PHYSICAL OR MENTAL STRESS, ISRAELI'S REPORT, PRYOPEN BLOOD-BRAIN BARRIER TO DRUGS

As protection against a possible nerve-gas attack, allied soldiers inthe Gulf War popped pills of pyridostigmine bromide.

The chemical-warfare weapons they pre-treated wereorganophosphates called soman and sarin. (See BioWorld Today,Nov. 6, 1996, p. 1.) These toxins shut down a vital enzyme,acetylcholinesterase, which controls levels of the body's mainneurotransmitter, acetylcholine.

Since long before the armed forces bought into pyridostigmine, thedrug has been used to treat myasthenia gravis, a muscle-weakeningdisease caused by the enzymic breakdown of insufficientacetylcholine. Pyridostigmine acts by inhibiting that inhibitor. Itsblockage of acetylcholinesterase (AChE) allows the neurotransmitterto accumulate at the neuromuscular junction.

As a natural alkaloid, the compound was extracted from jungleplants by Amerindians, to poison their arrowheads. As a synthesizeddrug, it received a positive charge on its molecule to render it toobulky to cross the blood-brain barrier.

This seamless inner lining of arteries, veins and capillaries thatnourish the central nervous system (CNS) keeps out all substancesother than water, sugar, salts and dissolved nutrients.

Pyridostigmine, the military reasoned, would blunt soman's onslaughton AChE in the peripheral (beyond-the-brain) nervous system (PNS),thereby preventing the nerve toxin's lethal effect on the CNS.

To the army's surprise, some of the international troops that dutifullygulped down their anti-nerve-toxin pyridostigmine tabletscomplained of side effects, notably headaches, insomnia, drowsiness,nervousness, unfocussed attention span, specific to the CNS. Amongthese were 213 Israeli soldiers on nerve-gas alert inside Israel. Theirsymptoms, triple the usual incidence, strongly suggested that the drughad penetrated the physiological chastity belt of their blood-brainbarrier (bbb).

With support from the U.S. Army Medical Research & DevelopmentCommand, the Israeli Defense Forces' Medical Corp set out toinvestigate what had caused the soldiers' bbb to let down theirdefenses against large molecules insulting the brain.

A paper in the December Nature Medicine presents a first answer tothis question. Its title: "Pyridostigmine brain penetration under stressenhances neuronal excitability and induces early immediatetranscriptional response."

Neurosurgeon and physiologist Alon Friedman is the article's firstauthor. "Today, pyridostigmine is the only drug available asprophylaxis against organophosphate poisoning. If given before anattack," he told BioWorld Today, "what it does actually is the samething as the nerve gas. It inhibits the soman, with the difference thatthe toxin binds irreversibly, and the drug binds reversibly."

Friedman and his co-authors, then at the Hebrew University inJerusalem, together with the Israeli army medical corp, took as theirpoint of departure the known concept that physical or emotionalstress could cause the bbb to let down its guard. They surmised thatthe stresses of warfare might have made the barrier temporarilypermeable.

Rodents' Ordeal By Water

So they stressed experimental mice in a test that made the animalsvirtually swim for their lives.

After such a forced-natation ordeal, the animals' bbb permeabilityrelaxed to a degree where the amount of pyridostigmine needed to cutAChE activity by half dropped to less than 1/100th of the usual dose.

But 35 unstressed, peacetime human volunteers, in a double-blindtrial, had only peripheral nervous system (PNS) symptoms ofpyridostigmine ingestion: diarrhea, excessive sweating and salivation.

By what mechanism might stress loosen the barrier? "I wish I couldtell you," Friedman responded. "I don't know; we are working on it."He added that "The `blood-brain barrier' is not really a barrier. Theterm itself," he explained, "is applied not only to physical barriers butalso to functional barriers. There are transporter and receptormolecules there, which we know exist, but as to exactly how theywork, we don't have answers yet."

The team successfully delivered several kinds of materials, albumin-binding Evans blue dye, c-fos protein, "even a 600-kb DNAplasmid," into the brains of the stressed-out mice. "This could berelevant for gene therapy," Friedman observed. "But it's still veryearly work."

He foresees the future of the group's ongoing research as "findingcertain drugs or chemicals that go into receptors in the human bbb,and will open it. One of the major problems is in people with braintumors, to get drugs into the brain, across the barrier."

Connection To Gulf War Syndrome? No Way!

Neuropsychopharmacologist Israel Hanin, at Loyola University inChicago, wrote a "News & Views" commentary on the Israeli reportin Nature Medicine. It is titled: "The Gulf War, stress and a leakyblood-brain barrier."

He told BioWorld Today that "It would be misleading, a far cry, tosay that there is any connection between the transient side effects ofpyridostigmine during the war and Gulf War syndrome." He added:"Because pyridostigmine is a very short-acting compound."

Hanin, whose focus is drug treatment of Alzheimer's disease (AD),observed: "A very similar compound to pyridostigmine, namelytacrine, also a cholinesterase inhibitor, is used to treat AD. So ifanything, I wouldn't expect negative CNS effects, but positive effectson memory.

"Drug discovery," he went on, "is where I think there are someexciting potentials. Because if the bbb can be compromised, even fora short period of time _ can be altered to become more porous underconditions of stress _ one could ultimately perhaps administermedications that normally wouldn't get into the brain."

Specifically, he envisions such treatment for brain cancer, "becausethere's no other way of getting therapeutics in there, short of cuttinga hole in the skull and either excising the tumor or administering thedrug."

Neither he nor Friedman foresee deliberately applying stress to apatient as a means of opening up the bbb. "I don't think you could dothat on a reliable basis from one person to the next," Hanin pointedout. "Every individual has his or her own threshold of stress."

Rather, he recommended "studying in experimental animals underconditions of stress what happens to make that bbb porous, thentrying to simulate that with technology." n

(c) 1997 American Health Consultants. All rights reserved.