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New Data, Insights on the Role of Astrocytes in Traumatic Brain Injury


doi: 10.1097/01.NT.0000343217.23537.b2
News From the Sfn Annual Meeting
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Investigators reported on the role astrocytes play in setting off metabolic changes that compound the damage of traumatic brain injury.

WASHINGTON—Traumatic brain injury, even when mild, sets off a cascade of metabolic changes that compound the damage, and astrocytes appear to be at the heart of these changes, according to research presented here in November at the annual meeting of the Society for Neuroscience (SFN).

Astrocytes produce calcium waves, which trigger the release of glutamate, which modulates neuronal signals. The calcium signaling and subsequent glutamate release are activated by purinergic receptors on astrocytes, which respond to ATP.

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David F. Meaney, PhD, professor in the department of bioengineering at the University of Pennsylvania, reported that mild mechanical injury to a mouse brain produces changes in the calcium signaling of astrocytes and an increase in the release of glutamate, which appear to contribute to excitotoxicity and neuronal death.

Dr. Meaney and his colleagues used two-photon imaging of a living mouse brain to monitor the calcium dynamics of astrocytes in response to repeated mechanical trauma. When they delivered mild blows to the exposed brain, calcium levels in astrocytes increased. When they administered a purinergic receptor antagonist that blocked ATP, it inhibited these responses, suggesting that the increase in astrocyte calcium signaling after mechanical brain trauma is mediated by ATP activation of purinergic receptors.

“At first glance it may seem contradictory that astrocytes, which are meant to provide mechanical and metabolic support to neurons, may end up damaging them,” Dr. Meaney said in a printed summary of his work, “but that's what we and others are now finding.”

Dr. Meaney contends that purinergic receptors may be a potential therapeutic target for reducing the release of glutamate from astrocytes following brain trauma. “If we can control the rise in calcium, we might be able to control the release of glutamate,” he said.



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Eli Gunnarson, MD, PhD, who is affiliated with the department of women and child health at the Astrid Lindgren Children's Hospital and the Karolinska Institute in Stockholm, reported that erythropoietin (EPO), a growth factor of blood cells that has emerged in recent years as a neuroprotective agent, appears to reduce brain swelling following trauma or stroke.

“By preventing or reducing the swelling, brain tissue may be rescued, making it possible to limit the extent of the final injury to the brain,” Dr. Gunnarson said, summarizing her work.

The water that produces edema accumulates in astrocytes, which swell and increase the risk of tissue death. Dr. Gunnarson and her colleagues found that in both tissue cultures and in mice, EPO prevents excess water uptake in astrocytes caused by glutamate. Mice given EPO, which easily crosses the blood-brain barrier, displayed significantly fewer neurological symptoms than controls given a saline solution.

According to Dr. Gunnarson, EPO works by blocking aquaporin-4 (AQP4), the most important water channel in the brain.

“The flow of water via aquaporin 4 is regulated by glutamate, a major signaling substance in the brain, and is known to contribute to brain injury,” she said. “Glutamate opens the water channel, and we found that EPO prevents this opening of the AQP4 water channel. Thus, EPO and EPO analogues represent promising new tools for preventing permanent brain damage following traumatic brain injury, stroke, and other types of brain edema.”



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TBI often causes seizures, which develop weeks to years after the injury, and this problem will affect many of the soldiers returning from Iraq who have been exposed to blast injuries, according to David Prince, MD, professor and chairman of the department of neurology at Stanford University.

“We don't know what the incidence will be after injuries from improvised explosive devices, or when the seizures will begin to occur, but we can expect an epidemic,” Dr. Prince told Neurology Today. “What happens between the injury and the development of epilepsy? That is a question many people are working on.”

Injured nerve cells sprout new connections, especially in the hippocampus and cerebral cortex, as shown by animal studies conducted by Dr. Prince and his colleagues, and this sprouting appears to contribute to the development of epilepsy. Placing a thin sheet containing tetrodotoxin over the injured cortex dampened all activity and prevented subsequent epileptic activity.

“That was proof of principle that we could block epileptogenesis in a rat model,” said Dr. Prince. “If we applied tetrodotoxin for three days and removed it, two weeks later the brain was not epileptic. There's a critical period in rats; we don't know if there's a critical period in humans.”

In addition, TBI appears to cause atrophy in cells that release gamma-aminobutyric acid (GABA), an inhibitor of neural activity. Dr. Prince has been exposing these cells to brain-derived neurotrophic factor, in an effort to rescue them and block epileptic activity.

However, the brain activity that causes seizures after a TBI may also contribute to healing.

“Are the same mechanisms involved in inducing epilepsy and in recovery, or are they different, or are they sequenced?” Dr. Prince asked. “If there's a critical period, maybe treating for a few days and then stopping would be adequate for preventing epilepsy while still allowing recovery.”

©2008 American Academy of Neurology