Receptor activation protects retina from diabetes destruction

A drug known for it pain-relieving power and believed to stimulate memory appears to prevent this retinal damage that leads to vision loss, researchers say.

"The effects of this drug on retinal health are phenomenal," says Dr. Sylvia Smith, retinal cell biologist and co-director of the Vision Discovery Institute in the Medical College of Georgia School of Medicine. She's comparing retinal images from a diabetic mouse model treated with (+)- pentazocine to one that wasn't. Even to the untrained eye, the differences are dramatic.

The findings, published in the September issue of Investigative Ophthalmology & Visual Science, suggest such compounds that bind with the sigma receptor in the eye may be good treatments for the top two causes of vision loss: diabetic retinopathy and glaucoma.

Sigma receptors are ubiquitous in the body, but their role and what naturally activates them are unknowns. Recent research suggests sigma receptors help protect cells from stress by ensuring an adequate level of the properly folded proteins they need for normal function. Dr. Smith and others have shown that sigma receptors are located within the endoplasmic reticulum of cells, which controls protein synthesis and regulates calcium levels. When needed, the receptors appear to chaperone these proteins to the cell powerhouse, or mitochondria. Dr. Smith suspects sigma receptors help manage this hotbed of cell stress. In fact, sigma receptor binding with pentazocine increases with cellular stress.

This cell protection role could help explain the resilience of the retina, which receives light and transforms it to a neural impulse that goes to the brain. The retina can tolerate regular insults, such as the light or high blood sugar, and still function for years. In the case of diabetic retinopathy for example, nerve cell damage and death are gradual, eventually spurring new blood vessels in an apparent attempt to get more blood and oxygen to dying cells. Instead, blood vessel proliferation results in further vision loss.

Dr. Smith' lab is collaborating with other MCG investigators to breed mice without a sigma receptor to better understand the receptor's role and whether regular treatment with the drug has a similar dramatic impact on other animal models of retinal disease. "We need to know if we just hit it lucky with the Akita mouse or do we have something that could be of widespread benefit."

Interestingly, pentazocine's binding with sigma receptors didn't impact insulin levels. "It does not solve that problem of diabetes; however our findings do suggest that just because you are hyperglycemic does not mean you will have diabetic retinopathy," Dr. Smith says.

Her lab's studies of sigma receptors' potential to protect against diabetes' blinding cascade are pioneering but sigma receptors have become a hot topic. Scientists are exploring their potential to treat problems from Alzheimer's to brain tumors to depression. As of early September, there were 2,700 papers on sigma receptors in the literature, Dr. Smith says.

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