Compound found in marijuana may defend against diabetic retinopathy

Mar 1 2006

A compound found in marijuana won't make you high but it may help keep your eyes healthy if you're a diabetic, researchers say.

Early studies indicate cannabidiol works as a consummate multi-tasker to protect the eye from growing a plethora of leaky blood vessels, the hallmark of diabetic retinopathy, says Dr. Gregory I. Liou, molecular biologist at the Medical College of Georgia.

"We are studying the role of cannabinoid receptors in our body and trying to modulate them so we can defend against diabetic retinopathy," Dr. Liou says. Diabetic retinopathy is the leading cause of blindness in working-age adults and affects nearly 16 million Americans.

High glucose levels resulting from unmanaged diabetes set in motion a cascade ultimately causing the oxygen-deprived retina to grow more blood vessels. Ironically, the leaky surplus of vessels can ultimately destroy vision.

Dr. Liou, who recently received a $300,000 grant from the American Diabetes Association, wants to intervene earlier in the process, as healthy relationships inside the retina first start to go bad.

Cannabinoid receptors are found throughout the body and endogenous cannabinoids are produced to act on them. "Their function is very different from organ to organ but in the central nervous system, cannabinoid receptors are responsible for the neutralization process that should occur after a nerve impulse is finished," says Dr. Liou.

Nerves come together at a point of communication called a synapse. Glutamate is a neurotransmitter that excites these nerves to action at their point of communication. "There are also inhibitory neurotransmitters such as GABA," Dr. Liou says. Endogenous cannabinoids help balance the excitation and inhibition, at least until oxygen gets scarce.

In the face of inadequate oxygen, or ischemia - another hallmark of diabetes - nerve endings start producing even more glutamate, setting in motion an unhealthy chain of events. Pumps that keep the right substances inside or outside of cells start to malfunction. Excess nitric oxide and superoxides are produced, which are toxic to the cells. Another irony is the heightened activity increases the retina's need for oxygen. "We are talking about nerve cell death," Dr. Liou says. "In the retina, if a lot of our nerve cells die, our vision is directly affected."

And that's not all that goes wrong in the nerve-packed retina. Glial cells, which support nerve cells by supplying nutrients and oxygen, are closely attuned to their charges. When they sense something is amiss, microglia, one type of glial cells, start eating the dying nerve cells.

"Microglial cells become voracious. They eat dying nerve cells, making the whole thing irreversibly bad," says Dr. Liou. Interestingly, the body start producing more endogenous cannabinoids to stop the role reversal, then produces an enzyme to destroy the cannabinoids because of concern there are too many of them. The same thing happens in the brain after a stroke. "Long before all these blood vessels start growing, the partnership between glial cells and nerve cells starts breaking down," says Dr. Liou.

That's why cannabidiol, an antioxidant, may help save the retina. Test-tube studies by others, as well as Dr. Liou's pilot studies in diabetic animal models show cannabidiol works to interrupt essentially all these destructive points of action.

"What we believe cannabidiol does is go in here as an antioxidant to neutralize the toxic superoxides. Number two, it inhibits the self-destructive system and allows the self-produced endogenous cannabinoids to stay there longer by inhibiting the enzyme that destroys them." Cannabidiol also helps keep microglial cells from turning on nerve cells by inhibiting cannabinoid receptors on microglial cells that are at least partially responsible for their ability to destroy rather than support the cells.

"Cannabinoids are trying to ease the situation on both sides. They help save the neuron and, at the same time, make sure the microglial cells stay in microglial form. How good do you want a drug to be?" Dr. Liou says.

His earliest studies in animal models, published in the January issue of the American Journal of Pathology, indicate it may be very good.

Co-authors on the study include Dr. Azza B. El-Remessy, MCG Department of Pharmacology and Toxicology; Drs. Mohamed Al-Shabrawey, Nai-Tse Tsai and Ruth B. Caldwell, MCG Vascular Biology Center; and Dr. Yousuf Khalifa, MCG Department of Ophthalmology.

"We are very pleased," he says of studies in which cannabidiol is injected into the stomachs of diabetic rats and mice.

He hopes the compound in marijuana may one day be given along with insulin to stop the early changes that set the stage for damaged or destroyed vision.