According to the American Stroke Association, stroke is the third leading cause of death in the U.S. And stroke has claimed among its victims an impressive number of stroke drugs. Clinical trial failures number in the dozens. (See BioWorld Today, Aug. 31, 2007.)

Preventive possibilities remain about equally slim. "There's not that many anticoagulants on the market," Craig Morrell told BioWorld Today. "The big options are basically aspirin and Plavix."

In an article published online in the Journal of Experimental Medicine, Feb. 18, 2008, senior author Morrell, an assistant professor in the department of molecular and comparative pathobiology at Johns Hopkins University School of Medicine, and his colleagues at Johns Hopkins; the University of Miyazaki in Japan; Ege University School of Medicine in Izmir, Turkey; and the Max Planck Institute for Medical Research in Heidelberg, Germany, reported that targeting AMPA-type glutamate receptors may offer another option for decreasing the risk of clots.

For those who know glutamate as a neurotransmitter, and AMPA receptors as major players in memory processes, the location of those glutamate receptors may come as a surprise - they are on platelets.

Previous studies had shown that platelets store glutamate and release it when they are activated by other stimuli, but the targets and molecular consequences of the release were unknown.

Morrell and his colleagues showed that such glutamate releases further activated the platelets, making them more likely to form clots, and that effect is mediated by their binding to AMPA receptors on the platelets. Platelets also have another type of glutamate receptor known as the NMDA receptor, whose role in the brain is to enable the formation of new memories, but inhibiting NMDA receptors had no effect on platelet aggregation.

Mechanistically, AMPA receptor activation allowed sodium to enter the platelets. Sodium influx activates g-protein receptor-coupled pathways in the platelets, and the effects of AMPA receptor agonists were specific to GPCR-coupled clotting signals. Thrombin and epinephrine-induced clotting was decreased by AMPA receptor antagonists, but collagen- induced clotting - which acts through a different intracellular messenger system - was unaffected.

In animal studies, "when we add our AMPA antagonists, we don't totally stop bleeding," Morrell said. "The mice do stop bleeding, and they do develop [clots] - it's just delayed."

Those data suggested that targeting AMPA receptors might be a good target for preventive anticlotting therapy, which, Morrell said, walks a thin line. "The holy grail is to get something that decreases platelet activation without increasing the risk of bleeding out," or hemorrhaging.

Glutamate is not the only neurotransmitter moonlighting in the circulation system. "Platelets and neurons are surprisingly similar," Morrell said. Serotonin is well known for having a role both on platelets and in the brain, and the alpha-synuclein also does double duty. "It's a suspect in Parkinson's disease, but the other place where it's highly expressed is in platelets," Morrell said.

Why there should be such similarities between blood clots and brain cells is unclear, but the findings could help explain one clinical observation: that smaller strokes sometimes can be followed by more massive ones a few days later.

Morrell stressed that a link between secondary strokes and glutamate release is "purely speculative" at this point. But such a link does have a plausible mechanism: "Certainly, if glutamate concentration is increased, the platelets will start to suck it up," through their transporters - and stroke-damaged neurons can release glutamate.