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Testosterone And Working Memory; Epilepsy And Schizophrenia; Toxins And Neuron Death; Oregon Researchers Present Findings At Society For Neuroscience

Oregon Health & Science University

Here is a summary of some of the material being presented by Oregon Health Sciences University researchers at the Society for Neuroscience annual meeting October 25-30 in New Orleans:

SCIENTISTS FIND TESTOSTERONE SUPPLEMENTS IMPROVE WORKING MEMORY IN OLDER MEN

OHSU scientists have discovered that older men given supplements of the male sex hormone testosterone showed significant improvement over time in working memory. "Working memory is the ability to hold information in one's mind while updating the information over brief periods of time," said Jeri Janowsky, Ph.D., lead author of the report and associate professor of neurology and behavioral neuroscience at OHSU. Earlier studies showed older men and women between the ages of 60 and 75 perform worse on working memory tests than matched groups of people between 25 and 35.

In the study being presented this week, older men tested first without supplementation then again after one month of testosterone supplementation showed significant improvement in performance and fewer errors than men tested after one month on a placebo. Janowsky says the study indicates that sex hormone supplementation in men may mitigate the loss of working memory associated with aging. Estrogen and testosterone levels were not related to working memory in either younger or older women.

While previous studies have shown that sex hormones are important for the development of the brain, this study shows that sex hormones may play a role in modulating brain function throughout life.

INVESTIGATORS EXPLORE OPPOSING RELATIONSHIPS BETWEEN EPILEPSY AND SCHIZOPHRENIA

Animal tests of a drug used to treat schizophrenia may shed light on the opposing relationship between that disorder and epilepsy, according to Janice Stevens, M.D., and Duane Denney, M.D. of the Departments of Neurology and Psychiatry at Oregon Health Sciences University.

Their work focuses on the drug clozapine, one of the more useful new drugs used for treating schizophrenia. Clozapine is particularly prone to cause epileptic seizures in some individuals. The OHSU investigators produced similar seizures (called myoclonus) in partially restrained laboratory animals given the equivalent of clinical doses of clozapine. They also showed that smaller doses given over a period of time eventually "kindle" seizures. Animals with those types of seizures showed increased neuronal activity in a deep brain area known as the thalamus. This brain area is important for both receiving sensory impressions and for maintaining arousal. The same area is overactivated during some types of epileptic seizures not connected with clozapine, including myoclonus.

Because some of the most important symptoms of schizophrenia are sensory distortions and difficulty focusing attention, the authors suggest that "kindling" with low doses of clozapine might activate brain areas critical to ameliorating symptoms of schizophrenia without triggering the seizures or other side effects sometimes caused by higher doses. Preliminary results from clinical studies at OHSU appear to bear out this conclusion.

More generally, the study helps advance understanding of the critical balance between epilepsy and schizophrenia.

DNA DAMAGE BY TOXINS MAY PRECIPITATE NEURODEGENERATIVE DISEASE

Scientists at Oregon Health Sciences University are shedding light on the mechanisms by which a plant toxin called cycasin causes neurodegenerative disease. Their findings suggest that environmental toxins that damage the DNA of nerve cells may precipitate neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease).

Glen Kisby, Ph.D. and other scientists from OHSU's Center for Research on Occupational and Environmental Toxicology (CROET) focused on the plant toxin cycasin, found in the cycad plant. Cycasin is composed of glucose and a well-known DNA-damaging agent known as MAM. Cycasin has recently been linked with a tragic motor neuron disease afflicting native people on the island of Guam, in New Guinea and in part of Japan. "Our team has proposed that cycasin/MAM may slowly kill neurons by damaging their DNA," says Kisby. "The cumulative death of neurons may trigger a cascade of events that ultimately leads to clinical symptoms such as trembling, paralysis and cognitive loss--manifestations typically associated with Alzheimer's disease, Parkinson's disease and ALS."

Kisby says the research leads to a broader question: Are agents similar to MAM in the American environment and workplace contributing to chronic neurodegenerative diseases?

PEPTIDE CONNECTED WITH PAIN NOW ALSO LINKED TO THE CIRCADIAN SYSTEM

Researchers at OHSU have discovered that the peptide orphanin, which is linked to the human opiate system (relating to pain), also plays a role in regulating the circadian system (relating to biological rhythms and sleep). Charles Allen of the Center for Research on Occupational and Environmental toxicology at OHSU (CROET), along with researchers from OHSU's Vollum Institute and the Department of Physiology and Pharmacology not only showed orphanin reglates the circadian system, but found the specific neuronal pathway through which orphanin acts. "This could lead to some important clinical applications," says Allen. "If we know the receptor site where orphanin works on the circadian system, we may be able to use that information to come up with new ways to regulate sleep."

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