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Stroke drug might improve learning, memory

February 09, 2009

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 by a team of Arizona scientists, including two researchers from Arizona State University.

Hydroxyfasudil, also known as 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 the current issue of the journal Behavioral Neuroscience that hydroxyfasudil improved spatial learning and working memory in middle-aged rats when negotiating a complicated maze. The findings suggest that hydroxyfasudil may be involved in similar cognitive processes in humans involving the hippocampus, a part of the brain that has been shown to decline in patients with age-related disorders.

“Fasudil shows great promise as a cognitive enhancer during aging,” said Heather Bimonte-Nelson, a co-author of the Behavioral Neuroscience paper and an ASU assistant professor of psychology. “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.”

“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,” said Matthew Huentelman, one of the authors and a member of TGen, Phoenix. “This could include diseases like Alzheimer’s, as well as general age-related impairment.”

Clinical trials are being explored in the areas of cognitive impairment and dementia, the researchers said.

Although far from proving anything about human use of the drug, the findings support 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.

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 of hydroxyfasudil successfully remembered more items of information than those given a low dose. Both dosed groups performed significantly better than control-group rats given saline solution. 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 known 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.

Joshua Talboom, an ASU graduate student, was also part of the research team.