Augusta University Discovers How Nrf2 Activator Preserves Sight in Retinal Degeneration Model

“We are very, very pleased that we can now explore the mechanisms,”, mentioned Dr. Sylvia Smith, chair of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Augusta University and co-director of the James and Jean Culver Vision Discovery Institute at AU.

In an exciting breakthrough scientists have discovered that a common pain medication often prescribed for chronic pain can help preserve vision in a model of severe, blinding retinal degeneration.

The vision preservation could activate one of the most powerful antioxidants in the human body known as Nrf2. This targets receptors to protect neurodegenerative diseases.

The drug is known as pentazocine, and is a receptor of sigma 1, a powerful natural antioxidant and Nrf2 activator.

“We are very, very pleased that we can now explore the mechanisms,”, mentioned Dr. Sylvia Smith, chair of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Augusta University and co-director of the James and Jean Culver Vision Discovery Institute at AU.

A new $1.14 million grant from the National Eye Institute is enabling research to explore the nrf2 protecting ability against sight-degrading conditions like retinitis pigmentosa, macular degeneration and glaucoma.

The protective power of activated Nrf2 through the Sigma 1 receptor (a well-established non-opioid pain receptor) is an essential means to a healthy retina. Without the sigma 1 receptor, the Müller cells that support our photoreceptor cells are overpowered by oxidative stress (cellular damage) impacting oxygen supply and light to enable healthy vision.

The studies showing Pentazocine activating the sigma 1 receptor have been reported in the 2016 Journal Proceedings of the National Academy of Sciences.

How does it work?

The proteins Nrf2 and Keap1 and cul3, congregate quietly in the cell cytoplasm. Excess production of antioxidants by Nrf2 activation moves to the cell proteasome to be eliminated.

But if needed such as in a case of increased oxidative stressas manifest in conditions like retinitis pigmentosa and aging – Nrf2 and Keap1 response activates hundreds of natural antioxidants and cell protection genes.

“It can launch an almost amazing response to stress,” says Smith. “I think it’s arguably the most important antioxidant in cells.”

Dr. Bobby Thomas, neuroscientist in the MCG Department of Pharmacology and Toxicology, is a coinvestigator with Smith on these studies and also exploring the pathway in Parkinson’s disease.

Dr. Smith explains, “Millions of super metabolically active photoreceptor cells in the retina – some 125 million rods and 6 million cones – use a lot of oxygen constantly converting light into images. In the case of retinitis pigmentosa, it’s actually a genetic mutation that kills off the rods but their death creates so much oxidative stress that the cones also are lost in a “bystander” effect.

It’s the cones pentazocine appears to protect, which should enable individuals to maintain functional vision. Interestingly and inexplicably, the high oxidative stress increases the binding of pentazocine to the sigma 1 receptor.”

The studies are being done in mouse cone cells from the retina and the supportive Müller cells. Other collaborators include Dr. Graydon B. Gonsalvez, cell biologist in the MCG Department of Cellular Biology and Anatomy, and Dr. Alan Saul, neuroscientist and electrophysiologist in the MCG Department of Ophthalmology.

For further information contact http://www.augusta.edu/mcg/

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1. Tang C, Li K, Yu Q, Jiang Q, Yao J, Cao C. Activation of Nrf2 by Ginsenoside Rh3 protects retinal pigment epithelium cells and retinal ganglion cells from UV. Free Radic Biol Med. February 2018. [PubMed]

2. Deliyanti D, Alrashdi S, Tan S, et al. Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2018;59(2):815-825. [PubMed]