In the stroke, researchers have traced the major cause of the death of brain cells due to artery blockage or bleeding in the brain.
They know that the resulting oxygen loss, or ischemia, unleashes a cascade of the brain chemical glutamate, which in turn triggers receptors on the surface of brain cells to snap open, allowing a lethal flood of calcium into the cells. Such receptors are pore-like proteins on the neuronal surface.
However, clinical trials of drugs to keep these receptors closed to calcium have largely failed, in large part because they disrupt normal function of the channels in otherwise unaffected brain areas.

Now, however, researchers have discovered the distinct molecular malfunction that renders some neurons particularly vulnerable to stroke damage. Those vulnerable are neurons are in the hippocampus, the brain region central to learning and memory. The researchers' findings could lead to drugs targeted to correct this specific malfunction, without compromising other brain cells.

The researchers, led by YouMing Lu of the University of Central Florida and the University of Calgary, published their findings in the Neuron.

Their studies concentrated on one of the glutamate receptors, called the AMPA receptor, that opens to cause calcium "poisoning" of neurons after ischemia. The other major receptor involved is called the NMDA receptor.

The researchers found in their experiments with rats that the AMPA receptor allows calcium influx in ischemia because such ischemia causes the receptor to be abnormally constructed in the first place. They found that in vulnerable neurons, early in the construction of the receptor, the machinery for correctly "editing" one part of the genetic blueprint, called messenger RNA, for a key AMPA receptor subunit has been disrupted. The editing consists of a pinpoint alteration in the messenger RNA when it is first produced, to prepare it to become a functioning blueprint in the protein-production machinery.

Significantly, the researchers found that, by using a genetic technique to switch this editing machinery back on in vulnerable neurons, they could protect them from ischemic injury.
Conversely, by switching it off in injury-resistant neurons, they could render those neurons vulnerable to ischemic damage.

They also traced the injury pathway further upstream, finding that an "executive" enzyme called CREB was responsible for regulating the editing machinery.
Other scientists had discovered that CREB was reduced in neurons vulnerable to ischemic damage. Thus, when Lu and his colleagues switched CREB on in vulnerable neurons, they could protect them from ischemic damage.

" To date, most clinical stroke trials targeting glutamate receptors ( AMPA or NMDA ) have failed, possibly because receptor antagonists also block the physiological actions of glutamate in noninjured neurons," wrote the researchers.

The researchers said that their findings showed that the AMPA receptor subunit editing "is an initial intracellular event that gates glutamate receptor injurious signals in forebrain ischemic insult."
Designing inhibitors that would target only the pathological form of the receptor could provide a potential strategy that would bypass the negative side effects seen with prior receptor antagonists.

Source: Neuron, 2006


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