Mar. 22, 2004 Researchers have identified a key molecule through which high doses of lead trigger brain edema, a potentially fatal swelling. According to the report published March 22 in the early on-line edition of the Annals of Neurology, drugs that interfere with the molecule can prevent edema in an animal model of lead poisoning.
"Our findings are in rodents and need to be confirmed in humans," cautioned senior author John Laterra, MD, PhD, a professor, Departments of Neurology, Neuroscience and Oncology, Johns Hopkins University School of Medicine and the Kennedy Krieger Research Institute
If confirmed, however, these results would justify examining whether the same molecule plays a role in the much more prevalent cognitive deficits caused by smaller, more gradual exposures to lead in children.
For many Americans, lead toxicity was thought to be a thing of the past, abolished when the metal was removed from paint in 1977. However, lead has recently reappeared in news headlines about dangerously high concentrations in some Washington, D.C., water supplies.
For poor children living in houses with old, flaking paint, lead poisoning has never ceased to be a health issue. And indeed, recent scientific findings indicate that even the tiniest amounts of lead can cause brain damage in children. This has triggered calls for stronger lead regulations.
Laterra, along with first author Mir A. Hossain, PhD, and their colleagues have been studying the more drastic type of lead poisoning caused by exposure to very high levels over a short period. In adults, this typically occurs in industrial settings and can lead to peripheral nerve and kidney damage, among others.
Children are more vulnerable because their brains have not yet developed adult safeguards against toxins. Small children can get quite high brain exposures if they ingest flakes of lead-based paint or inhale dust containing old lead paint, in combination with lead from other sources such as water pipes.
"Acute high-level lead toxicity, while less common now in the U.S., continues in developing countries and causes brain edema and even death," said Laterra.
Laterra and colleagues had previously found that a protein called vascular endothelial growth factor (VEGF) is elevated in nervous system cells exposed to lead. VEGF is known to be able to trigger brain edema.
In the current experiments, the researchers found that young rats that ingested high concentrations of lead accumulated the metal in their brains. This was accompanied by significant edema, as well as increases in VEGF.
VEGF is part of a so-called biochemical "pathway." Changes in the levels or activity of one molecule in a pathway affects another, which affects another, and so on down the pathway.
In an experiment that may point to improved treatment for lead toxicity, Laterra and colleagues found that a drug which blocks the ability of VEGF to effect molecular changes inside cells prevented edema in the young rats.
"It is possible that VEGF pathway inhibitors, if approved by the FDA, could be used to prevent the development of brain swelling in children acutely intoxicated with lead. It is also possible that other, more subtle, cognitive aspects of low-level lead toxicity are caused by changes in VEGF levels," said Laterra.
Even if regulatory measures manage to eliminate most sources of new lead in the environment, lead stays in the environment for a long time. There remains a pressing need to understand the mechanisms of lead toxicity, conclude the authors in their article.
The Annals of Neurology, the preeminent neurological journal worldwide, is published by the American Neurological Association, the world's oldest and most prestigious neurological association. The 1,400 members of the ANA--selected from among the most respected academic neurologists and neuroscientists in North America and other countries--are devoted to furthering the understanding and treatment of nervous system disorders. For more information, visit http://www.aneuroa.org.
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