During the Gulf War, one of the biggest fears of allied troops was that Iraq would attack with chemical and biological weapons. To protect themselves, Israeli soldiers took a drug called pyridostigmine. Luckily the troops never had to find out how well the drug might have worked; the feared chemical attacks never materialized. But the drug itself took a toll on the soldiers. Many complained of headaches, nausea, and dizziness. The complaints surprised doctors because those symptoms, which occur only if the drug reaches the brain, had been reported only rarely when the drug was tested before the war. Why had the side effects increased during combat? Biochemist Hermona Soreq of Hebrew University and Alon Friedman, a physician at Soroka Hospital in Beersheva, have now found that stress dramatically increases the ability of chemicals to pass from the blood into the brain.
Pyridostigmine molecules generally can’t get into the brain. They’re blocked by the same fatty sheath surrounding the brain’s blood vessels that also keeps infectious agents from passing through the bloodstream. Yet pass into the brain they did, in nearly one-quarter of the soldiers who took the drug during the war.
Pyridostigmine was designed to protect against chemical weapons by reacting with an enzyme--acetyl cholinesterase--that is found in many cells and is crucial to everything from breathing to memory to digestion. Many chemical weapons react with the same enzyme. But unlike the weapons, which kill the enzyme, pyridostigmine is slowly broken down by the enzyme. The drug thus keeps the enzyme temporarily occupied, preventing it from being permanently taken out by the poisons in chemical weapons.
Soreq and Friedman wondered whether the stress of war might somehow have increased the permeability of the blood-brain barrier. To find out, they took a group of mice and stressed some by dunking them in water. They then injected into the rodents’ hearts a chemical that turns blue when it binds to albumin, a common protein in blood. From the intensity of the blue visible in autopsied brains, the researchers could tell how much of the dye had penetrated the blood-brain barrier. They found that the dye had passed much more readily into the brains of the stressed animals.
The results are medically promising but also portentous, notes Soreq. Now we know that there are certain conditions under which we can get drugs to reach the brain, she says. But there are also drugs that people have developed under the assumption that they will stay in the periphery. As of now, you have to test those drugs also under stress conditions.