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Glucose triggers brain cell death in rats after hypoglycemic coma

Brain damage that was thought to be caused by hypoglycemic coma actually occurs when glucose is administered to treat the coma, according to a study in rodents led by researchers at the San Francisco VA Medical Center.

The results are surprising, say the authors, and may be of clinical significance for the treatment of diabetics in hypoglycemic coma, though they caution that the results cannot be immediately extrapolated to humans.

Insulin is an essential hormone that moves glucose from the bloodstream to individual cells, where it is broken down and used for energy. Diabetics do not produce enough of their own insulin and must take it several times a day.

A severe insulin overdose can reduce levels of glucose in the blood to extremely low levels –?a condition known as hypoglycemia –?and cause hypoglycemic coma, resulting in destruction of neurons in the hippocampus and cerebral cortex, which are essential to memory and cognition.

"This study tells us for the first time that, in rats, the brain damage occurs not during the coma, but after it, when we give them glucose and their blood glucose levels return to normal," says principal investigator Raymond A. Swanson, MD, chief of the neurology and rehabilitation service at SFVAMC.

Furthermore, says Swanson, he and his fellow researchers have identified the cause of the damage: the sudden return of glucose to the brain activates the enzyme NADPH oxidase, which in turn initiates a process of oxidative stress that is fatal to neurons.

Oxidative stress occurs when cells are poisoned by highly reactive forms of oxygen. Previously, it had been assumed that oxidative stress in neurons was initiated primarily by mitochondria, which process oxygen for energy within cells.

The paper appears in the April 2007 issue of the Journal of Clinical Investigation.

In their study, the researchers subjected rodents to a model of severe hypoglycemic coma. "The rats could remain hypoglycemic without evidence of significant oxidative stress for at least 60 minutes," says Swanson, who is also professor and vice-chair of neurology at the University of California, San Francisco. "It was only when we gave them glucose to reverse the hypoglycemia that the oxidative stress occurred. This was a real surprise."

The researchers then discovered that oxidative stress and neuron death were prevented when the rats were given an inhibitor of NADPH oxidase, indicating a key role for this enzyme.

"It is well-established that mitochondria can be a source of oxidative stress," says Swanson. "But in this setting, oxidative stress comes from an entirely different source." He adds that the normal role of NADPH oxidase in the brain is "completely unknown."

The authors also found that the degree of oxidative stress was directly dependent upon the amount of glucose given. "We think that this stems from a known link between glucose and NADPH oxidase," Swanson says. "Glucose is a precursor for NADPH, which in turn is used by NADPH oxidase in generating oxidative stress."

Swanson explains that the results have implications for both basic and clinical science. For basic science, he says, "this calls for a reconsideration of our concepts about the causes of oxidative stress in other settings –?especially in ischemic stroke, where the blood supply to the brain is diminished and there’s a big burst of oxidative stress when the blood returns. That burst has always been blamed on oxygen, but it may be that glucose is the culprit. And it may depend on how much glucose is put in."

In terms of clinical science, Swanson observes that "as clinicians, our first reaction when we see a patient in hypoglycemic coma is to give lots of glucose, fast. But our rodent model makes it clear that overshooting glucose levels is very bad for rat brains. The way we treat patients for hypoglycemia may have to be reevaluated ."

Swanson adds two strong cautions, however: "First, the work was done in rodents, and it is not legitimate to immediately extrapolate these findings to humans. Second, there are many ways to go wrong in humans by not treating hypoglycemia aggressively enough. The results of this one paper do not mean that clinicians should take an overly cautious approach to hypoglycemic coma."

In his own current research, Swanson is investigating the possible roles of glucose and NADPH oxidase as agents of oxidative stress in a rodent model of ischemic stroke. "So far, the results are very promising," he says.
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Source:University of California - San Francisco


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