke and adjusted for factors that might affect stroke risk, including chronic illness, self-reported health and sociodemographic, behavioral, biological and psychological conditions.

"Optimism seems to have a swift impact on stroke," said Kim, noting that researchers followed participants for only two years. The protective effect of optimism may primarily be due to behavioral choices that people make, such as taking vitamins, eating a healthy diet and exercising, researchers said. However, some evidence suggests positive thinking might have a strictly biological impact as well.

Stroke is the No. 3 killer in the United States, behind heart disease and cancer, and a leading cause of disability.

Co-authors of the study are Nansook Park, Ph.D., and Christopher Peterson, Ph.D. Author disclosures are on the manuscript.

The Robert Wood Johnson Foundation's Pioneer Portfolio funded a part of the study through the Positive Psychology Center of the University of Pennsylvania.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Heart Association.

Journal Reference:

Eric S. Kim, Nansook Park, Christopher Peterson. Health and Retirement Study. Stroke, 2011; DOI: 10.1161/STROKEAHA.111.613448

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here