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Mystery mechanism keeps nerve cells alive.

Mystery mechanism keeps nerve cells alive

For decades, researchers have struggled to understand the chemical changes that trigger the death of neurons (SN: 12/5/87, p. 360). Some are testing experimental treatments to prolong the life of injured nerve cells or protect them from damage caused by disease. In stroke patients, for instance, clinicians are assessing drugs known as calcium channel blockers for their ability to protect brain cells deprived of blood flow. Scientists base such studies on the knowledge that these drugs can manipulate the extracellular environment, expanding constricted vessels in the brain or preventing a toxic concentration of calcium ions from entering neurons.

But new animal studies have prompted two investigators to propose that some calcium channel blockers may protect nerve cells through an as-yet-unknown, intracellular mechanism. If this proves correct, the researchers say, it may suggest new therapies for treating neuronal injury while providing new insights into neuron death.

Keith M. Rich and James P. Hollowell of Washington University School of Medicine in St. Louis tested a calcium channel blocker called flunarizine, which is used in humans to treat migraines and epilepsy and is under study as a treatment for stroke. In newborn rats treated with flunarizine, they found that 71 percent fewer severed peripheral nerve cells died after one week compared with severed cells in untreated rats. And in cell cultures, flunarizine prevented the death of peripheral nerve cells from rat embryos after withdrawal of nerve growth factor, a chemical vital for their survival. But flunarizine protected the cells only at doses far greater than the amount needed to block the entry of calcium ions, the neurosurgeons report in the June 15 SCIENCE. Moreover, they say, their in vitro work excludes the possibility that the drug prolongs cell survival through blood vessel dilation alone.

Rich and Hollowell propose instead that flunarizine acts inside the neuron to prolong life, possibly by preventing toxic metabolism of calcium ions.

Some supporting evidence for their theory, Hollowell says, comes from a report in the March 23 SCIENCE by John H. Weiss, Dennis W. Choi and their colleagues at the Stanford University School of Medicine. Those researchers found that the calcium channel blocker nifedipine slowed damage of cultured mouse brain cells exposed to toxins--but only at drug doses higher than believed required to block calcium ions.

Choi emphasizes that the nifedipine dose needed to block calcium ions in the brain cells might be higher than the value he extrapolated from studies of peripheral nerves. But he says an unidentified intracellular action of the drug, perhaps in combination with its calcium-blocking ability, seems a likely explanation for the protective effect.

Even if researchers solve the mystery of the protective mechanism, human applications will require further study, says David H. Martin at the Washington University School of Medicine. But he adds: "The dream of clinical application--that's what motivates all our work."
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Author:Cowen, Ron
Publication:Science News
Date:Jun 16, 1990
Words:479
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