Experimental drugs reduce neuron death in rats following insulin shock

November 19, 2003

In a study conducted in rats, scientists have determined that drugs that block the action of a group of DNA-repair enzymes can protect brain cells from damage triggered by an overdose of insulin. If these drugs are shown to produce the same effect in humans, they could become the first tool available for prevention of brain damage that can result from hypoglycemic shock, also known as insulin shock, in patients with diabetes. The study was conducted by scientists at the San Francisco Veterans Affairs Medical Center (SFVAMC) and appears in the November 19 issue of the Journal of Neuroscience.

The drugs, PARP inhibitors, have already been shown to protect human heart and brain cells from damage following heart attack and stroke, and are currently approved for testing in phase-2 clinical trials for victims of heart attack.

"Every hospital emergency department sees one or more cases of hypoglycemic coma each year," says Raymond Swanson, MD, chief of Neurology Service at SFVAMC and a professor in the Department of Neurology, University of California, San Francisco (UCSF.) "Up to this point, we don't have any way to treat these patients except to give them glucose, which pulls them out of insulin shock, but doesn't do anything to stop the cell death process that is triggered by severe hypoglycemia. PARP inhibitors rescue neurons [brain cells] which would otherwise go on to die even though blood glucose is restored."

About five to six million people in the United States take insulin to control diabetes, a chronic disease characterized by the body's impaired use or diminished production of insulin, a hormone produced in the pancreas that regulates glucose (sugar) levels in the blood. Diabetes patients monitor their blood sugar, often several times a day, and inject themselves with insulin to maintain appropriate blood sugar levels. However, calculating the correct dose of insulin can be difficult: The body's requirement changes depending on the content and quantity of food consumed, exercise, alcohol consumption and other factors. If insulin levels are too high, blood sugar can drop to dangerously low levels, producing hypoglycemia, which causes symptoms such as confusion, anxiety, shakiness, dizziness and difficulty speaking.

Diabetes patients can normally detect the onset of hypoglycemia and control it by eating small, sugar-laden snacks. But if not treated promptly, hypoglycemia can rapidly worsen, depriving the brain of needed glucose. When this happens, a person may experience seizures or lapse into a coma. This is the stage of hypoglycemia known as hypoglycemic shock or coma, or insulin shock, and when it occurs, a biochemical chain reaction is initiated that ends with the destruction of neurons, particularly in the hippocampus, a region of the brain instrumental in processing memories. Permanent memory impairment is a common and serious complication of severe hypoglycemic shock.

Intravenous injections of glucose can reverse insulin shock and rescue a patient, but they cannot prevent brain injury that already may have been initiated. The destructive biochemical pathway triggered by insulin shock shares some similarities to pathways that damage heart and brain cells as a result of heart attack and stroke. From his previous work and that of other investigators, Swanson knew that PARP inhibitors -- which block the action of PARP, an enzyme that floods cell nuclei when DNA is damaged -- can inhibit these destructive pathways. To test whether they can also protect brain cells from insulin shock, he and his team examined the effects of the drugs in brain cell cultures derived from mice, as well as on rats subjected to induced hypoglycemic coma.

In the cell culture test, two sets of brain cells underwent five hours of complete glucose deprivation. One set had PARP inhibitors mixed into the culture at the start of the period of glucose deprivation; the other set did not receive the drug. Twenty-four hours later, only about 10 percent of the brain cells in the drug-free culture were still alive, while about 50 percent of brain cells survived in the culture with added PARP inhibitors.

For the rat tests, Swanson and his colleagues devised several scenarios that simulate the kinds of circumstances that might occur when a person goes into hypoglycemic shock.

In one experiment, rats were held in hypoglycemic comas for 30 minutes before being rescued by glucose injections. Some of these rats, the control group, did not receive PARP inhibitors following the glucose injections, while some rats received immediate injections of PARP inhibitors, and others received injections one, two, or three hours later. Compared to controls, rats that immediately received PARP inhibitors experienced 85 to 90 percent reductions in brain cell death. Rats that received the drug one hour after the end of glucose deprivation experienced about 70 percent reduction in cell damage, and rats that received the drug two hours afterwards experienced about 50 percent reduction in cell damage. Rats that received PARP inhibitors three hours after the end of glucose deprivation experienced minimal reductions in cell damage.

Six weeks after these tests, rats that had been immediately treated with PARP inhibitors were able to complete memory and learning tests just as well as rats that had not been subjected to hypoglycemia, while rats in the control group (those that had not received PARP inhibitors following hypoglycemic coma) fared poorly in the tests. Neither the control group nor the PARP-treated group had impaired motor abilities, a confirmation that damage from hypoglycemic coma is primarily restricted to the brain's memory processing centers. (Swanson's team did not conduct these behavioral tests on the groups of rats that had received PARP inhibitors one, two or three hours after glucose rescue.)

In another experiment, Swanson extended the duration of hypoglycemic coma to 45 minutes. In rats that did not receive PARP inhibitors following the reversal of coma, about 70 percent of cells in two regions of the hippocampus died. But in rats that immediately received the inhibitors following the reversal of coma, brain cell death was reduced by about 85 percent in one of these regions, and 35 percent in the other.

"I was surprised by what a large effect we found," Swanson says. "There are already studies that have proved PARP inhibitor's efficacy in reducing cell death in heart attack and stroke, but what was most exciting here was that we saw large effects even when we delayed administration of PARP inhibitors up to two hours after reversal of hypoglycemia. This is the kind of time situation that can occur in real life."

Before PARP inhibitors can be used in practice they must first be tested in a clinical trial, but, says, Swanson, this won't be easy. Each hospital in the country treats only a few insulin shock patients each year, so a prospective clinical study would likely require participation by dozens of sites. "I'm very enthusiastic about the clinical potential of this approach and have begun discussions with the Juvenile Diabetes Research Foundation about possible ways to get this organized. Our study shows that it is possible to rescue neurons that would otherwise go on to die after severe hypoglycemia, and I think it is important to translate this approach to clinical practice as rapidly as possible."

Co-authors of the study are: lead author Sang Won Suh, MD, PhD, research fellow; Koji Aoyama, MD, PhD, research fellow; Philippe Garnier, PhD, research fellow; and Yongmei Chen, MD, PhD, research fellow, all with Neurology Service, SFVAMC and the Department of Neurology, UCSF; Elizabeth Gum, MS, research associate with Neurology Service, SFVAMC; and Yasuhiko Matsumori, MD, visiting postdoctoral scholar, and Jialing Liu, PhD, adjunct professor, both with Neurosurgery Service, SFVAMC and the Department of Neurosurgery, UCSF. The study was supported by the Juvenile Diabetes Research Foundation, the National Institutes of Health, and the Department of Veterans Affairs.

Poly(ADP-ribose) polymerase, is a family of enzymes that help repair damaged DNA, the genetic material contained in all cell nuclei. But when extensive DNA damage occurs, an overabundance of PARP may be activated, and instead of repairing damage, it can kill cells by depleting their energy resources. Severe hypoglycemia triggers the release of a chemical messenger called glutamate, which in turn triggers a chain reaction of biochemical events leading to overactivation of PARPs.

The NIH reports that in 2002 there were 18.2 million people in the United States with diabetes, a number that is steadily increasing. About five to ten percent of diabetes cases are "type 1 diabetes," formerly known as childhood-onset or juvenile diabetes. The pancreas's ability to produce insulin is destroyed in type 1 diabetes, so all people with this form of the disease must take insulin.

The vast majority of diabetes patients in the U.S. have type 2 diabetes, a form of the disease that can often be controlled through exercise, diet, and weight management. If these measures do not adequately control the disease, there are several medications that can help. However, type 2 diabetes can progress to a stage that requires use of insulin. The population of people in the U.S. requiring insulin to control type-2 diabetes is also steadily growing. About 22 percent of all adult diabetes patients in the United States use insulin and no other medications to control diabetes, while another11 percent use insulin and other medications.

National Diabetes Statistics: http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7

University of California - San Francisco

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