February 2, 2009
TGen and ASU Scientsist Find Drug That Could Reduce Risk of Alzheimer’s
A drug used to improve blood flow to the brain also could help improve learning and memory and reduce the risk of Alzheimer's disease, according to a new study released today by investigators at the Translational Genomics Research Institute (TGen) and Arizona State University.
Fasudil has been used for more than 10 years to help protect the brain in stroke patients by dilating blood vessels when blood flow is curtailed.
Now, a team of Arizona psychologists, geneticists and neuroscientists report in today's edition of the journal Behavioral Neuroscience that hydroxyfasudil, the active form of the parent drug Fasudil, improved spatial learning and working memory in middle-aged rats when negotiating a complicated maze.
The findings suggest that hydroxyfasudil may influence similar cognitive processes in humans involving the hippocampus, a part of the brain that has been shown to deteriorate in patients with age-related disorders.
"If Fasudil proves to be safe and effective in enhancing learning and memory, it could represent a viable new option for the prophylactic treatment of disorders with a cognitive decline component. This could include diseases like Alzheimer's as well as general age-related impairment. In short, it may be a new pharmaceutical weapon that could be used even before the occurrence of symptoms," said Dr. Matthew Huentelman, an Investigator in TGen's Neurogenomics Division.
Clinical trials are being explored in the areas of cognitive impairment and dementia, said Huentelman, the scientific paper's first author.
Although far from proving anything about human use of the drug, the findings supports the scientific quest for a substance that could treat progressive cognitive impairment, cushion the impact of aging, or even enhance learning and memory throughout one's life span.
"Fasudil shows great promise as a cognitive enhancer during aging,'' said Dr. Heather Bimonte-Nelson, an Assistant Professor in ASU's Department of Psychology and the paper's lead author. "The effects in our aging-animal model were robust, showing enhancements in both learning and two measures of memory. The possibility that these findings may translate to benefits to human brain health and function is very exciting."
In the study, the researchers gave daily injections of hydroxyfasudil to middle-aged (17-18 months old) male rats, starting four days before behavioral testing and continuing throughout testing. Injection made it easy to give the drug to rats, but people take it in the form of a pill.
Rats were tested on a water radial-arm maze, which assessed how well they remembered which of the radiating arms had a reward, a sign of accurate spatial learning and working memory. Rats given a high dose (0.3750 mg per kg of weight) of hydroxyfasudil successfully remembered more items of information than those given a low dose (0.1875 mg per kg). Both dosed groups performed significantly better than control-group rats given saline solution. On this same test, the high-dose group showed the best learning (fewest total errors) and best working memory (measured two different ways).
For every test of learning, the scores of the low-dose group fell between the scores of the no-dose and high-dose groups, meaning that learning and memory boosts depended on the size of the dose.
Fasudil, is used to protect the brain by dilating blood vessels when blood flow is curtailed. In the body, Fasudil breaks down into the more potent hydroxyfasudil molecule, which the authors hypothesize may alter memory by affecting the function of a gene called KIBRA. The authors recently demonstrated that KIBRA might play a role in memory in healthy young and late-middle-aged humans.
Hydroxyfasudil inhibits the activity of Rho-kinase enzymes, which have been shown to inhibit Rac, a vital protein that supports key cellular functions. The authors speculated that blocking Rho-kinase enables Rac, in turn, to activate more of an enzyme called protein kinase C-zeta, which may in turn affect the KIBRA protein.
The authors received financial support from the Evelyn F. McKnight Brain Research Foundation, the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the state of Arizona. They maintain that they have no competing financial interests. Four of the authors hold stock in Sygnis Pharma AG, a German pharmaceutical company that owns the rights to develop this drug class as a potential memory enhancer. They stated that Sygnis was not directly involved in this study, did not fund any part of it, and did not influence the decision to study these drugs or the conclusion.
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