Flavonoids Could Represent Two-Fisted Assault on Diabetic Complications and Nervous System Disorders

LA JOLLA, CA-A recent study from scientists at the Salk Institute for Biological Studies suggests that a strawberry a day (or more accurately, 37 of them) could keep not just one doctor away, but an entire fleet of them, including the neurologist, the endocrinologist, and maybe even the oncologist.

Investigations conducted in the Salk Institute's Cellular Neurobiology Laboratory (CNL) will appear in the June 27, 2011, issue of PLoS ONE. The report explains that fisetin, a naturally-occurring flavonoid found most abundantly in strawberries and to a lesser extent in other fruits and vegetables, lessens complications of diabetes. Previously, the lab showed that fisetin promoted survival of neurons grown in culture and enhanced memory in healthy mice. That fisetin can target multiple organs strongly suggests that a single drug could be used to mitigate numerous medical complications.

"This manuscript describes for the first time a drug that prevents both kidney and brain complications in a type 1 diabetes mouse model," says David Schubert, Ph.D., professor and head of the Cellular Neurobiology Laboratory and one of the manuscript's co-authors. "Moreover, it demonstrates the probable molecular basis of how the therapeutic is working."

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study's corresponding author. Maher initially identified fisetin as a neuroprotective flavonoid ten years ago. "In plants, flavonoids act as sunscreens and protect leaves and fruit from insects," she explains. "As foods they are implicated in the protective effect of the 'Mediterranean Diet.'"

Other celebrity flavonoids include polyphenolic compounds in blueberries and red wine.

Although her group's focus is neurobiology, Maher and colleagues reasoned that, like other flavonoids, fisetin might ameliorate a spectrum of disorders seen in diabetic patients. To test this, they evaluated effects of fisetin supplementation in Akita mice, a very robust model of type 1 diabetes, also called childhood onset diabetes.

Akita mice exhibit increased blood sugar typical of type 1 diabetes and display pathologies seen in serious human complications of both type 1 and 2 diabetes. Those include diabetic nephropathy or kidney disease, retinopathy, and neuropathies in which patients lose touch or heat sensations.

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney enlargement-or hypertrophy-seen in untreated mice was reversed, and high urine protein levels, a sure sign of kidney disease, fell. Moreover, fisetin ingestion ameliorated anxiety-related behaviors seen in diabetic mice. "Most mice put in a large area become exploratory," says Maher. "But anxious mice tend not to move around. Akita mice showed enhanced anxiety behavior, but fisetin feeding restored their locomotion to more normal levels."

The study also defines a likely molecular mechanism underlying these effects. Researchers observed that blood and brain levels of sugars affixed to proteins known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated compared to untreated Akita mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors.