Study suggests antibiotic may limit or prevent vision problems caused by diabetes

05/10/05

HERSHEY, PAA Penn State College of Medicine study suggests that a common antibiotic called minocycline may slow or prevent diabetic retinopathy, a complication of diabetes that is the leading cause of blindness in people ages 20 to 74.

The team found that minocycline, often used to treat acne, limits by about 50 percent the retinal damage caused by microglia. Microglia are cells that act as the "cleanup crew" for the Central Nervous System (CNS). They destroy damaged cells by releasing toxins and they engulf them, much like a PacmanTM. Should they become activated and release their toxins in the retina, those toxins will kill the healthy neurons critical for normal vision.

"Our studies in rats suggest that this antibiotic may be a strong candidate for further consideration as a therapeutic drug in reducing the retinal complications of diabetes," said Kyle Krady, Ph.D., assistant professor of neural and behavioral sciences, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "Further studies are necessary to test the prediction that minocycline will reduce damage to the retina."

The study titled "Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy" was published in the May edition of Diabetes, a journal of the American Diabetes Association.

Previous studies have shown that the changes diabetes causes in the body lead to increased production of cytokines, proteins that cause inflammation of the nerves. This study goes a step further to show that in early diabetes elevated levels of cytokines activate microglia, which produce neurotoxins and kill nerve cells. The neuron death causes the progressive vision loss characteristic of diabetic retinopathy and results in 12,000 to 24,000 new cases of blindness each year in the U.S.

After establishing that microglia are activated early in the course of diabetes, the team compared the mRNA levels of cytokines in the retinas of rats with diabetes to healthy rats. Increasing mRNA levels are an indicator of increasing cytokine production. The team found that there was a four- to six-fold increase in cytokines present in the retinas of diabetic rats. Because cytokines activate microglia, the investigators asked whether the microglia in the retinas of diabetic rats were activated, and established that, indeed, they were. Then, the team treated diabetic rats with minocycline and the mRNA levels of cytokines were subsequently measured.

"Minocycline reduces the neuroinflammation in the retina caused by cytokines, which reduces microglia activation, and hence, reduces their production of neurotoxins with the net result being that there is less retinal nerve death," said Steve Levison, Ph.D., professor of neural and behavioral sciences, Penn State College of Medicine, and professor of neurology and neuroscience, University of Medicine and Dentistry in New Jersey. "These results confirm studies that showed that diabetes causes an early increase in the expression of inflammatory mediators within the retina, and it shows that minocycline reduces this inflammatory component."

To determine whether the toxins from activated microglia kill the retinal cells, the team grew active microglia with retinal cells. Some cultures were treated with minocycline while others were not. Activated microglia caused a 2.5-fold increase in retinal cell death. By contrast, in co-cultures treated with minocycline, nearly all retinal cells survived. An additional study in rats confirmed the results.

"This study has shed more light on the processes that lead to vision loss in those with diabetes," Levison said. "We hope that these discoveries will lead to new treatments for diabetic retinopathy, which remains a leading cause of blindness."

In addition to Krady and Levison, the study team included: Anirban Basu and Colleen M. Allen, Department of Neural and Behavioral Sciences; Yuping Xu, Kathryn LaNoue, and Thomas W. Gardner, Department of Cellular and Molecular Physiology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center.

All research methods followed the Association for Research in Vision and Ophthalmology statement on the Use of Animals in Ophthalmology and Vision Research and were approve by the Animal Care and Use Committee of Penn State College of Medicine. This study was supported by a program project grant from the Juvenile Diabetes Research Foundation.

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