Years before an overgrowth of vessels destroys the sight of diabetics, vital nerve cells in the retina begin to die.
The dying cells have a characteristic appearance. "They are often adjacent to cells that appear normal; it's kind of a civilized death," says Dr. Sylvia Smith, retinal cell biologist at the Medical College of Georgia, as she looks at a microscopic image of the dying cells.
While the specific initiating event that leads to late-onset vascular changes is not certain, the death of these neurons may contribute to the complex cascade of events that disrupts the beautifully organized retina over years; eventually, this back portion of the eye begins to grow new blood vessels, presumably in an attempt to rescue dying cells by providing more blood and oxygen.
Unfortunately, the growth of new vessels obstructs vision. They can leak and cause scarring in a condition called diabetic retinopathy, the number-one cause of vision loss in working-age adults.
Dr. Smith recently received a $1 million, four-year grant from the National Eye Institute to understand better how these dying ganglion cells live and why the increased glucose levels in diabetics prompt their death.
Better still, she wants to know if drugs called sigma receptor ligands can preserve ganglion cells and stop the destructive blood vessel proliferation that seems to follow.
"We are not studying the vascular problems in this project as they set in after many years of diabetes in humans and animal models. We are interested in the early changes and we have evidence that there are changes in the nerve cells in the retina long before you have these gross blood vessels growing," she says.
Problems seem to start with ganglion cells, nerve cells found in the inner part of the retina. "The axons of these cells join to form the optic nerve, which then goes to the brain and delivers a visual image," she says. While the idea that these cells might be affected by diabetes is not new, its acceptance is.
Evidence is mounting that transporters, which carry vital substances into and out of cells, may be affected by high glucose levels in diabetes, Dr. Smith says. Without proper transportation, out-of-place and out-of-control substances such as glutamate, an amino acid plentiful inside ganglion cells where it works as a communicator, can be toxic. "It's all about location and balance," says Dr. Smith. If glutamate accumulates outside of the cell it can over-stimulate the cell by binding to a glutamate receptor. One such receptor, the NMDA receptor, is particularly sensitive to excessive levels of glutamate. Over-stimulation of NMDA receptors allows too much calcium to enter the cells where it triggers formerly dormant cell-death pathways.
"The hypothesis we are testing is does this increase in glucose, this hyperglycemic state that occurs in diabetes, affect the transport of glutamate such that it might subject cells to an excessive level of glutamate, which is toxic?" Dr. Smith says of her studies in diabetic animal models.
The researcher has evidence that transport of folate or folic acid, a vitamin essential to RNA, DNA and ultimately protein synthesis, is disrupted in diabetes as well. A deficiency in folate can precipitate an increase in the level of homocysteine, an excitatory amino acid that, like glutamate, can stimulate the NMDA receptor.
Additionally, high glucose may impair other transporters found on supportive cells such as retinal Muller cells, which help eliminate unnecessary or even harmful substances in and around cells. Muller cells, for example, can take up glutamate and convert it to harmless glutamine, so Dr. Smith also is studying how these cells are affected by high glucose.
While continuing to dissect the process that results in ganglion cell death and the ultimate role that death plays in abnormal blood vessel growth, Dr. Smith already is working to interrupt it.
In an animal model, she is using sigma receptor ligands, compounds not naturally occurring in the body but known for their ability to protect cells and under study for their potential in memory disorders and other diseases. She has preliminary evidence that, at least early on, these ligands can prevent ganglion cell death perhaps by interfering with glutamate's over-stimulation of NMDA receptors.
"These are potent drugs and they seem to have a multitude of neuro-protective functions including inhibiting NMDA activation that sets up this deadly cascade," Dr. Smith says. "So we are testing these sigma receptor ligands to prevent this neuronal death. It may be a little ambitious, but that is what we are doing. If we can get strong evidence that these drugs have a beneficial effect on ganglion cell death, that is an important finding."
She recently submitted for publication findings documenting the dramatic reduction in cell death resulting from the injections of the ligand, Pentazocine. "We have a long way to go, but nevertheless, I think it's quite promising," Dr. Smith says.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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